ACS Publications. Most Trusted. Most Cited. Most Read
Quick View

OR SEARCH CITATIONS

My Activity
Publications
CONTENT TYPES

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Appl. Mater. Interfaces 2022, 14, 26, 29467-29482
RETURN TO ISSUEBiological and Medic...Biological and Medical Applications of Materials and InterfacesNEXT

Bioprinting Decellularized Breast Tissue for the Development of Three-Dimensional Breast Cancer Models

  • Barbara Blanco-Fernandez*
    Barbara Blanco-Fernandez
    Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
    *Email: [email protected]
    More by Barbara Blanco-Fernandez
    Orcidhttps://orcid.org/0000-0001-5050-9663
  • , 
  • Sergi Rey-Vinolas
    Sergi Rey-Vinolas
    Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
    More by Sergi Rey-Vinolas
  • , 
  • Gülsün Bağcı
    Gülsün Bağcı
    Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
    More by Gülsün Bağcı
  • , 
  • Gerard Rubi-Sans
    Gerard Rubi-Sans
    Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
    More by Gerard Rubi-Sans
    Orcidhttps://orcid.org/0000-0003-2782-8716
  • , 
  • Jorge Otero
    Jorge Otero
    Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
    More by Jorge Otero
  • , 
  • Daniel Navajas
    Daniel Navajas
    Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
    More by Daniel Navajas
  • , 
  • Soledad Perez-Amodio
    Soledad Perez-Amodio
    Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
    More by Soledad Perez-Amodio
  • , and 
  • Elisabeth Engel*
    Elisabeth Engel
    Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
    *Email: [email protected]
    More by Elisabeth Engel
    Orcidhttps://orcid.org/0000-0003-4855-8874
Cite this: ACS Appl. Mater. Interfaces 2022, 14, 26, 29467–29482
Publication Date (Web):June 23, 2022
https://doi.org/10.1021/acsami.2c00920

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0.
  • Open Access

Article Views

4714

Altmetric

-

Citations

13
LEARN ABOUT THESE METRICS
PDF (3 MB)
Get e-Alerts
Supporting Info (1)»
SUBJECTS:

Abstract

High Resolution Image
Download MS PowerPoint Slide

The tumor extracellular matrix (ECM) plays a vital role in tumor progression and drug resistance. Previous studies have shown that breast tissue-derived matrices could be an important biomaterial to recreate the complexity of the tumor ECM. We have developed a method for decellularizing and delipidating a porcine breast tissue (TDM) compatible with hydrogel formation. The addition of gelatin methacrylamide and alginate allows this TDM to be bioprinted by itself with good printability, shape fidelity, and cytocompatibility. Furthermore, this bioink has been tuned to more closely recreate the breast tumor by incorporating collagen type I (Col1). Breast cancer cells (BCCs) proliferate in both TDM bioinks forming cell clusters and spheroids. The addition of Col1 improves the printability of the bioink as well as increases BCC proliferation and reduces doxorubicin sensitivity due to a downregulation of HSP90. TDM bioinks also allow a precise three-dimensional printing of scaffolds containing BCCs and stromal cells and could be used to fabricate artificial tumors. Taken together, we have proven that these novel bioinks are good candidates for biofabricating breast cancer models.

This publication is licensed under

CC-BY 4.0.
  • cc licence
  • by licence
KEYWORDS:

1. Introduction

ARTICLE SECTIONS
Jump To
Breast cancer is the most diagnosed cancer in women, yet it is a clinical challenge owing to the complexity of its tumor microenvironment (TME). The breast TME is formed by a heterogeneous population of epithelial breast cancer cells (BCCs), an altered extracellular matrix (ECM), soluble factors (i.e., cytokines and growth factors), and stromal cells, such as adipocytes, immune cells, fibroblasts, or endothelial cells. (1) Among the components of the breast TME, the ECM is crucial in the tumor outcome, being involved in tumor growth and metastasis, immunosuppression, angiogenesis, or even drug resistance. (1−4) Indeed, the role of the ECM in tumor progression is still not fully understood due to the difficulty in its evaluation. (2,5,6)
The importance of the tumor ECM has stimulated the creation of new biomaterials that can recapitulate its main physicochemical, biological, and mechanical properties. Of these, proteinaceous hydrogels have been widely used to develop 3D in vitro cancer models (7) as they can mimic important ECM features such as cell adhesion sites, biodegradation sequences, viscoelasticity, mechanical properties, and architecture. (8) In breast cancer modeling, hydrogels made of collagen type 1 (Col1) and gelatin methacrylamide (GelMA) (1) have been widely used to recreate the stiffness of the ECM. (7) However, the absence of tumor ECM components in these biomaterials can limit their application when studying the role of the ECM in cancer physiopathology. Hydrogels made of a native ECM have also been used to recreate the breast cancer ECM, with Matrigel being the gold standard in cancer modeling. (9−11) However, the high variability between batches and undefined composition of Matrigel can affect the model’s reproducibility. Decellularized tissues and organ-derived matrices (TDMs) have recently been explored to recreate the tumor ECM. (12) TDMs consist of complex protein mixtures combined with other molecules, which retain important biological cues of the native tissue. (13) TDM hydrogels and scaffolds have shown their extraordinary bioactive properties, such as cell proliferation and behavior, (12,14) enabling the development of more physiologically relevant cancer models. Decellularized breast and adipose tissues can mimic the ECM as a whole, but they are still relatively underexplored. (15−18) Indeed, Ruud and coworkers reported that BCCs have a different metabolic profile, invasiveness, and morphology to native cancer cells when cultured in a decellularized tissue material compared to Matrigel or Col1 hydrogels. (19) Therefore, it has been shown that decellularized breast tumors could recapitulate the native breast tumor. (20) This evidence suggests that biomaterials based on breast TDMs could be a better candidate to mimic the breast tumor ECM in breast cancer 3D in vitro models.
Within the TME, there are complex interactions between cells and the ECM, cancer and stromal cells are arranged hierarchically, and their organization evolves during the tumor progression. (21) 3D bioprinting can assist in the replication of this cellular organization. More biomimetic, anatomically relevant, and complex models have been achieved using this technology, recreating in this way the physiology and functionality of tissues. (22,23) In breast cancer, 3D bioprinting has allowed the development of tumor models with precise control over BCCs and stromal cell location, (24) enabling the deposition of different cell types in different locations and with different bioinks. For example, models of the interface between the bone and breast tumors were created by 3D bioprinting to study the metastases to these tissues. (25) Also, hydrogels consisting of a core of BCCs and an outer layer of adipose-derived mesenchymal stem cells (hAMSCs) made by 3D bioprinting have shown that MSCs increase the resistance of BCCs against oncology drugs. (26) Despite the advances in this field, there is still an urgent need to increase the availability of tumor biomimetic bioinks to study the crosstalk between the tumor ECM, stromal cells, and BCCs. In recent years, new efforts have been made to develop bioinks using TDMs for tissue engineering applications and cancer modeling. (27) However, these biomaterials do not possess suitable mechanical properties to be bioprinted without the use of sacrificial materials or a supporting secondary structure, (14) and the stiffness of TDM hydrogels cannot recreate the tumor stiffness. To allow the TDM bioprinting by itself, researchers have incorporated rheological modifiers into the bioink or chemically functionalized the TDM to incorporate photopolymerizable groups. (28,29)
In this work, we present an approach for bioprinting cell-laden hydrogels made of a breast TDM, without the requirement of any sacrificial material, which has never been reported before. We propose the incorporation of alginate and GelMA to a porcine breast TDM for the fabrication of bioinks with suitable mechanical properties for 3D bioprinting and hydrogels with appropriate stiffness to recreate the tumor. The addition of GelMA into the bioinks enables the printability of the TDM with suitable shape fidelity, whereas the incorporation of alginate ensures an appropriate Young’s modulus and physical integrity. This novel bioink provides the mechanical and biological cues necessary for the fabrication of breast cancer models. To show the unique properties of this bioink and its versatility in tumor modeling, we evaluate the effect of Col1, which is overexpressed in breast tumors, in tumor progression and drug effectivity.

2. Experimental Section

ARTICLE SECTIONS
Jump To

2.1. Materials

Alginate (ref. 71238), bovine serum albumin (BSA), calcein AM, DNase I, calcium chloride (CaCl2), deuterium oxide, doxorubicin, fetal bovine serum (FBS), gelatin from porcine skin type A, hydrochloric acid (HCl), isopropanol, methacrylic anhydride (MA), N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES), oil red O, paraformaldehyde, pepsin, phalloidin–tetramethylrhodamine B isothiocyanate, sodium deoxycholate (SDC), sodium hydroxide (NaOH), Triton X-100, 3-((3-cholamidopropyl)dimethylammonium)-1-propanesulfonate (CHAPS), and 4′,6-diamidino-2-phenylindole (DAPI) were acquired from Sigma Aldrich. A Tissue-Tek O.C.T. Compound and Irgacure 2959 were purchased from Sakura Finetek and BASF, respectively. Advanced Dulbecco’s modified Eagle’s medium (advanced DMEM), Dulbecco’s phosphate-buffered saline (DPBS) 10×, l-glutamine, penicillin–streptomycin, phosphate-buffered saline (PBS), and propidium iodide (PI) were purchased from Thermo Fisher Scientific. Goat serum, an anti-E-cadherin antibody (ab201499), and Alexa Fluor 488 goat antirabbit IgG H&L (ab150077) were purchased from Abcam.

2.2. Preparation of TDMs

Breast tissues from 3–6-month-old female pigs were purchased from the Comparative Medicine and Bioimage Centre of Catalonia (Spain) after the approval by their ethical committee and immediately frozen and stored at −80 °C to avoid ECM degradation. Frozen tissues were thawed at 4 °C and washed several times with PBS before the mammary glands were surgically harvested. Then, mammary tissues were sliced into 1–2 cm3 pieces, homogenized in ice-cold deionized ddH2O in a domestic blender, and spun (3000g, 5 min, RT). The precipitated tissue was collected, and this process was repeated four times to guarantee maximum fat removal. Then, the breast tissues were decellularized at 4 °C under magnetic stirring. Tissues were incubated in 4% SDC for 24 h and 8 mM CHAPS for 24 h (with a change of each solution after 12 h). After each decellularization of solution, the tissues were washed with deionized ddH2O for 1 h. Next, tissues were incubated with DNase I (100 U/mL, 2 h, RT), washed with ddH2O (20 min, three times), incubated with isopropanol for 24 h (change after 12 h, 4 °C), washed with ddH2O (20 min, three times), freeze-dried, and stored at −80 °C. TDMs were then milled at 5 min at 10 CPS in liquid N2 using a freezer mill (6775 SPEX SamplePrep) and stored again at −80 °C. Rat and mouse mammary glands were kindly provided by Prof. del Río (Institute for Bioengineering of Catalonia, Spain) and the Institute for Advanced Chemistry of Catalonia (Spain), respectively. Rat and mouse breast tissues were subjected to the same decellularization protocol, but these tissues were not blended nor spun due to their small size.

2.3. TDM Characterization

The content of collagen, GAGs, and cells remaining in the TDM powder was evaluated. The remaining DNA was determined using a Quant-iT PicoGreen dsDNA assay kit (Thermo Fisher Scientific). The total glycosaminoglycan (GAG) content was measured using a Glycosaminoglycan Assay Blyscan kit (Biocolor) following the manufacturer’s instructions. The collagen content was quantified by a hydroxyproline method (Supporting Information). Part of the TDMs before cryomilling was embedded in paraffin or a Tissue-Tek O.C.T. Compound and sectioned. Hematoxylin and eosin staining (H&E) was performed to ensure the complete removal of the cells. Collagens were visualized with a picrosirius red stain kit (Abcam), and the remaining fat in the TDMs was determined by oil red O staining.

2.4. Cell Culture

MCF-7 (HTB-22, ATCC) and hAMSCs were cultured in advanced DMEM supplemented with 10% FBS, 1% penicillin–streptomycin, and 1% l-glutamine. hAMSCs were obtained from adipose tissue samples from an anonymous donor after his consent (Delfos Hospital). (30)

2.5. TDM Hydrogel Preparation

Powder TDMs were resuspended at 5% in a solution of pepsin at 0.5% in 0.1 N HCl and stirred at room temperature for 16 h. Then, the solution was stored at 4 °C for 1 day and used for the hydrogel preparation. Briefly, the TDM solution was neutralized with 1 M NaOH, and DPBS 10× was added to guarantee a suitable osmolarity for cell culture. To obtain the desired concentrations (10, 20, or 30 mg/mL), PBS or cell culture media was added in appropriate amounts (Table 1).
Table 1. Composition of the Bioinks Useda
components TDM GelMA alginate Col1 Irgacure cross-linking
T1 1%         37 °C
T2 2%         37 °C
T3 3%         37 °C
T2_A0.5 2%   0.5%     37 °C + CaCl2
T2_A1 2%   1%     37 °C + CaCl2
T2_A2 2%   2%     37 °C + CaCl2
T2_G4_A0.5 2% 4% 0.5%   0.1% 37 °C + CaCl2 + UV
T2_G2.5_A0.5 (TGA) 2% 2.5% 0.5%   0.1% 37 °C + CaCl2 + UV
T2_G2.5_A0.5_Col1 (TGAC) 2% 2.5% 0.5% 0.15% 0.1% 37 °C + CaCl2 + UV
a

NaOH was added to each bioink to neutralize the pH, being adjusted individually. DPBS 10× was added to guarantee the cell-friendly osmolarity of the bioink and was calculated according to the volume of TDM, Col1, and NaOH used. PBS or cell media was added to reach 100% in each bioink.

2.6. TDM Bioink Preparation

GelMA was fabricated as previously reported with some modifications. (31) Gelatin was dissolved in PBS at 10% at 40 °C. MA was added dropwise under stirring and left to react for 1 h to have a final concentration in the reaction mixture of 4.8% v/v. Then, the reaction mixture was dialyzed against ddH2O at 40 °C for 5 days (MWCO of 12.4 kDa) and freeze-dried. The degree of substitution (DS) was calculated by 1H NMR in deuterium oxide, (32,33) by calculating the areas of the methylene protons of lysine (3.1–3.2 ppm) according to the following equation:
(1)
Each value was normalized by the area of aromatic amino acids (7.2–7.5 ppm). The resulting DS was 53%.
Col1 was extracted from rat tails as previously published. (34) The total protein content of Col1 was quantified by microBCA (Thermo Fisher Scientific) using Col1 as a standard (OptiCol Rat Collagen Type I, no. MS18, Cell Guidance Systems).
The TDM bioink composition is described in Table 1, using the format TX_GX_AX_Col1, where “X” is the concentration in % (w/v) of TDM (T), GelMA (G), or alginate (A), and Col1 was used at 0.15% in all formulations. When a letter in the code is missing, this indicates its absence from the bioink, and in order to simplify, the selected bioinks were named TGA (T2_G2.5_A0.5) and TGAC (T2_G2.5_A0.5_Col1), and they were prepared as follows. First, TDM digested as specified in Section 2.3 was placed in an ice bath, and the pH of the solution was neutralized with 1 M NaOH. Then, enough DPBS 10× was added to the solution to have a final concentration 1× to ensure a cell-friendly osmolarity. Second, solutions containing GelMA, Irgacure 2959, and alginate were prepared in PBS. Finally, both solutions were mixed, placed in bioplotter syringes, and stored at 4 °C before their use. In the case of cell-laden bioinks, the cell suspension was added lastly. The TDM bioink with Col1 was prepared in the same manner, by diluting the Col1 solution into the TDM.

2.7. Bioprinting

TDM bioinks were printed with a 3D bioplotter (RegenHU, 3D Discovery). Bioinks were extruded through a dispensing tip with an internal diameter of 0.51 mm (Nordson) at temperatures ranging from 8 to 20 °C, pressures of 0.25–0.5 bar, and speeds of 3–5 mm/s. The hydrogels were then cross-linked by UV light (365 nm), by incubating them for 2 min with 0.58% CaCl2 in 10 mM HEPES and by placing them in a cell incubator for 30 min at 37 °C. When bioinks were forming drops instead or a continuous linear filament, a bed of 4 mL of Pluronic at 23% at 37 °C was used. Pluronic beds were removed by several washes with cold PBS.

2.8. Printability and Shape Fidelity of TDM Bioinks

TGA and TGAC bioinks were bioprinted at 8 °C and 0.5 bar and a speed of 4 mm/s. The formation of a filament or a drop after extrusion was verified visually. Twelve filaments of 14 mm were bioprinted, and images were acquired with a stereomicroscope (Leica). Their diameter and length were calculated using ImageJ software (National Institutes of Health). The filament diameter was determined at 30 different locations. The spreading ratio was calculated by dividing the diameter of the printed filament by the internal diameter of the needle. (35) Filament fusion tests were performed with one layer of the bioink. The scaffold showed the architecture described in Figure 5A. The printability and the diffusion rate were calculated as previously described. (36)
(2)
(3)
where At is the theoretical pore area, As the pore area of the scaffold, and L the perimeter of the pore. The pore’s morphology was determined visually by fabricating scaffolds with theoretical pores of 3 × 3 mm (area after subtracting the thinness of the bioink, 0.51 mm of 6.2 mm2). The angle shape of filaments with an L shape was assessed visually by bioprinting filaments as described in Figure 5A.

2.9. Mechanical Testing

The rheological properties of the bioinks were measured with a rheometer (dynamic mechanical analyzer MCR 702, Anton Paar) using a cone plate of 40 mm diameter (CP40-1, no. 2627, Anton Peer) with a gap of 0.078 mm. Temperature sweeps were performed from 4 to 37 °C at an increasing rate of 4 °C/min at a shear rate of 1 Hz. (37) Amplitude sweeps at 1 Hz and at a temperature of 8 (for TGA and TGAC) or 37 °C (for T2) were carried out. Flow curves at variable shear rates were also obtained at 8 °C. In all cases, TDM bioinks obtained from different digestions were used (N = 3). The Young’s modulus of TGA and TGAC hydrogels was measured with a Zwick column with a load cell of 5 N (Zwick, Roell, Germany) using hydrogels of 400 μL prepared in 48-well plates. Compression tests were carried out at a speed of 50% deformation/min (N = 3). Hydrogels made of only a TDM, alginate, GelMA, and their combinations (see Table S1) were also prepared under the same conditions to determine the effect of each component on the hydrogel’s stiffness.

2.10. Bioink Merging during Bioprinting

To study if TGA and TGAC bioinks enable the 3D printing of several cell types with a precise location and without the blending of the layers for an appropriate recapitulation of breast tumors, colored bioinks were prepared with food coloring. A scaffold consisting of a core for recreating the tumor site and an outer layer to mimic the stromal layer in breast tumors was designed (Figure 6A). TGA and TGAC bioinks were prepared as described before, and then, a drop of food coloring was added. Bioinks with no food coloring were used for the inner core (tumor core), and bioinks stained in red were used for the outer layer (stromal layer). Cell-laden scaffolds with an MCF-7 core and an hAMSC outer layer were also bioprinted (Figure 6A) to ensure that there was no cell merging when bioprinting. hAMSCs and MCF-7 were marked with Vybrant DiO and DiD, respectively, according to the manufacturer’s instructions (Thermo Fisher Scientific) and then resuspended in the bioink (hAMSCs, 1 × 106 cells/mL; MCF-7, 1.5 × 106 cells/mL). Cell-laden scaffolds were cultured in the same media as cancer cells and kept in culture for only 1 day. Then, hydrogels were fixed with 4% PFA and visualized in a Thunder Imager 3D live cell microscope (Leica Microsystems).

2.11. Bioprinting Cell-Laden Bioinks

MCF-7 cells were resuspended in the bioinks at a concentration of 1.5 × 106 cells/mL unless otherwise stated and bioprinted under the same conditions as described before. The scaffold architecture is described in Figure 7A. Cell media was replaced every other day in all cell-laden hydrogels, and they were kept for 14 days in culture.

2.12. Cellular Staining

Cell survival on the bioprinted and nonbioprinted hydrogels was evaluated with live/dead staining using calcein AM/PI. Cell-laden hydrogels at different time points were washed twice with PBS at 37 °C and incubated with 2 μM calcein AM and 4 μM PI in PBS for 20 min. The cell viability was calculated with a 3D object counter in FIJI software. (38) For immunofluorescence images, cell-laden hydrogels were washed twice with PBS, fixed with paraformaldehyde (20 min, RT), permeabilized with 0.1% Triton X-100 (5 min, RT), blocked with 10% goat serum in 3% BSA in PBS (1 h, RT), incubated with an anti-E-cadherin antibody (1:250, overnight, 4 °C), incubated with goat antirabbit IgG H&L (1:1000, 1 h, RT), and incubated with phalloidin–tetramethylrhodamine B isothiocyanate (45 min, RT) and DAPI (10 min, RT). Three washes of 3% BSA in PBS were done between each step. To study the cellular morphology in hydrogels, cells were stained only with phalloidin and DAPI, using the same procedure. Hydrogels were visualized with a Thunder Imager 3D live cell microscope (Leica Microsystems). Nonbioprinted hydrogels made of Col1 at 4 mg/mL encapsulating MCF-7 at 1.5 × 106 cells/mL were used as controls.

2.13. Cell Proliferation and Drug Response

Cellular proliferation in the bioprinted hydrogels was measured with alamarBlue (Thermo Fisher Scientific). At different time points, cell media was replaced by alamarBlue at 10% in cell media. After 1 h of incubation, fluorescence was measured (560/590 nm). Four replicas per condition were used. A calibration curve of MCF-7 cells was also obtained to determine the cell density. For drug response studies, cell-laden bioprinted hydrogels were cultured for 14 days to enable MCF-7 growth. Then, hydrogels were incubated with doxorubicin at different concentrations for 2 days, and the cell viability was determined by alamarBlue as specified before. Hydrogels were washed with PBS twice before a solution of 10% alamarBlue in the cell media was added. Then, hydrogels were incubated for 1 h at 37 °C, and the fluorescence was measured. Nontreated bioprinted hydrogels were used as controls. IC50 values were calculated using GraphPad Prism 8.0 software (GraphPad Software). 2D experiments and Col1 hydrogels at 4 mg/mL (20 μL) were run in parallel as controls. In order to study if the cell density had any effect on the drug response, nonbioprinted TGA, TGAC, and Col1 cell-laden hydrogels (20 μL) containing 1.5 or 3 × 106 cells/mL were cultured and treated under the same conditions as bioprinted hydrogels.

2.14. Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR)

In order to analyze the expression of tumoral markers before and after the treatment with doxorubicin, TGA, TGAC, and Col1 cell-laden hydrogels were cultured for 14 days followed by a 48 h drug treatment (0 or 0.1 μM, 16 days in total). Cell-laden hydrogels were washed with PBS and stored at −80 °C in 350 μL of RLT lysis buffer containing 1% β-mercaptoethanol until RNA isolation. For 2D samples, cells were cultured for 9 days with a 48 h doxorubicin treatment (0 or 0.1 μM). On the day of RNA isolation, samples were sonicated on ice (50% amplitude, 3 cycles of 30 s, with each cycle followed by 30 s of vortexing). Then, samples were freeze–thawed three times. After centrifugation at +4 °C (5 min, 13,000g), the supernatant was transferred to a gDNA Eliminator spin column, and RNA isolation was performed using an RNeasy Plus Mini Kit (Qiagen, no. 74134) following the manufacturer’s instruction. The RNA concentration was measured using a Nanodrop instrument (ND-1000, NanoDrop). cDNA synthesis from RNA was performed by using an RT2 First Strand Kit (Qiagen, no. 330404). An appropriate amount of cDNA was mixed with an RT2 SYBR Green ROX qPCR master mix (Qiagen, no. 330524) and a primer mix. Human β-actin was acquired from Qiagen (ACTB, PPH00073G-200), whereas the rest of the primers were purchased from Sigma Aldrich (sequences of primers listed on Table S1). RT-qPCRs were run in a StepOnePlus system (Applied Biosystems) under the following conditions: 1 cycle of 10 min at 95 °C followed by 40 cycles for 15 s at 95 °C and 1 min at 60 °C, and the following melting curves were run. Experiments were performed in triplicate with three technical replicates per sample. The fold change in the gene expression was calculated using the 2–ΔΔCt method, using β-actin as a housekeeping gene.

2.15. Statistical Analysis

GraphPad Prism 8.0 software (GraphPad Software) was used to run the statistical analysis. t-Tests and one-way or two-way ANOVAs, whenever appropriate, were used to study whether there were statistical differences between conditions, with p values below 0.05 being considered statistically different. All data points presented on charts are the mean values ± standard deviation (n = 3, unless specified).

3. Results and Discussion

ARTICLE SECTIONS
Jump To
The role of the ECM in tumor progression has motivated the creation of novel biomimetic biomaterials that recreate the tumor ECM complexity. In this regard, a native breast tissue has already shown its suitability in the creation of relevant cancer models. (15,39) The similarities between the human and pig genome, availability, and large size of the pig mammary glands have prompted the use of this type of breast tissue for the preparation of a biomimetic ECM bioink. (40) To the best of our knowledge, this is the first time that decellularized breast tissue bioinks mimicking the mechanical and biochemical characteristics of the breast ECM have been developed.

3.1. Decellularization and Delipidation of Breast Tissues

The decellularization and delipidation of breast tissues with minimal damage and loss of the ECM are critical when preparing hydrogels from TDMs. (41) The whole porcine breast tissues were decellularized and delipidated as described in the Experimental Section and are summarized in Scheme 1. In our protocol, we combined the use of two mild detergents, SDC and CHAPS, to decellularize the tissue, isopropanol and physical treatment (blending) to remove the lipids of the tissue, and the incubation with DNase I to ensure the removal of any remaining DNA.

Scheme 1

Scheme 1. Schematic Illustration Showing the Workflow of the TDM Hydrogel Fabrication
High Resolution Image
Download MS PowerPoint Slide
The efficiency of decellularization was assessed through the quantification of the remaining DNA in the biomaterial, being below 5 ng/mg dried ECM (4.53 ± 2.10 ng/mg). TDMs were also stained with H&E to examine the presence of any remaining cellular components after the decellularization process. As shown in Figure 1A, cellular nuclei were not observed. The absence of the nuclear material (Figure 1A) and DNA values below 50 ng/mg dried ECM indicated a suitable and efficient decellularization process. (14,41) In addition, the efficiency of the delipidation was assessed through oil red O staining of tissue sections. Figure 1A clearly shows that the decellularization and the physical delipidation combined with the isopropanol treatment provoked a high lipid reduction when compared with the native breast tissue. However, some lipid drops were still visible, something which has been previously seen with other decellularization processes of breast or adipose tissues. (17)

Figure 1

Figure 1. (A) Histological comparison of the native porcine breast tissue (left) and the decellularized breast tissue (TDM, right). Hematoxylin and eosin staining of tissue sections (scale bar of 100 μm), oil red O staining (scale bar of 200 μm), and picrosirius red staining (scale bar of 100 μm). (B) Total collagen and GAG contents in the porcine breast tissue and the decellularized breast tissue (TDM).

High Resolution Image
Download MS PowerPoint Slide

3.2. TDM Biochemical Characterization and Jellification

Since mammary glands consist of lipids, collagens, and GAGs, (42) the quantity of these last two macromolecules in TDMs and native tissues was evaluated (Figure 1B). We found a high content of collagen and GAG after the harsh decellularization and delipidation processes, suggesting that TDM could recreate the human breast ECM. We observed a statistically significant increase of total collagens in TDMs when compared with the native tissue, which could be explained by the removal of the lipids as well as the cellular components from the breast tissues. Picrosirius staining of tissue sections also confirmed the high content of collagen in TDMs. Also, the GAG content was slightly higher in the case of the TDMs, but this was not statistically significant.
Then, the capability of the porcine TDM to gel was visually tested (Figure 2A). TDMs were cryomilled and digested with pepsin in an acid solution. TDM pre-gel solutions (T1, T2, and T3) were formed by neutralizing the pH and correcting osmolarity to ensure its biocompatibility, keeping the solution at 4 °C to avoid the cross-linking of the ECM. Next, hydrogels were cross-linked by incubating them at 37 °C (Scheme 1 and Figure 2A). The inversion of the vial after the incubation showed that the biomaterial was able to gel in a thermally dependent manner, mainly caused by the presence of collagen. This result was confirmed by rheometry, showing an increase in the storage modulus above 30 °C (Figure 2B). The Young’s modulus of TDM hydrogels was also determined. T1 hydrogels were too fragile to be handled, and their Young’s modulus could not be measured. In contrast, T2 and T3 hydrogels were easier to handle with moduli of 0.64 ± 0.16 kPa for T2 and 1.08 ± 0.24 kPa for T3 (Figure 2C). The increase in the TDM concentration in the hydrogel allowed an increase in the Young’s modulus, but it was not statistically significant (t-test, p = 0.057), and none of the hydrogels could recreate the stiffness reported in human breast tumors, (43,44) which has been already seen in hydrogels made of TDMs of other origins. (29)

Figure 2

Figure 2. (A) Hydrogel formation from TDMs of various sources. Mouse, rat, and porcine breast tissues (first column) were decellularized (second column), lyophilized, cryomilled, and enzymatically digested (third column), and pre-gel solutions were used to prepare TDM hydrogels (fourth column). (B) Rheological properties of T2 at different temperatures. (C) Young’s moduli of T2 and T3 hydrogels.

High Resolution Image
Download MS PowerPoint Slide
Mouse and rat breast tissues were also evaluated to check whether this protocol was translatable to other animal tissues. For this purpose, tissues were subjected to the same decellularization process, but in this case, the blending step could not be performed due to the small size of the tissues (Figure 2A). Unfortunately, rat breast tissues could only partially gel, whereas mouse breast tissues could not form any gel, and only the porcine breast tissue rendered TDMs able to cross-link and form hydrogels (Figure 2A). We hypothesize that this phenomenon could be due to the high lipid content remaining in the rat and, especially, in the mice breast TDMs. Also, the differences in the ECM composition between species, which has been already reported for other tissues, (45) might interfere with the jellification of the biomaterial, suggesting that the decellularization process should be adjusted to each individual tissue species.

3.3. TDM Hydrogels Support Cell Proliferation

To study the cellular behavior and cytocompatibility of TDM hydrogels, MCF-7 cells were dispersed in a T2 pre-gel solution, and then, hydrogels were prepared by incubating them at 37 °C. The cellular distribution, cytocompatibility, and proliferation were evaluated with phalloidin/DAPI staining, vital staining, and alamarBlue (which has been reported to be suitable for measuring the proliferation of cancer cells in proteinaceous hydrogels). (15) MCF-7 cells were homogeneously distributed in the hydrogels, and at day 14, BCCs formed cell aggregates (Figure 3A). TDM hydrogels were cytocompatible on day one (Figure 3B). However, at day 7 and, especially, on day 14, some cell death was observed. Surprisingly, cellular proliferation was increased up to day 14 (Figure 3C). This result might be explained by the formation of some spherical cell aggregates observed at day 14 (Figure 3A). These results confirmed the cytocompatibility of the biomaterial and the ability of MCF-7 cells to form cell spheroids in TDM hydrogels.

Figure 3

Figure 3. MCF-7 viability, proliferation, and organization in TDM hydrogels at 2%. (A) Cellular organization over time (cell cytoskeletons stained with phalloidin (red) and nuclei stained with DAPI (blue), scale bar of 100 μm). (B) MCF-7 viability over time (viable cells stained with calcein AM in green and dead cells stained with PI in red, scale bar of 100 μm). (C) Cellular proliferation over time by alamarBlue.

High Resolution Image
Download MS PowerPoint Slide

3.4. The Incorporation of Alginate and GelMA into the TDM Pre-gel Solution Allows TDM Bioprinting

Then, we tested the bioprintability potential of TDM hydrogels. The first step in testing the printability of a bioink is the formation of a linear filament when extruded through the nozzle. (46) T1, T2, and T3 pre-gel solutions were extruded through the nozzle at temperatures ranging from 8 to 20 °C. However, no filament could be formed to allow the bioprinting of the biomaterial by itself. Amplitude sweeps confirmed the low storage modulus of the TDM, which explains the unsuitability of the biomaterial to be bioprinted by itself (Figure S6D). The use of a sacrificial material was also tested to check if it enabled the TDM bioprinting. A Pluronic F127 bed at 23% was used (Figure S1) as a bed, as it is easily removed with cold PBS washing. Bioinks with TDM concentrations of 20 (T2) and 30 mg/mL (T3) were the only ones successfully bioprinted in the bedding. These TDMs were jellified at 37 °C for 30 min, and then, the bedding was removed through several washes with cold PBS to solubilize the Pluronic (Figure S1). None of the scaffolds made with T2 maintained their shape after the removal of the bedding, whereas some scaffolds with T3 did. As the increase in TDM concentration did not allow the bioprinting of the biomaterial with good shape fidelity neither suitable stiffness to recreate the breast tumor, the addition of rheological modifiers was studied. In any case, the conditions of temperature and pressure needed to 3D print TDMs did not affect the cellular viability of MCF-7 (Figure S2).
In order to improve the TDM bioink printability as well as increase the Young’s modulus of the hydrogels, we first explored the addition of alginate to the TDM pre-gel solutions at different concentrations (0.5, 1, and 2%) (Figure 4 and Figures S3 and S4). We selected alginate as a rheological modifier, as it has allowed the bioprinting of collagen bioinks before, which is one of the components of the TDM. (47) The incorporation of alginate did not alter the TDM thermal mechanical properties (Figure S3A), but it increased the hydrogels’ stiffness (Figure 4C) to more closely recreate the breast TME. However, the concentrations tested were still not enough to allow the formation of a continuous linear filament through the nozzle, requiring again the use of a sacrificial material (Figure S3B). Nevertheless, MCF-7 cells were viable up to 14 days in culture in these hydrogels (Figure S4). Interestingly, BCCs were not able to form cell aggregates at alginate concentrations above 1%, implying that the addition of alginate as a rheological modifier was not sufficient to allow the TDM bioprinting by itself at the concentrations needed to allow cell interactions.

Figure 4

Figure 4. (A,B) Formation of linear and continuous filaments of TDM bioinks containing 20 mg/mL TDM, 0.5% alginate, and 2.5 (A, TGA bioink) or 4% (B, T2_G4_A0.5) GelMA. (C,D) Temperature sweeps of TGA (C) and TGAC (D) bioinks. (E) Young’s moduli of TGA, TGAC, T2_A0.5, T2_A1, G2.5_A0.5, and G2.5_A0.5_Col1 hydrogels.

High Resolution Image
Download MS PowerPoint Slide
In order to avoid the use of a sacrificial material, a combination of GelMA (2.5–4%) and alginate (0.5%) was added. We decided to use GelMA as it is a commercially available bioink that has been widely used for bioprinting tissues (48) and is also recently shown to be beneficial for bioprinting other decellularized materials. (29) We also decided to incorporate alginate to ensure suitable stiffness to recreate the tumor, as alginate has been previously added into other bioinks with suitable properties for cell culture. (29) In this case, all the conditions tested enabled the formation of a filament at temperatures below 15 °C (Figure 4A,B), and the lowest concentration of GelMA (2.5%) was used for further studies. Temperature sweeps showed that the addition of GelMA at 2.5% provoked a modification in the rheological behavior of the TDM, with the rheological properties being similar to other GelMA bioinks. (49) In addition, the highest storage modulus was achieved at 8 °C (Figure 4C), and therefore, we decided to bioprint the bioink at 8 °C. As the addition of GelMA at 2.5% into the hydrogels makes them more fragile, hindering the hydrogel manipulation, alginate at 0.5% was also incorporated in the bioink to give them more stability as well as to allow hydrogel stiffness comparable to breast tumors, being reported between 4 and 5.7 kPa (Figure 4E). (43,44)
To study the effect of each component on the final hydrogels’ stiffness, the Young’s modulus of each component as well as their combinations were measured. GelMA at 2.5% had a modulus comparable to TDM hydrogels (Figure S5), whereas alginate at 0.5% had a higher modulus (2.96 ± 1.29 kPa, Figure S5), proving that the addition of alginate into the bioink will have a greater impact on the hydrogels’ stiffness. We decided to use the lowest concentration of alginate tested (0.5%), as it allowed the formation of higher numbers of spheroids (Figure S4) at the same time as it rendered hydrogels with the Young’s modulus in the range of breast tumors. The TDM also had a positive impact on the hydrogel’s stiffness, as its absence reduced its Young’s modulus (Figure 4E). Therefore, we selected T2_G2.5_A0.5 (TGA) for further studies.

3.5. TDM Bioinks Allow the Incorporation of ECM Proteins Improving Their Bioprintability

The ECM plays an active role in breast cancer progression, metastasis, and drug resistances. (42) During breast tumor development, the ECM experiences alterations in composition, structure, and mechanical properties, in comparison with healthy tissues; (42) for instance, the production of fibrillar collagens, fibronectin, laminin, and proteoglycans is increased. (42) Among ECM proteins, Col1 is overexpressed in breast tumors and is involved in the proliferation, survival, and metastasis of BCCs. (50) Since the porcine TDM used for the bioink fabrication has a nontumoral origin, as it is obtained from healthy female pigs, we decided to modify its composition by including Col1 in the TGA bioink (TGAC). This ECM protein is produced by cancer-associated fibroblasts, and it is involved in tumor progression, metastasis, and the stiffening of the tumor. (42) We decided to tune the bioink only with one molecule overexpressed in breast tumors to analyze whether its addition may promote breast cancer ECM proliferation and survival, avoiding changes in the printability of the biomaterial and the stiffness. Therefore, the addition of Col1 in GelMA hydrogels has shown to increase BCC invasion. (51) A concentration of 0.15 mg/mL of Col1 was added to the bioink as it was able to modulate the activity of BCCs. (52)
First, we evaluate the printability and mechanical and rheological properties of the TDM bioink, and then, we assess whether the addition of Col1 had any impact on the bioink properties. The incorporation of Col1 in the TDM bioink did not modify the thermal behavior of the bioink obtained in the temperature sweeps, being also the highest storage modulus at 8 °C (Figure 4D). Therefore, TGAC was also bioprinted at this temperature to ensure the optimal shape fidelity. In addition, Col1 did not alter the bioink printability, forming a linear and continuous filament when extruded at 8 °C.
To evaluate the bioink printability and shape fidelity, we first studied the shape fidelity of single lines by quantifying the filament’s diameter and spreading ratio. TGA and TGAC bioinks showed a higher diameter than the internal diameter of the dispensing tip (0.51 mm) and a shorter length than the designed filament (14 mm, Figure 5A, B(1,5), and C). We also evaluated the spreading ratio for both bioinks, with these values being similar to previously reported spreading rates for GelMA at 10%. (35) In this case, the TGAC bioink has a statistically significant lower spreading ratio (1.69 ± 0.18) than the TGA bioink (2.21 ± 0.28) (t-test, p < 0.0001). Nevertheless, both values are accepted to be low enough to ensure a precise bioprinting. (35) Next, the roundness/sharpness of the angle in filaments with an L shape (90° angle) was evaluated. The addition of Col1 impacted the corner of the filament, being sharper when Col1 was incorporated into the bioink (Figure 5A,B(2,6)). The morphology of pores in bioprinted scaffolds was also assessed by fabricating constructs with one layer and 3 mm × 3 mm pores (Figure 5A,B(3,7)). No visual differences were observed between both bioinks. The fusion of the filaments was also calculated by measuring the diffusion rate and printability, as described in the methodology section, using scaffolds with the architecture specified in Figure 5A,B(4,8). Both bioinks showed a decrease in diffusion and an increase in printability at larger pore sizes (Figure 5D,E). Interestingly, the addition of Col1 improved the diffusion rate as well as the printability at small pore sizes (<0.09cm2, p < 0.001). All these results indicate that the addition of a low concentration of Col1 (0.15%) had a positive impact on the printability and shape fidelity of the scaffold. The higher storage modulus of the TGAC bioink compared to the TGA bioink allows the 3D printing of constructs with better precision.

Figure 5

Figure 5. (A) Design of the bioprinted scaffolds to study the printability and shape fidelity. (B) Bioprinted scaffolds to determine the printability and shape fidelity of the bioinks. (1,5) Filaments of 14 mm in length, (2,6) filaments with an L shape (3,7) scaffolds with pores of 3 × 3 mm (4,8), and scaffolds for the filament fusion test. (C) Length and diameter of bioprinted filaments (theoretical sizes: 14 mm length, 0.51 mm diameter). (D) Diffusion rate of both bioinks. (E) Printability of both bioinks.

High Resolution Image
Download MS PowerPoint Slide
TGA and TGAC bioinks have shear-thinning properties, which are crucial for bioprinting through extrusion (Figure S6A). (29) Amplitude sweeps showed that the presence of Col1 in the bioinks enabled a 1.5-fold increase in the storage modulus at 8 °C, confirming the better properties for bioprinting of the TGAC bioink (Figure S6B,C). In both cases, the storage moduli were higher in the TGA and TGAC bioinks than in only the TDM (Figure S6D). The mechanical properties of TGAC hydrogels were also measured. TGA and TGAC hydrogels showed similar Young’s moduli of approximately 4 kPa (TGA, 4.15 ± 0.66 kPa; TGAC, 4.22 ± 1.02 kPa, Figure 4E), proving that the addition of Col1 at this concentration did not modify the stiffness of the hydrogels and that their stiffness can recreate the stiffness of breast tumors.
The crosstalk of BCCs and stromal cells plays a vital role in tumor progression as well as drug resistances, and therefore, it needs to be recreated in 3D in vitro models. (53,54) In this way, 3D bioprinting could assist in the creation of more physiological relevant models, by allowing the control of the location of BCCs and stromal cells in a precise and accurate manner. (24) To determine whether TDM bioinks could be used to bioprint cancer and stromal cells, with a precise location of both cell types, a scaffold consisting of a core that recreates the BCC environment and an outer layer of stromal cells (human adipose mesenchymal stem cells, hAMSCs) was bioprinted (Figure 6A). First, a scaffold with two different colors of bioinks was fabricated to verify whether it was possible to bioprint BCCs and stromal cell-laden bioinks without their merging. A core of two layers was made to recreate the tumor environment (white bioink), and an outer layer with four layers (red bioink) was chosen to recreate the stromal environment. Both bioinks could be used to fabricate this type of scaffold without any fusion of the bioinks in the interface (Figure 6B). To ensure that this interface between stromal cells and BCCs was maintained after the bioprinting, hAMSCs and MCF-7 cells were marked with a cell tracker, and images of the bioprinted scaffolds were taken. Both cell types were localized in the bioprinted area, with no evident merging of hAMSCs or MCF-7 (Figure 6C). Overall, these findings suggest that TDM bioinks could be used for the bioprinting of more complex cancer models, where a precise location of cancer and stromal cells is needed.

Figure 6

Figure 6. MCF-7- and hAMSC-laden bioprinted scaffolds. (A) Architecture of the bioprinted scaffolds with BCC- and stromal-cell-laden hydrogels (diameter, D; interline distance, di; height, h). (B) Bioprinted scaffolds (without cells) with a white core (1,5) recreating the tumor and an outer layer in pink (2,3,6,7) mimicking the stromal layer and cut in half (4,8). (C) Bioprinted hydrogels consisting of a core of MCF-7 (in red) and an outer layer of hAMSCs (in green). On the left is the hydrogel view from the bottom of the hydrogel, and on the right is the hydrogel view from the middle after slicing it in half.

High Resolution Image
Download MS PowerPoint Slide

3.6. TDM Bioprinted Scaffolds Can Be Used to Study the Role of the ECM in BCC Progression and Drug Resistance

Finally, we tested whether the presence of Col1 in the developed bioinks had an impact on BCC proliferation and drug efficacy outcomes. MCF-7 cells were resuspended in TGA and TGAC bioinks, and cylinder scaffolds recreating the tumor core shown in Figure 7A were bioprinted. Hydrogels were maintained for 14 days in culture with media replacement every other day. Vital staining and the cell proliferation by alamarBlue were carried out at different time points. It is important to note that the mechanical properties were sufficient to allow hydrogel handling. Calcein AM/PI staining at day 1 showed that MCF-7 cells were homogeneously distributed in both hydrogels, indicating that they were successfully resuspended in the bioink, and no sedimentation was observed during the hydrogel cross-linking (Figure 7B). Bioprinted BCC-laden hydrogels showed good cytocompatibility up to 14 days in culture (Figure 7B and Table S3), comparable to Col1 hydrogels, with no visible hydrogel disintegration. As Col1 may influence BCC proliferation, an assay using alamarBlue was performed at different time points (Figure 7C) and compared to cells growing in 2D and Col1 hydrogels. In both bioinks and Col1 hydrogels, the cell proliferation was higher in cells growing in 2D than in hydrogels after 7 days in culture; however after 11 days in 2D, cells started to detach from the wells. Cells growing in the bioprinted hydrogels showed an increase in proliferation in the presence of Col1 at 0.15% at all time points, but this was only statistically significant from day 9 until the end of the culture period. Indeed, TGAC hydrogels showed cell proliferation and density values comparable to Col1 hydrogels (Figure 7C and Figure S6). This finding suggests that the presence of Col1 has a positive impact on cell proliferation. Furthermore, as there are no differences in the Young’s moduli between both types of hydrogels, the differences in cell proliferation observed may be due to the addition of Col1 and not to changes in the stiffness of the hydrogels.

Figure 7

Figure 7. MCF-7-laden bioprinted scaffolds. (A) Architecture of the scaffolds (diameter, D; interline distance, di; height, h). (B) Cell viability after 1, 7, and 14 days in culture (in green are cells stained with calcein AM (alive), and in red are cells dyed with PI (dead)). (C) MCF-7 proliferation by alamarBlue.

High Resolution Image
Download MS PowerPoint Slide
Next, BCC distribution in the hydrogels was studied. Phalloidin/DAPI staining showed that cells were homogeneously and individually distributed in the bioprinted hydrogel on day 1 (Figure 8A). On day 7, MCF-7 cells formed small cell clusters, and only on day 14, proper cell spheroids and cell clusters were observed. When Col1 was incorporated in the TDM bioink, no differences between cell aggregates were observed (Figure 8A). Interestingly, differences were observed when comparing these hydrogels with Col1. MCF-7 cells were able to form cell aggregates colonizing the full hydrogel, which might be explained by the lower stiffness of Col1 hydrogels (<1 kPa). (55)

Figure 8

Figure 8. MCF-7-laden bioprinted scaffolds. (A) MCF-7 stained with phalloidin–rhodamine (red) and DAPI (blue) at day 1, 7, and 14. (B) Expression of E-cadherin (green) in MCF-7 clusters after 14 days in culture.

High Resolution Image
Download MS PowerPoint Slide
The expression of E-cadherin was also evaluated. This adhesion molecule is present in diverse breast cancer types, and its lower expression is linked with tumor progression and metastasis. (56) Interestingly, this adhesion molecule was not highly expressed, being only present in some cell aggregates and especially in hydrogels containing Col1 (Figure 8B), which might be explained by the presence of Col1, as this marker was highly expressed in Col1 hydrogels. This finding agrees with previous results using decellularized adipose tissue scaffolds. Dunne and coworkers showed a lower expression of this adhesion molecule in TDM scaffolds when compared with Matrigel and 2D cultures of MCF-7. (15)
We further explored if the presence of Col1 in the bioinks has a positive impact on the expression of malignant tumor markers, such as Col1, fibronectin, heat shock proteins of 90 kDa (HSP90), and calcium and potassium ion channels (Figure 9 and Figure S8). We first explored the expression of Col1 (COL1A1) and fibronectin (FN1), as both are hallmarks of breast cancer and are linked to poor prognosis and metastasis. (42,57−59) Cells grown in TGA, TGAC, and Col1 exhibited an upregulation in the expression of COL1A1 in comparison to 2D cultures, suggesting a malignant transformation in all hydrogels (Figure 9). Nevertheless, there were no statistical differences between conditions, implying that the addition of Col1 at 0.15% was not sufficient to have a synergic effect between the TDM and Col1 in the upregulated COL1A1. Conversely, there was a downregulation of FN1 in the cell-laden hydrogels, especially in the case of TGAC, which implies that the absence of Col1 is beneficial to maintaining the fibronectin expression (Figure 9). We also evaluated the expression of two chaperone HSP90s, Hsp90alpha (HSP90AA1) and HSP90beta (HSP90AB1), due to their involvement in many breast cancer pathways, metastasis, angiogenesis, and antiapoptotic activity, and their upregulation is related to poor prognosis. (60,61) We also found a gene upregulation for both proteins in comparison with 2D cultures, but no differences among conditions were detected (Figure 9). Ca2+ signaling has also shown its involvement in tumor progression, (62) with the T-type voltage-gated calcium channels such as Cav3.1 (CACNA1G) being involved in its regulation in numerous cancer cells. In MCF-7, the overexpression of Cav3.1 has been linked with a reduction in the cell proliferation. (63) Both bioprinted hydrogels showed no expression of CACNA1G (Ct values above 35) in contrast to 2D cultures (Figure S8), suggesting that cells growing in TGA and TGAC had a closer phenotype to breast cancer cells, where this gene is low expressed. (64) We also decided to study the expression of Kv1.1 protein (KCNA1) as it has been reported to be expressed in MCF-7 cells and has also been involved in the progression and the malignancy grade of breast tumors. (65) Again, no expression of KCNA1 (Ct values above 35, Figure S8) was found, whereas it was expressed in cells growing in 2D, indicating that cells growing in TGA and TGAC can recreate a reduction in the expression of this specific channel occurring in vivo. (66) We also evaluated if TGA and TGAC bioinks might promote the expression of multidrug resistance proteins (MDR), by measuring the expression of multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1) and breast cancer resistance protein (BCRP, encoded by ABCG2) (Figure 9). Both MDR proteins were more highly expressed in the cell-laden hydrogels than in 2D, but only TGA showed a higher upregulation of ABCC1. Altogether, the addition of Col1 into the TDM bioink does not cause a synergistic effect in the expression of drug resistance and tumor malignancy markers. Moreover, the TGA bioink’s higher expression of MRP1 and fibronectin indicates that the addition of Col1 might not improve the biological properties of the TDM.

Figure 9

Figure 9. COL1A1, FN1, HSP90AA1, HSP90AB1, ABCC1, and ABCG2 expressions in MCF-7 cells cultured in TGA, TGAC, or Col1 for 14 days. 2–ΔΔCt values were calculated with the ΔCts from 2D cultures.

High Resolution Image
Download MS PowerPoint Slide
Finally, we evaluated whether these bioprinted cell-laden hydrogels could be used for the screening of chemotherapy agents, by comparing the efficacy of doxorubicin. We selected doxorubicin as a drug model because it is widely used in chemotherapy against breast cancer. (67) 2D culture was carried out to compare the efficacy of the drug with the bioprinted models, and they showed that doxorubicin was effective at doses below 0.1 μM (IC50 = 0.094 μM, Figure 10A). Then, 3D experiments were carried out. TDM cell-laded bioprinted hydrogels were cultured for 14 days to allow BCC proliferation, and then, they were treated with doxorubicin at different concentrations. The IC50 values obtained for the bioprinted samples were statistically significantly higher than the values achieved in 2D cultures (TGA: IC50 > 10 μM; TGAC: IC50 = 7.032 μM, Figure 10A). When treated with doxorubicin, the IC50 values were 70-fold higher than those of the 2D cultures. This reduction in chemotherapy agent sensitivity in 3D cultures vs 2D cultures has already been shown, with the cell–ECM and cell–cell interactions being important players in the differences observed. (68) Surprisingly, TGAC bioinks showed lower IC50 than TGA bioinks. When comparing the MCF-7 viability of Col1 cell-laden hydrogels treated with doxorubicin, we observed that in three out of the four concentrations tested, TGA cell-laden hydrogels showed a statistically significant higher cell viability, whereas in TGAC hydrogels, only hydrogels treated with 0.1 μM had a statistically significant higher cell viability than Col1.

Figure 10

Figure 10. (A) MCF-7 viability after incubating the cell-laden hydrogels with doxorubicin for 48 h (a: p < 0.001 for TGA or TGAC vs the 2D control, b: p < 0.001 for Col1 vs the 2D control, c: p < 0.0011 for TGA vs TGAC, d: p < 0.0011 for TGA vs Col1, and e: p < 0.0011 for TGAC vs Col1). (B) COL1A1, FN1, HSP90AA1, HSP90AB1, ABCC1, and ABCG2 fold expressions in MCF-7 cells cultured in TGA, TGAC, Col1, or 2D and treated for 2 days with doxorubicin at 0.1 μM, after 14 days in culture for hydrogels and 7 days for 2D. 2–ΔΔCt values of each sample were calculated with the ΔCts of cell-laden hydrogels or 2D cultures for 16 or 9 days, respectively. (C–E) MCF-7 viability after incubating the TGA (C), TGAC (D), and Col1 (E) nonbioprinted cell-laden hydrogels with two cell densities with doxorubicin for 48 h. (F) Fluorescence intensity of the negative controls (cell-laden hydrogels not treated with doxorubicin) used for the calculation of the cell viability in C–E).

High Resolution Image
Download MS PowerPoint Slide
We hypothesized that the differences in drug response could be caused by the higher cell proliferation activity in the TGAC, making it more susceptible to doxorubicin. (69) Therefore, to ensure that the differences in cell viability upon doxorubicin treatment were not caused by cell number differences among conditions, we prepared cell-laden hydrogels of TGA, TGAC, and Col1 having different cell densities (1.5 or 3 × 106 cells/mL). Even with the high cell density difference between conditions (2-fold) on day 1, only TGA and TGAC had statistically significant different cell densities after 16 days in culture (Figure 10F). We found out that only at the highest doxorubicin concentration (100 μM) (Figure 10C–E), the cell density had an impact on drug efficacy in TGA and TGAC (Figure 10C,D), which did not explain the differences observed at concentrations below 100 μM. In an effort to clarify the differences observed between TGA and TGAC, we evaluated if there were any alterations in gene expression after the drug treatment. MCF-7-laden hydrogels were treated with doxorubicin at 0.1 μM for 48 h to ensure that the cell density was not the responsible for the differences observed in gene expression. We first evaluated the expression of tumor markers (HSP90AA1, HSP90AB1, COL1A1, and FN1). Cell-laden TGA hydrogels showed an upregulation of HSP90AB1 compared to TGAC, Col1, or 2D cultures. Conversely, there were no differences in gene expression of the tumor markers HSP90AA1, COL1A1, and FN1 between conditions, although the tendency to a lower expression of HSP90AA1 and a higher expression of FN1 in TGAC hydrogels vs TGA hydrogels was observed. We also evaluated the expression of ABCC1 and ABCG2, which have both been reported to be overexpressed in cancer cells resistant to doxorubicin. (70,71) Again, no statistically significant differences were observed between conditions, implying that the differences observed in the drug response were not dependent on the expression of these MDR proteins. These findings suggest that the higher expression of HSP90AB1, an antiapoptotic protein, could be one of the reasons for the higher survival rate in the presence of doxorubicin. Indeed, we hypothesize that the presence of Col1 provokes a downregulation of HSP90AB1 in hydrogels made of TDMs with Col1, as in Col1 hydrogels, this gene is downregulated. Altogether, the addition of Col1 at 0.15%, although it improves the cell proliferation and printability, does not improve the biological properties of the TDM. However, modifications in Col1 concentration or the addition of other overexpressed proteins in breast tumors such as fibronectin could improve its biological properties. Overall, TGA bioinks have shown great potential to develop breast cancer models and to recreate the breast tumor microenvironment.

4. Conclusions

ARTICLE SECTIONS
Jump To
In this work, we have created a novel bioink formed by decellularized breast tissues to recreate the complex composition of breast tumors. We developed a method for obtaining decellularized porcine breast tissues rich in GAGs and collagen that meets the decellularization criteria previously established by other authors and that enables the formation of hydrogels. This material is biocompatible; however, the rheological properties were not suitable for its bioprinting. For this reason, a Pluronic bed and alginate at low concentrations (0.5–2%) were used. In order to support the TDM bioprinting without a bed, GelMA and alginate were added, having an optimal shape fidelity and printability, comparable with other proteinaceous hydrogels. We further tuned the bioink composition to be closer to the tumor ECM by adding Col1 so that it is overexpressed in breast tumors. The incorporation of Col1 improved the bioink printability and shape fidelity without affecting the Young’s modulus of the hydrogels, both being in the range of stiffness previously reported for breast tumors. To further analyze whether these bioinks will allow the fabrication of models with a precise location of cancer and stromal cells, we bioprinted constructs containing BCCs and hAMSCs. The construct consisted of an inner core of BCCs and an outer layer of stromal cells, which maintained its stability after bioprinting, with no cell and bioink blending. We then used the developed bioinks to print a breast tumor model. Both bioinks showed a high MCF-7 cell viability and high proliferation and allowed the formation of cell clusters or spheroids with a low expression of E-cadherin, a higher expression of tumor markers than in 2D cultures, and low chemotherapy responsiveness. The addition of Col1 increased cell proliferation as well as the drug sensitivity of the bioprinted tumors associated with a downregulation of HSP90AB1. Overall, these results demonstrate the great potential of these bioinks for fabricating breast tumor models by bioprinting. Further studies using these biomaterials will manifest the importance of recreating the complexity of the ECM using decellularized native tissues to ensure closer recreation of tumors to study the interactions of cancer and stromal cells and the extracellular matrix.

Supporting Information

ARTICLE SECTIONS
Jump To

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsami.2c00920.

  • Additional experimental details; composition (%) and Young’s moduli (E) of the hydrogels; primers used in RT-qPCR; cell viability of MCF-7 cells in TGA and TGAC bioinks and in Col1 hydrogels; TDM bioprinting at different concentrations; MCF-7 viability in cell-laden TDM bioprinted hydrogels; temperature sweeps, bioprinting, and MCF-7 viability of TDM and alginate bioinks; MCF-7 viability with calcein AM/PI staining in TDM and alginate hydrogels; Young’s moduli of T2, T3, G2.5, and A0.5 hydrogels; amplitude sweeps and flow curves; cell proliferation in TGA and TGAC bioinks, Col1 hydrogels, and in 2D; CACNA1G and KCNA1Ct values (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

ARTICLE SECTIONS
Jump To
  • Corresponding Authors
  • Authors
    • Sergi Rey-Vinolas - Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
    • Gülsün Bağcı - Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
    • Gerard Rubi-Sans - Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain;  Orcidhttps://orcid.org/0000-0003-2782-8716
    • Jorge Otero - Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
    • Daniel Navajas - Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
    • Soledad Perez-Amodio - Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10-12, Barcelona 08028, Spain
  • Author Contributions

    The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

ARTICLE SECTIONS
Jump To

This work was funded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 712754 and by the Spanish Ministry of Economy and Competitiveness under the Severo Ochoa grants SEV-2014-0425 and CEX2018-000789-S, the Tecnologies Emergents program of the General Directorate for Research–Generalitat de Catalunya (grant no. 001-P-001646, cofunded by the FEDER Operational Program of Catalonia 2014–2020), the Programme/Generalitat de Catalunya (2017-SGR-359), the European Regional Development Fund (FEDER) and the Spanish Ministry of Science, Innovation and Universities (RTI2018-096320-B-C21 and MAT2015-68906-R), the Spanish Ministry of Economy, Industry and Competitiveness (EUIN2017-89173), the CERCA Program/Generalitat de Catalunya, and the European Commission-Euronanomed3 nAngioderm Project (JTC2018-103 and PCI2019-103648). We thank Dr. Elena Rebollo for her help with the Thunder Imager 3D live cell microscope and Prof. del Rio for the donation of rat mammary glands.

References

ARTICLE SECTIONS
Jump To

This article references 71 other publications.

  1. 1
    Bahcecioglu, G.; Basara, G.; Ellis, B. W.; Ren, X.; Zorlutuna, P. Breast Cancer Models: Engineering the Tumor Microenvironment. Acta Biomater. 2020, 106, 1– 21,  DOI: 10.1016/j.actbio.2020.02.006
    Google Scholar
    1
    Breast cancer models: Engineering the tumor microenvironment
    Bahcecioglu, Gokhan; Basara, Gozde; Ellis, Bradley W.; Ren, Xiang; Zorlutuna, Pinar
    Acta Biomaterialia (2020), 106 (), 1-21CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
    A review. The mechanisms behind cancer initiation and progression are not clear. Therefore, development of clin. relevant models to study cancer biol. and drug response in tumors is essential. In vivo models are very valuable tools for studying cancer biol. and for testing drugs; however, they often suffer from not accurately representing the clin. scenario because they lack either human cells or a functional immune system. On the other hand, two-dimensional (2D) in vitro models lack the three-dimensional (3D) network of cells and extracellular matrix (ECM) and thus do not represent the tumor microenvironment (TME). As an alternative approach, 3D models have started to gain more attention, as such models offer a platform with the ability to study cell-cell and cell-material interactions parametrically, and possibly include all the components present in the TME. Here, we first give an overview of the breast cancer TME, and then discuss the current state of the pre-clin. breast cancer models, with a focus on the engineered 3D tissue models. We also highlight two engineering approaches that we think are promising in constructing models representative of human tumors: 3D printing and microfluidics. In addn. to giving basic information about the TME in the breast tissue, this review article presents the state-of-the-art tissue engineered breast cancer models. Involvement of biomaterials and tissue engineering fields in cancer research enables realistic mimicry of the cell-cell and cell-extracellular matrix (ECM) interactions in the tumor microenvironment (TME), and thus creation of better models that reflect the tumor response against drugs. Engineering the 3D in vitro models also requires a good understanding of the TME. Here, an overview of the breast cancer TME is given, and the current state of the pre-clin. breast cancer models, with a focus on the engineered 3D tissue models is discussed. This review article is useful not only for biomaterials scientists aiming to engineer 3D in vitro TME models, but also for cancer researchers willing to use these models for studying cancer biol. and drug testing.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjsFSrsrw%253D&md5=1c27cf2ab68188e5a18f6c0217bb6c45
  2. 2
    Winkler, J.; Abisoye-Ogunniyan, A.; Metcalf, K. J.; Werb, Z. Concepts of Extracellular Matrix Remodelling in Tumour Progression and Metastasis. Nat. Commun. 2020, 11, 1– 19,  DOI: 10.1038/s41467-020-18794-x
    Google Scholar
    There is no corresponding record for this reference.
  3. 3
    Jena, M. K.; Janjanam, J. Role of Extracellular Matrix in Breast Cancer Development: A Brief Update. F1000Res 2018, 7, 274,  DOI: 10.12688/f1000research.14133.2
    Google Scholar
    3
    Role of extracellular matrix in breast cancer development: a brief update
    Jena Manoj Kumar; Janjanam Jagadeesh
    F1000Research (2018), 7 (), 274 ISSN:2046-1402.
    Evidence is increasing on the crucial role of the extracellular matrix (ECM) in breast cancer progression, invasion and metastasis with almost all mortality cases owing to metastasis. The epithelial-mesenchymal transition is the first signal of metastasis involving different transcription factors such as Snail, TWIST, and ZEB1. ECM remodeling is a major event promoting cancer invasion and metastasis; where matrix metalloproteinases (MMPs) such as MMP-2, -9, -11, and -14 play vital roles degrading the matrix proteins for cancer spread. The β-D mannuronic acid (MMP inhibitor) has anti-metastatic properties through inhibition of MMP-2, and -9 and could be a potential therapeutic agent. Besides the MMPs, the enzymes such as LOXL2, LOXL4, procollagen lysyl hydroxylase-2, and heparanase also regulate breast cancer progression. The important ECM proteins like integrins (b1-, b5-, and b6- integrins), ECM1 protein, and Hic-5 protein are also actively involved in breast cancer development. The stromal cells such as tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and adipocytes also contribute in tumor development through different processes. The TAMs become proangiogenic through secretion of VEGF-A and building vessel network for nourishment and invasion of the tumor mass. The latest developments of ECM involvement in breast cancer progression has been discussed in this review and this study will help researchers in designing future work on breast cancer pathogenesis and developing therapy targeted to the ECM components.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FlvFajtA%253D%253D&md5=f528ea31ddab81c6b08b7d56d5d9dad5
  4. 4
    Quail, D.; Joyce, J. Microenvironmental Regulation of Tumor Progression and Metastasis. Nat. Med. 2013, 19, 1423– 1437,  DOI: 10.1038/nm.3394
    Google Scholar
    4
    Microenvironmental regulation of tumor progression and metastasis
    Quail, Daniela F.; Joyce, Johanna A.
    Nature Medicine (New York, NY, United States) (2013), 19 (11), 1423-1437CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
    A review. Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslCmsrjL&md5=52d5ff0b56fb4749d0a42fedb3b83eb2
  5. 5
    Nallanthighal, S.; Heiserman, J.; Cheon, D. The Role of the Extracellular Matrix in Cancer Stemness. Front Cell Dev. Biol. 2019, 7, 86,  DOI: 10.3389/fcell.2019.00086
    Google Scholar
    5
    The Role of the Extracellular Matrix in Cancer Stemness
    Nallanthighal Sameera; Heiserman James Patrick; Cheon Dong-Joo
    Frontiers in cell and developmental biology (2019), 7 (), 86 ISSN:2296-634X.
    As our understanding of cancer cell biology progresses, it has become clear that tumors are a heterogenous mixture of different cell populations, some of which contain so called "cancer stem cells" (CSCs). Hallmarks of CSCs include self-renewing capability, tumor-initiating capacity and chemoresistance. The extracellular matrix (ECM), a major structural component of the tumor microenvironment, is a highly dynamic structure and increasing evidence suggests that ECM proteins establish a physical and biochemical niche for CSCs. In cancer, abnormal ECM dynamics occur due to disrupted balance between ECM synthesis and secretion and altered expression of matrix-remodeling enzymes. Tumor-derived ECM is biochemically distinct in its composition and is stiffer compared to normal ECM. In this review, we will provide a brief overview of how different components of the ECM modulate CSC properties then discuss how physical, mechanical, and biochemical cues from the ECM drive cancer stemness. Given the fact that current CSC targeting therapies face many challenges, a better understanding of CSC-ECM interactions will be crucial to identify more effective therapeutic strategies to eliminate CSCs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MvgtF2jtg%253D%253D&md5=1f33e808fbbdb1fa20ef3b9cac2aef0c
  6. 6
    Filipe, E. C.; Chitty, J. L.; Cox, T. R. Charting the Unexplored Extracellular Matrix in Cancer. Int. J. Exp. Pathol. 2018, 99, 58– 76,  DOI: 10.1111/iep.12269
    Google Scholar
    6
    Charting the unexplored extracellular matrix in cancer
    Filipe Elysse C; Chitty Jessica L; Cox Thomas R; Cox Thomas R
    International journal of experimental pathology (2018), 99 (2), 58-76 ISSN:.
    The extracellular matrix (ECM) is present in all solid tissues and considered a master regulator of cell behaviour and phenotype. The importance of maintaining the correct biochemical and biophysical properties of the ECM, and the subsequent regulation of cell and tissue homeostasis, is illustrated by the simple fact that the ECM is highly dysregulated in many different types of disease, especially cancer. The loss of tissue ECM homeostasis and integrity is seen as one of the hallmarks of cancer and typically defines transitional events in progression and metastasis. The vast majority of cancer studies place an emphasis on exploring the behaviour and intrinsic signalling pathways of tumour cells. Their goal was to identify ways to target intracellular pathways regulating cancer. Cancer progression and metastasis are powerfully influenced by the ECM and thus present a vast, unexplored repository of anticancer targets that we are only just beginning to tap into. Deconstructing the complexity of the tumour ECM landscape and identifying the interactions between the many cell types, soluble factors and extracellular-matrix proteins have proved challenging. Here, we discuss some of the emerging tools and platforms being used to catalogue and chart the ECM in cancer.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MjktlGhsw%253D%253D&md5=3bb538d5d6f8d4653ea588bfcaef1ad0
  7. 7
    Blanco-Fernandez, B.; Gaspar, V. M.; Engel, E.; Mano, J. F. Proteinaceous Hydrogels for Bioengineering Advanced 3D Tumor Models. Adv. Sci. 2021, 2003129, 1– 38,  DOI: 10.1002/advs.202003129
    Google Scholar
    There is no corresponding record for this reference.
  8. 8
    Mantha, S.; Pillai, S.; Khayambashi, P.; Upadhyay, A.; Zhang, Y.; Tao, O.; Pham, H. M.; Tran, S. D. Smart Hydrogels in Tissue Engineering and Regenerative Medicine. Materials 2019, 12, 3323,  DOI: 10.3390/ma12203323
    Google Scholar
    8
    Smart hydrogels in tissue engineering and regenerative medicine
    Mantha, Somasundar; Pillai, Sangeeth; Khayambashi, Parisa; Upadhyay, Akshaya; Zhang, Yuli; Tao, Owen; Pham, Hieu M.; Tran, Simon D.
    Materials (2019), 12 (20), 3323CODEN: MATEG9; ISSN:1996-1944. (MDPI AG)
    The field of regenerative medicine has tremendous potential for improved treatment outcomes and has been stimulated by advances made in bioengineering over the last few decades. The strategies of engineering tissues and assembling functional constructs that are capable of restoring, retaining, and revitalizing lost tissues and organs have impacted the whole spectrum of medicine and health care. Techniques to combine biomimetic materials, cells, and bioactive mols. play a decisive role in promoting the regeneration of damaged tissues or as therapeutic systems. Hydrogels have been used as one of the most common tissue engineering scaffolds over the past two decades due to their ability to maintain a distinct 3D structure, to provide mech. support for the cells in the engineered tissues, and to simulate the native extracellular matrix. The high water content of hydrogels can provide an ideal environment for cell survival, and structure which mimics the native tissues. Hydrogel systems have been serving as a supportive matrix for cell immobilization and growth factor delivery. This review outlines a brief description of the properties, structure, synthesis and fabrication methods, applications, and future perspectives of smart hydrogels in tissue engineering.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXotFGkt7c%253D&md5=d6cf64ff65b28e2d447e196b5e468a52
  9. 9
    Horning, J. L.; Sahoo, S. K.; Vijayaraghavalu, S.; Dimitrijevic, S.; Vasir, J. K.; Jain, T. K.; Panda, A. K.; Labhasetwar, V. 3-D Tumor Model for In Vitro Evaluation of Anticancer Drugs. Mol. Pharmaceutics 2008, 5, 849– 862,  DOI: 10.1021/mp800047v
    Google Scholar
    9
    3-D Tumor Model for In Vitro Evaluation of Anticancer Drugs
    Horning, Jayme L.; Sahoo, Sanjeeb K.; Vijayaraghavalu, Sivakumar; Dimitrijevic, Sanja; Vasir, Jaspreet K.; Jain, Tapan K.; Panda, Amulya K.; Labhasetwar, Vinod
    Molecular Pharmaceutics (2008), 5 (5), 849-862CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    The efficacy of potential anticancer drugs during preclin. development is generally tested in vitro using cancer cells grown in monolayer; however, a significant discrepancy in their efficacy is obsd. when these drugs are evaluated in vivo. This discrepancy, in part, could be due to the three-dimensional (3-D) nature of tumors as compared to the two-dimensional (2-D) nature of monolayer cultures. Therefore, there is a need for an in vitro model that would mimic the 3-D nature of tumors. With this objective, we have developed surface-engineered, large and porous biodegradable polymeric microparticles as a scaffold for 3-D growth of cancer cells. Using the MCF-7 cell line as model breast cancer cells, we evaluated the antiproliferative effect of three anticancer drugs: doxorubicin, paclitaxel and tamoxifen in 3-D model vs in 2-D monolayer. With optimized compn. of microparticles and cell culture conditions, a d. of 4.5 × 106 MCF-7 cells/mg of microparticles, which is an 18-fold increase from the seeding d., was achieved in six days of culture. Cells were obsd. to have grown in clumps on the microparticle surface as well as in their interior matrix structure. The antiproliferative effect of the drugs in 3-D model was significantly lower than in 2-D monolayer, which was evident from the 12- to 23-fold differences in their IC50 values. Using doxorubicin, the flow cytometry data demonstrated ∼2.6-fold lower drug accumulation in the cells grown in 3-D model than in the cells grown as 2-D monolayer. Further, only 26% of the cells in 3-D model had the same concn. of drug as the cells in monolayer, thus explaining the reduced activity of the drugs in 3-D model. The collagen content of the cells grown in 3-D model was 2-fold greater than that of the cells grown in 2-D, suggesting greater synthesis of extracellular matrix in 3-D model, which acted as a barrier to drug diffusion. The microarray anal. showed changes in several genes in cells grown in 3-D, which could also influence the drug effect. In conclusion, the cells grown in 3-D are more resistant to chemotherapy than those grown in 2-D culture, suggesting the significant roles of cellular architecture, phenotypic variations, and extracellular matrix barrier to drug transport in drug efficacy. We propose that our model provides a better assessment of drug efficacy than the currently used 2-D monolayer as many of its characteristic features are similar to an actual tumor. A well-characterized 3-D model can particularly be useful for rapid screening of a large no. of therapeutics for their efficacy during the drug discovery phase.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptlejs7o%253D&md5=87f323b84674ba0ab5bbe1c5d799e281
  10. 10
    Shekhar, M. P.; Werdell, J.; Santner, S. J.; Pauley, R. J.; Tait, L. Breast Stroma Plays a Dominant Regulatory Role in Breast Epithelial Growth and Differentiation: Implications for Tumor Development and Progression. Cancer Res. 2001, 61, 1320– 1326
    Google Scholar
    10
    Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: implications for tumor development and progression
    Shekhar, Malathy P. V.; Werdell, Jill; Santner, Steve J.; Pauley, Robert J.; Tait, Larry
    Cancer Research (2001), 61 (4), 1320-1326CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    Although growth factors and extracellular matrix (ECM) are recognized as important contributors to breast epithelial growth, morphogenesis, hormone responsiveness, and neoplastic progression, the influence of functional interactions between breast stromal and epithelial cells on these processes has not been defined. Using a novel three-dimensional cell-cell interaction model, the authors have compared the abilities of different mesenchymal cell types, including breast fibroblasts derived from redn. mammoplasty and tumor tissues, and human umbilical endothelial cells (HUVECs) to induce three-dimensional morphogenesis and growth of normal MCF10A and preneoplastic MCF10AT1-EIII8 (referred as EIII8) human breast epithelial cells. The authors' data demonstrate a requirement for organ-specific fibroblasts in the induction of epithelial morphogenesis. Whereas inclusion of normal redn. mammoplasty fibroblasts inhibit or retard morphol. conversion and growth of MCF10A and EIII8 cells, resp., tumor-derived breast fibroblasts evoke ductal-alveolar morphogenesis of both MCF10A and EIII8 cells. The growth and morphogenesis inhibitory effects of normal fibroblasts remain even in the presence of estrogen because they are able to suppress the estrogen-induced growth of EIII8 cells, whereas tumor fibroblasts support and maintain estrogen responsiveness of EIII8 cells. The inductive morphogenic effects of tumor fibroblasts on EIII8 cells is further augmented by the inclusion of HUVECs because these cocultures undergo a dramatic increase in proliferation and branching ductal-alveolar morphogenesis that is accompanied by an increase in invasion, degrdn. of coincident ECM, and expression of MMP-9. Therefore, tumor fibroblasts confer morphogenic and mitogenic induction of epithelial cells, and further enhancement of growth and progression requires active angiogenesis. These data illustrate the importance of structural and functional interactions between breast stromal and epithelial cells in the regulation of breast epithelial growth and progression.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhvVelsbY%253D&md5=5cbe47c6ef81f610a42e8ede4ba3de57
  11. 11
    Cavo, M.; Caria, M.; Pulsoni, I.; Beltrame, F.; Fato, M.; Scaglione, S. A New Cell-Laden 3D Alginate-Matrigel Hydrogel Resembles Human Breast Cancer Cell Malignant Morphology, Spread and Invasion Capability Observed “in Vivo.”. Sci. Rep. 2018, 8, 1– 12,  DOI: 10.1038/s41598-018-23250-4
    Google Scholar
    11
    A new cell-laden 3D Alginate-Matrigel hydrogel resembles human breast cancer cell malignant morphology, spread and invasion capability observed ''in vivo''
    Cavo, Marta; Caria, Marco; Pulsoni, Ilaria; Beltrame, Francesco; Fato, Marco; Scaglione, Silvia
    Scientific Reports (2018), 8 (1), 1-12CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
    Purpose of this study was the development of a 3D material to be used as substrate for breast cancer cell culture. We developed composite gels constituted by different concns. of Alginate (A) and Matrigel (M) to obtain a structurally stable-in-time and biol. active substrate. Human aggressive breast cancer cells (i.e. MDA-MB-231) were cultured within the gels. Known the link between cell morphol. and malignancy, cells were morphol. characterized and their invasiveness correlated through an innovative bioreactor-based invasion assay. A particular type of gel (i.e. 50% Alginate, 50% Matrigel) emerged thanks to a series of significant results: 1. cells exhibited peculiar cytoskeleton shapes and nuclear fragmentation characteristic of their malignancy; 2. cells expressed the formation of the so-called invadopodia, actin-based protrusion of the plasma membrane through which cells anchor to the extracellular matrix; 3. cells were able to migrate through the gels and attach to an engineered membrane mimicking the vascular walls hosted within bioreactor, providing a completely new 3D in vitro model of the very precursor steps of metastasis.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1yktrrK&md5=06bd01d9da7b51e9381f274f2b4810bd
  12. 12
    Ferreira, L. P.; Gaspar, V. M.; Mano, J. F. Decellularized Extracellular Matrix for Bioengineering Physiomimetic 3D in Vitro Tumor Models. Trends Biotechnol. 2020, 38, 1397– 1414,  DOI: 10.1016/j.tibtech.2020.04.006
    Google Scholar
    12
    Decellularized Extracellular Matrix for Bioengineering Physiomimetic 3D in Vitro Tumor Models
    Ferreira, Luis P.; Gaspar, Vitor M.; Mano, Joao F.
    Trends in Biotechnology (2020), 38 (12), 1397-1414CODEN: TRBIDM; ISSN:0167-7799. (Elsevier Ltd.)
    A review. Recent advances in the extn. and purifn. of decellularized extracellular matrix (dECM) obtained from healthy or malignant tissues open new avenues for engineering physiomimetic 3D in vitro tumor models, which closely recapitulate key biomol. hallmarks and the dynamic cancer cell-ECM interactions in the tumor microenvironment. We review current and upcoming methodologies for chem. modification of dECM-based biomaterials and advanced bioprocessing into organotypic 3D solid tumor models. A comprehensive review of disruptive advances and shortcomings of exploring dECM-based biomaterials for recapitulating the native tumor-supporting matrix is also provided. We hope to drive the discussion on how 3D dECM testing platforms can be leveraged for generating microphysiol. tumor surrogates that generate more robust and predictive data on therapeutic bioperformance.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXovVCht7k%253D&md5=01da7431f6c4f1bbc5d2f7b3719e61e2
  13. 13
    Saldin, L. T.; Cramer, M. C.; Velankar, S. S.; White, L. J.; Badylaka, S. F. Extracellular Matrix Hydrogels from Decellularized Tissues: Structure and Function. Acta Biomater. 2017, 49, 1– 15,  DOI: 10.1016/j.actbio.2016.11.068
    Google Scholar
    13
    Extracellular matrix hydrogels from decellularized tissues: Structure and function
    Saldin, Lindsey T.; Cramer, Madeline C.; Velankar, Sachin S.; White, Lisa J.; Badylak, Stephen F.
    Acta Biomaterialia (2017), 49 (), 1-15CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
    A review. Extracellular matrix (ECM) bioscaffolds prepd. from decellularized tissues have been used to facilitate constructive and functional tissue remodeling in a variety of clin. applications. The discovery that these ECM materials could be solubilized and subsequently manipulated to form hydrogels expanded their potential in vitro and in vivo utility; i.e. as culture substrates comparable to collagen or Matrigel, and as injectable materials that fill irregularly-shaped defects. The mechanisms by which ECM hydrogels direct cell behavior and influence remodeling outcomes are only partially understood, but likely include structural and biol. signals retained from the native source tissue. The present review describes the utility, formation, and phys. and biol. characterization of ECM hydrogels. Two examples of clin. application are presented to demonstrate in vivo utility of ECM hydrogels in different organ systems. Finally, new research directions and clin. translation of ECM hydrogels are discussed. More than 70 papers have been published on extracellular matrix (ECM) hydrogels created from source tissue in almost every organ system. The present manuscript represents a review of ECM hydrogels and attempts to identify structure-function relationships that influence the tissue remodeling outcomes and gaps in the understanding thereof. There is a Phase 1 clin. trial now in progress for an ECM hydrogel.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFKqsrzF&md5=61a751f33ddaa825cd19400a094f1c17
  14. 14
    Pati, F.; Jang, J.; Ha, D.-H.; Kim, S. W.; Rhie, J.-W.; Shim, J.-H.; Kim, D.-H.; Cho, D.-W. Printing Three-Dimensional Tissue Analogues with Decellularized Extracellular Matrix Bioink. Nat. Commun. 2014, 5, 3935,  DOI: 10.1038/ncomms4935
    Google Scholar
    14
    Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink
    Pati, Falguni; Jang, Jinah; Ha, Dong-Heon; Won Kim, Sung; Rhie, Jong-Won; Shim, Jin-Hyung; Kim, Deok-Ho; Cho, Dong-Woo
    Nature Communications (2014), 5 (), 3935CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
    The ability to print and pattern all the components that make up a tissue (cells and matrix materials) in three dimensions to generate structures similar to tissues is an exciting prospect of bioprinting. However, the majority of the matrix materials used so far for bioprinting cannot represent the complexity of natural extracellular matrix (ECM) and thus are unable to reconstitute the intrinsic cellular morphologies and functions. Here, we develop a method for the bioprinting of cell-laden constructs with novel decellularized extracellular matrix (dECM) bioink capable of providing an optimized microenvironment conducive to the growth of three-dimensional structured tissue. We show the versatility and flexibility of the developed bioprinting process using tissue-specific dECM bioinks, including adipose, cartilage and heart tissues, capable of providing crucial cues for cells engraftment, survival and long-term function. We achieve high cell viability and functionality of the printed dECM structures using our bioprinting method.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvF2mu77P&md5=bf583e49f37c1ec2bb11657dc85522f8
  15. 15
    Dunne, L. W.; Huang, Z.; Meng, W. X.; Fan, X. J.; Zhang, N. Y.; Zhang, Q. X.; An, Z. G. Human Decellularized Adipose Tissue Scaffold as a Model for Breast Cancer Cell Growth and Drug Treatments. Biomaterials 2014, 35, 4940– 4949,  DOI: 10.1016/j.biomaterials.2014.03.003
    Google Scholar
    15
    Human decellularized adipose tissue scaffold as a model for breast cancer cell growth and drug treatments
    Dunne, Lina W.; Huang, Zhao; Meng, Weixu; Fan, Xuejun; Zhang, Ningyan; Zhang, Qixu; An, Zhiqiang
    Biomaterials (2014), 35 (18), 4940-4949CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    Human adipose tissue extracellular matrix, derived through decellularization processing, has been shown to provide a biomimetic microenvironment for adipose tissue regeneration. This study reports the use of human adipose tissue-derived extracellular matrix (hDAM) scaffolds as a three-dimensional cell culturing system for the investigation of breast cancer growth and drug treatments. The hDAM scaffolds have similar extracellular matrix compn. to the microenvironment of breast tissues. Breast cancer cells were cultured in hDAM scaffolds, and cell proliferation, migration, morphol., and drug responses were investigated. The growth profiles of multiple breast cancer cell lines cultured in hDAM scaffolds differed from the growth of those cultured on two-dimensional surfaces and more closely resembled the growth of xenografts. HDAM-cultured breast cancer cells also differed from those cultured on two-dimensional surfaces in terms of cell morphol., migration, expression of adhesion mols., and sensitivity to drug treatment. Our results demonstrated that the hDAM system provides breast cancer cells with a biomimetic microenvironment in vitro that more closely mimics the in vivo microenvironment than existing two-dimensional and Matrigel three-dimensional cultures do, and thus can provide vital information for the characterization of cancer cells and screening of cancer therapeutics.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXksleku70%253D&md5=9e9dfcde46cc19180dd9a648087152d1
  16. 16
    Liu, G.; Wang, B.; Li, S.; Jin, Q.; Dai, Y. Human Breast Cancer Decellularized Scaffolds Promote Epithelial-to-Mesenchymal Transitions and Stemness of Breast Cancer Cells in Vitro. J. Cell. Physiol. 2019, 234, 9447– 9456,  DOI: 10.1002/jcp.27630
    Google Scholar
    16
    Human breast cancer decellularized scaffolds promote epithelial-to-mesenchymal transitions and stemness of breast cancer cells in vitro
    Liu, Gang; Wang, Biao; Li, Shubin; Jin, Qin; Dai, Yanfeng
    Journal of Cellular Physiology (2019), 234 (6), 9447-9456CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)
    Breast cancer, with unsatisfactory survival rates, is the leading cause of cancer-related death in women worldwide. Recent advances in the genetic basis of breast cancer have benefitted the development of gene-based medicines and therapies. Tissue engineering technologies, including tissue decellularizations and reconstructions, are potential therapeutic alternatives for cancer research and tissue regeneration. In our study, human breast cancer biopsies were decellularized by a detergent technique, with sodium lauryl ether sulfate (SLES) soln., for the first time. And the decellularization process was optimized to maximally maintain tissue microarchitectures and extracellular matrix (ECM) components with minimal DNA compds. preserved. Histol. anal. and DNA quantification results confirmed the decellularization effect with maximal genetic compds. removal. Quantification, immunofluorescence, and histol. analyses demonstrated better preservation of ECM components in 0.5% SLES-treated scaffolds. Scaffolds seeded with MCF-7 cells demonstrated the process of cell recellularization in vitro, with increased cell migration, proliferation, and epithelial-to-mesenchymal transition (EMT) process. When treated with 5-fluorouracil, the expressions of stem cell markers, including Oct4, Sox2, and CD49F, were maximally maintained in the recellularized scaffold with decreased apoptosis rates compared with monolayer cells. These results showed that the decellularized breast scaffold model with SLES treatments would help to simulate the pathogenesis of breast cancer in vitro. And we hope that this model could further accelerate the development of effective therapies for breast cancer and benefit drug screenings.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlSgs7%252FO&md5=318fe70c0f4c5a5d915b30895064054f
  17. 17
    Mollica, P.; Booth-Creech, E.; Reid, J.; Zamponi, M.; Sullivan, S.; Palmer, X.; Sachs, P.; Robert, D. 3D Bioprinted Mammary Organoids and Tumoroids in Human Mammary Derived ECM Hydrogels. Acta Biomater. 2019, 95, 201– 213,  DOI: 10.1016/j.actbio.2019.06.017
    Google Scholar
    17
    3D bioprinted mammary organoids and tumoroids in human mammary derived ECM hydrogels
    Mollica, Peter A.; Booth-Creech, Elizabeth N.; Reid, John A.; Zamponi, Martina; Sullivan, Shea M.; Palmer, Xavier-Lewis; Sachs, Patrick C.; Bruno, Robert D.
    Acta Biomaterialia (2019), 95 (), 201-213CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
    The extracellular matrix (ECM) of tissues is an important mediator of cell function. Moreover, understanding cellular dynamics within their specific tissue context is also important for developmental biol., cancer research, and regenerative medicine. However, robust in vitro models that incorporate tissue-specific microenvironments are lacking. Here we describe a novel mammary-specific culture protocol that combines a self-gelling hydrogel comprised solely of ECM from decellularized rat or human breast tissue with the use of our previously described 3D bioprinting platform. We initially demonstrate that undigested and decellularized mammary tissue can support mammary epithelial and tumor cell growth. We then describe a methodol. for generating mammary ECM exts. that can spontaneously gel to form hydrogels. These ECM hydrogels retain unique structural and signaling profiles that elicit differential responses when normal mammary and breast cancer cells are cultured within them. Using our bioprinter, we establish that we can generate large organoids/tumoroids in the all mammary-derived hydrogel. These findings demonstrate that our system allows for growth of organoids/tumoroids in a tissue-specific matrix with unique properties, thus providing a suitable platform for ECM and epithelial/cancer cell studies. Factors within extracellular matrixes (ECMs) are specific to their tissue of origin. It has been shown that tissue specific factors within the mammary gland's ECM have pronounced effects on cellular differentiation and cancer behavior. Understanding the role of the ECM in controlling cell fate has major implications for developmental biol., tissue engineering, and cancer therapy. However, in vitro models to study cellular interactions with tissue specific ECM are lacking. Here we describe the generation of 3D hydrogels consisting solely of human or mouse mammary ECM. We demonstrate that these novel 3D culture substrates can sustain large 3D bioprinted organoid and tumoroid formation. This is the first demonstration of an all mammary ECM culture system capable of sustaining large structural growths.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht1yitLfI&md5=52b6c9b874e5129fb96a34965523072a
  18. 18
    Rijal, G.; Wang, J.; Yu, I.; Gang, D. R.; Chen, R. K.; Li, W. Porcine Breast Extracellular Matrix Hydrogel for Spatial Tissue Culture. Int. J. Mol. Sci. 2018, 19, 2912,  DOI: 10.3390/ijms19102912
    Google Scholar
    18
    Porcine breast extracellular matrix hydrogel for spatial tissue culture
    Rijal, Girdhari; Wang, Jing; Yu, Ilhan; Gang, David R.; Chen, Roland K.; Li, Weimin
    International Journal of Molecular Sciences (2018), 19 (10), 2912/1-2912/13CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    Porcine mammary fatty tissues represent an abundant source of natural biomaterial for generation of breast-specific extracellular matrix (ECM). Here we report the extn. of total ECM proteins from pig breast fatty tissues, the fabrication of hydrogel and porous scaffolds from the extd. ECM proteins, the structural properties of the scaffolds (tissue matrix scaffold, TMS), and the applications of the hydrogel in human mammary epithelial cell spatial cultures for cell surface receptor expression, metabolomics characterization, acini formation, proliferation, migration between different scaffolding compartments, and in vivo tumor formation. This model system provides an addnl. option for studying human breast diseases such as breast cancer.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntVKqtrw%253D&md5=30f34bdc2bf94772b7101bb5415c845d
  19. 19
    Ruud, K. F.; Hiscox, W. C.; Yu, I.; Chen, R. K.; Li, W. Distinct Phenotypes of Cancer Cells on Tissue Matrix Gel. Breast Cancer Res. 2020, 22, 82,  DOI: 10.1186/s13058-020-01321-7
    Google Scholar
    19
    Distinct phenotypes of cancer cells on tissue matrix gel
    Ruud, Kelsey F.; Hiscox, William C.; Yu, Ilhan; Chen, Roland K.; Li, Weimin
    Breast Cancer Research (2020), 22 (1), 82CODEN: BRCRFS; ISSN:1465-542X. (BioMed Central Ltd.)
    Breast cancer cells invading the connective tissues outside the mammary lobule or duct immerse in a reservoir of extracellular matrix (ECM) that is structurally and biochem. distinct from that of their site of origin. The ECM is a spatial network of matrix proteins, which not only provide phys. support but also serve as bioactive ligands to the cells. It becomes evident that the dimensional, mech., structural, and biochem. properties of ECM are all essential mediators of many cellular functions. To better understand breast cancer development and cancer cell biol. in native tissue environment, various tissue-mimicking culture models such as hydrogel have been developed. Collagen I (Col I) and Matrigel are the most common hydrogels used in cancer research and have opened opportunities for addressing biol. questions beyond the two-dimensional (2D) cell cultures. Yet, it remains unclear whether these broadly used hydrogels can recapitulate the environmental properties of tissue ECM, and whether breast cancer cells grown on CoI I or Matrigel display similar phenotypes as they would on their native ECM. We investigated mammary epithelial cell phenotypes and metabolic profiles on animal breast ECM-derived tissue matrix gel (TMG), Col I, and Matrigel. Atomic force microscopy (AFM), fluorescence microscopy, acini formation assay, differentiation expts., spatial migration/invasion assays, proliferation assay, and NMR (NMR) spectroscopy were used to examine biol. phenotypes and metabolic changes. Student's t test was applied for statistical analyses. Our data showed that under a similar physiol. stiffness, the three types of hydrogels exhibited distinct microstructures. Breast cancer cells grown on TMG displayed quite different morphologies, surface receptor expression, differentiation status, migration and invasion, and metabolic profiles compared to those cultured on Col I and Matrigel. Depleting lactate produced by glycolytic metab. of cancer cells abolished the cell proliferation promoted by the non-tissue-specific hydrogel. The full ECM protein-based hydrogel system may serve as a biol. relevant model system to study tissue- and disease-specific pathol. questions. This work provides insights into tissue matrix regulation of cancer cell biomarker expression and identification of novel therapeutic targets for the treatment of human cancers based on tissue-specific disease modeling.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFejs77N&md5=eff0b71bb4e851ad47ae3f61488d98a9
  20. 20
    Landberg, G.; Landberg, P.; Fitzpatrick, P.; Jonasson, J.; Jonasson, E.; Karlsson, J.; Larsson, E.; Svanström, A.; Rafnsdottir, S.; Persson, E.; Gustafsson, A.; Andersson, D.; Rosendah, J.; Petronis, S.; Panji, P.; Gregersson, P.; Magnusson, Y.; Håkansson, J.; Ståhlberg, A. Patient-Derived Scaffolds Uncover Breast Cancer Promoting Properties of the Microenvironment. Biomaterials 2020, 235, 119705,  DOI: 10.1016/j.biomaterials.2019.119705
    Google Scholar
    20
    Patient-derived scaffolds uncover breast cancer promoting properties of the microenvironment
    Landberg, Goeran; Fitzpatrick, Paul; Isakson, Pauline; Jonasson, Emma; Karlsson, Joakim; Larsson, Erik; Svanstroem, Andreas; Rafnsdottir, Svanheidur; Persson, Emma; Gustafsson, Anna; Andersson, Daniel; Rosendahl, Jennifer; Petronis, Sarunas; Ranji, Parmida; Gregersson, Pernilla; Magnusson, Ylva; Haakansson, Joakim; Staahlberg, Anders
    Biomaterials (2020), 235 (), 119705CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    Tumor cells interact with the microenvironment that specifically supports and promotes tumor development. Key components in the tumor environment have been linked to various aggressive cancer features and can further influence the presence of subpopulations of cancer cells with specific functions, including cancer stem cells and migratory cells. To model and further understand the influence of specific microenvironments we have developed an exptl. platform using cell-free patient-derived scaffolds (PDSs) from primary breast cancers infiltrated with standardized breast cancer cell lines. This PDS culture system induced a series of orchestrated changes in differentiation, epithelial-mesenchymal transition, stemness and proliferation of the cancer cell population, where an increased cancer stem cell pool was confirmed using functional assays. Furthermore, global gene expression profiling showed that PDS cultures were similar to xenograft cultures. Mass spectrometry analyses of cell-free PDSs identified subgroups based on their protein compn. that were linked to clin. properties, including tumor grade. Finally, we obsd. that an induction of epithelial-mesenchymal transition-related genes in cancer cells growing on the PDSs were significantly assocd. with clin. disease recurrences in breast cancer patients. Patient-derived scaffolds thus mimics in vivo-like growth conditions and uncovers unique information about the malignancy-inducing properties of tumor microenvironment.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlajsLs%253D&md5=d3ba9113dd3ea82e0483532873a073c3
  21. 21
    Monteiro, M. v.; Zhang, Y. S.; Gaspar, V. M.; Mano, J. F. 3D-Bioprinted Cancer-on-a-Chip: Level-up Organotypic in Vitro Models. In Trends in Biotechnology; Elsevier Ltd 2021.
    Google Scholar
    There is no corresponding record for this reference.
  22. 22
    Langer, E. M.; Allen-Petersen, B. L.; King, S. M.; Kendsersky, N. D.; Turnidge, M. A.; Kuziel, G. M.; Riggers, R.; Samatham, R.; Amery, T. S.; Jacques, S. L.; Sheppard, B. C.; Korkola, J. E.; Muschler, J. L.; Thibault, G.; Chang, Y. H.; Gray, J. W.; Presnell, S. C.; Nguyen, D. G.; Sears, R. C. Modeling Tumor Phenotypes In Vitro with Three-Dimensional Bioprinting. Cell Rep. 2019, 26, 608– 623.e6,  DOI: 10.1016/j.celrep.2018.12.090
    Google Scholar
    22
    Modeling Tumor Phenotypes In Vitro with Three-Dimensional Bioprinting
    Langer, Ellen M.; Allen-Petersen, Brittany L.; King, Shelby M.; Kendsersky, Nicholas D.; Turnidge, Megan A.; Kuziel, Genevra M.; Riggers, Rachelle; Samatham, Ravi; Amery, Taylor S.; Jacques, Steven L.; Sheppard, Brett C.; Korkola, James E.; Muschler, John L.; Thibault, Guillaume; Chang, Young Hwan; Gray, Joe W.; Presnell, Sharon C.; Nguyen, Deborah G.; Sears, Rosalie C.
    Cell Reports (2019), 26 (3), 608-623.e6CODEN: CREED8; ISSN:2211-1247. (Cell Press)
    The tumor microenvironment plays a crit. role in tumor growth, progression, and therapeutic resistance, but interrogating the role of specific tumor-stromal interactions on tumorigenic phenotypes is challenging within in vivo tissues. Here, we tested whether three-dimensional (3D) bioprinting could improve in vitro models by incorporating multiple cell types into scaffold-free tumor tissues with defined architecture. We generated tumor tissues from distinct subtypes of breast or pancreatic cancer in relevant microenvironments and demonstrate that this technique can model patient-specific tumors by using primary patient tissue. We assess intrinsic, extrinsic, and spatial tumorigenic phenotypes in bioprinted tissues and find that cellular proliferation, extracellular matrix deposition, and cellular migration are altered in response to extrinsic signals or therapies. Together, this work demonstrates that multi-cell-type bioprinted tissues can recapitulate aspects of in vivo neoplastic tissues and provide a manipulable system for the interrogation of multiple tumorigenic endpoints in the context of distinct tumor microenvironments.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht1egt78%253D&md5=d00d3e243296ac49df727528b89a9ebf
  23. 23
    Datta, P.; Dey, M.; Ataie, Z.; Unutmaz, D.; Ozbolat, I. T. 3D Bioprinting for Reconstituting the Cancer Microenvironment. npj Precis. Oncol. 2020, 4, 18,  DOI: 10.1038/s41698-020-0121-2
    Google Scholar
    23
    3D bioprinting for reconstituting the cancer microenvironment
    Datta Pallab; Dey Madhuri; Ataie Zaman; Ozbolat Ibrahim T; Unutmaz Derya; Ozbolat Ibrahim T; Ozbolat Ibrahim T; Ozbolat Ibrahim T
    NPJ precision oncology (2020), 4 (), 18 ISSN:2397-768X.
    The cancer microenvironment is known for its complexity, both in its content as well as its dynamic nature, which is difficult to study using two-dimensional (2D) cell culture models. Several advances in tissue engineering have allowed more physiologically relevant three-dimensional (3D) in vitro cancer models, such as spheroid cultures, biopolymer scaffolds, and cancer-on-a-chip devices. Although these models serve as powerful tools for dissecting the roles of various biochemical and biophysical cues in carcinoma initiation and progression, they lack the ability to control the organization of multiple cell types in a complex dynamic 3D architecture. By virtue of its ability to precisely define perfusable networks and position of various cell types in a high-throughput manner, 3D bioprinting has the potential to more closely recapitulate the cancer microenvironment, relative to current methods. In this review, we discuss the applications of 3D bioprinting in mimicking cancer microenvironment, their use in immunotherapy as prescreening tools, and overview of current bioprinted cancer models.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38fltlejug%253D%253D&md5=e865b51d9160bad39d35627109289326
  24. 24
    Sharifi, M.; Baia, Q.; Babadaei, M. M. N.; Chowdhury, F.; Hassan, M.; Taghizadeh, A.; Derakhshankhah, H.; Khan, S.; Hasan, A.; Falahati, M. 3D Bioprinting of Engineered Breast Cancer Constructs for Personalized and Targeted Cancer Therapy. J. Control Rel. 2021, 333, 91– 106,  DOI: 10.1016/j.jconrel.2021.03.026
    Google Scholar
    There is no corresponding record for this reference.
  25. 25
    Zhou, X.; Zhu, W.; Nowicki, M.; Miao, S.; Cui, H.; Holmes, B.; Glazer, R. I.; Zhang, L. G. 3D Bioprinting a Cell-Laden Bone Matrix for Breast Cancer Metastasis Study. ACS Appl. Mater. Interfaces 2016, 8, 30017– 30026,  DOI: 10.1021/acsami.6b10673
    Google Scholar
    25
    3D Bioprinting a Cell-Laden Bone Matrix for Breast Cancer Metastasis Study
    Zhou, Xuan; Zhu, Wei; Nowicki, Margaret; Miao, Shida; Cui, Haitao; Holmes, Benjamin; Glazer, Robert I.; Zhang, Lijie Grace
    ACS Applied Materials & Interfaces (2016), 8 (44), 30017-30026CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Metastasis is one of the deadliest consequences of breast cancer, with bone being one of the primary sites of occurrence. Insufficient 3D biomimetic models currently exist to replicate this process in vitro. In this study, we developed a biomimetic bone matrix using 3D bioprinting technol. to investigate the interaction between breast cancer (BrCa) cells and bone stromal cells (fetal osteoblasts and human bone marrow mesenchymal stem cells (MSCs)). A tabletop stereolithog. 3D bioprinter was employed to fabricate a series of bone matrixes consisting of osteoblasts or MSCs encapsulated in gelatin methacrylate (GelMA) hydrogel with nanocryst. hydroxyapatite (nHA). When BrCa cells were introduced into the stromal cell-laden bioprinted matrixes, we found that the growth of BrCa cells was enhanced by the presence of osteoblasts or MSCs, whereas the proliferation of the osteoblasts or MSCs was inhibited by the BrCa cells. The BrCa cells co-cultured with MSCs or osteoblasts presented increased vascular endothelial growth factor (VEGF) secretion in comparison to that of monocultured BrCa cells. Addnl., the alk. phosphatase activity of MSCs or osteoblasts was reduced after BrCa cell co-culture. These results demonstrate that the 3D bioprinted matrix, with BrCa cells and bone stromal cells, provides a suitable model with which to study the interactive effects of cells in the context of an artificial bone microenvironment and thus may serve as a valuable tool for the investigation of postmetastatic breast cancer progression in bone.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslWjsL3N&md5=727074490fefdd2e67cb7428c6123250
  26. 26
    Wang, Y.; Shi, W.; Kuss, M.; Mirza, S.; Qi, D.; Krasnoslobodtsev, A.; Zeng, J.; Band, H.; Band, V.; Duan, B. 3D Bioprinting of Breast Cancer Models for Drug Resistance Study. ACS Biomater. Sci. Eng. 2018, 4, 4401– 4411,  DOI: 10.1021/acsbiomaterials.8b01277
    Google Scholar
    26
    3D Bioprinting of Breast Cancer Models for Drug Resistance Study
    Wang, Ying; Shi, Wen; Kuss, Mitchell; Mirza, Sameer; Qi, Dianjun; Krasnoslobodtsev, Alexey; Zeng, Jiping; Band, Hamid; Band, Vimla; Duan, Bin
    ACS Biomaterials Science & Engineering (2018), 4 (12), 4401-4411CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)
    Adipose-derived mesenchymal stem/stromal cells (ADMSC) are one of the major stromal cells in the breast cancer microenvironment that promote cancer progression. Previous studies on the effects of ADMSC on breast cancer metastasis and drug resistance, using two-dimensional (2D) cultures, remained inconclusive. In the present study, we compared cocultured ADMSC and human epidermal receptor 2 pos. breast primary breast cancer cells (21PT) in 2D and three-dimensional (3D) cultures and then examd. their response to doxorubicin (DOX). We examd. 3D bioprinted constructs with breast cancer cells in the middle and ADMSC in the edge region, which were made by using dual hydrogel-based bioinks. We found that the percentage of cleaved Caspase-3 pos. cells was significantly lower in the bioprinted constructs with ADMSC and 21PT than that in the cancer cell alone constructs, in response to low DOX dose. We further increased the thickness of the ADMSC layers to mimic the status of obesity and then examd. the effect of ADMSC thickness on DOX resistance and lysyl oxidase (LOX) secretion. In the moderate and thick-layered ADMSC constructs, significantly more cells were stained neg. for cleaved Caspase-3, indicating less apoptosis. Both ADMSC and 21PT intrinsically expressed LOX, regardless of changes in thickness or DOX administration. Notably, treatment with a LOX inhibitor significantly decreased the stiffness in the ADMSC region but did not affect the stiffness in the 21PT region. In addn., LOX inhibitor treatment enhanced DOX sensitivity of 21PT in the bioprinted constructs, as seen by a decrease in LOX secretion and downregulation of ATP-binding cassette transporter gene expression. Taken together, we demonstrate that 3D bioprinted these breast cancer models faithfully reproduce in vivo conditions and should provide better models for examg. breast cancer biol. and for screening for drug discoveries.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1SgsbfO&md5=a79510a12bde91f7726c0bcb0857f2c5
  27. 27
    Badylak, S. F.; Freytes, D. O.; Gilbert, T. W. Reprint of: Extracellular Matrix as a Biological Scaffold Material: Structure and Function. Acta Biomater. 2015, 23, S17– S26,  DOI: 10.1016/j.actbio.2015.07.016
    Google Scholar
    There is no corresponding record for this reference.
  28. 28
    Skardal, A.; Devarasetty, M.; Kang, H.; Mead, I.; Bishop, C.; Shupe, T.; Lee, S.; Jackson, J.; Yoo, J.; Soker, S.; Atala, A. A Hydrogel Bioink Toolkit for Mimicking Native Tissue Biochemical and Mechanical Properties in Bioprinted Tissue Constructs. Acta Biomater. 2015, 25, 24– 34,  DOI: 10.1016/j.actbio.2015.07.030
    Google Scholar
    28
    A hydrogel bioink toolkit for mimicking native tissue biochemical and mechanical properties in bioprinted tissue constructs
    Skardal, Aleksander; Devarasetty, Mahesh; Kang, Hyun-Wook; Mead, Ivy; Bishop, Colin; Shupe, Thomas; Lee, Sang Jin; Jackson, John; Yoo, James; Soker, Shay; Atala, Anthony
    Acta Biomaterialia (2015), 25 (), 24-34CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
    Advancement of bioprinting technol. is limited by the availability of materials that both facilitate bioprinting logistics as well as support cell viability and function by providing tissue-specific cues. Herein we describe a modular hyaluronic acid (HA) and gelatin-based hydrogel toolbox comprised of a 2-crosslinker, 2-stage polymn. technique, and the capability to provide tissue specific biochem. and mech. accurate signals to cells within biofabricated tissue constructs. First, we prepd. and characterized several tissue-derived decellularized extracellular matrix-based solns., which contain complex combinations of growth factors, collagens, glycosaminoglycans, and elastin. These solns. can be incorporated into bioinks to provide the important biochem. cues of different tissue types. Second, we employed combinations of PEG-based crosslinkers with varying mol. wts., geometries (linear, 4-arm, and 8-arm), and functional groups to yield hydrogel bioinks that supported extrusion bioprinting and the capability to achieve final construct shear stiffness values ranging from approx. 100 Pa to 20 kPa. Lastly, we integrated these hydrogel bioinks with a 3-D bioprinting platform, and validated their use by bioprinting primary liver spheroids in a liver-specific bioink to create in vitro liver constructs with high cell viability and measurable functional albumin and urea output. This hydrogel bioink system has the potential to be a versatile tool for biofabrication of a wide range of tissue construct types. Biochem. and mech. factors both have important implications in guiding the behavior of cells in vivo, yet both realms are rarely considered together in the context of biofabrication in vitro tissue construct models. We describe a modular hydrogel system that (1) facilitates extrusion bioprinting of cell-laden hydrogels, (2) incorporates tissue-specific factors derived from decellularized tissue extracellular matrix, thus mimicking biochem. tissue profile, and (3) allows control over mech. properties to mimic the tissue stiffness. We believe that employing this technol. to attend to both the biochem. and mech. profiles of tissues, will allow us to more accurately recapitulate the in vivo environment of tissues while creating functional 3-D in vitro tissue constructs that can be used as disease models, personalized medicine, and in vitro drug and toxicol. screening systems.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1GrurnL&md5=c3e7f1490962d6ec2e9bba3fd49b0747
  29. 29
    Kort-Mascort, J.; Bao, G.; Elkashty, O.; Flores-Torres, S.; Munguia-Lopez, J. G.; Jiang, T.; Ehrlicher, A. J.; Mongeau, L.; Tran, S. D.; Kinsella, J. M. Decellularized Extracellular Matrix Composite Hydrogel Bioinks for the Development of 3D Bioprinted Head and Neck in Vitro Tumor Models. ACS Biomater. Sci. Eng. 2021, 5288,  DOI: 10.1021/acsbiomaterials.1c00812
    Google Scholar
    29
    Decellularized Extracellular Matrix Composite Hydrogel Bioinks for the Development of 3D Bioprinted Head and Neck in Vitro Tumor Models
    Kort-Mascort, Jacqueline; Bao, Guangyu; Elkashty, Osama; Flores-Torres, Salvador; Munguia-Lopez, Jose G.; Jiang, Tao; Ehrlicher, Allen J.; Mongeau, Luc; Tran, Simon D.; Kinsella, Joseph M.
    ACS Biomaterials Science & Engineering (2021), 7 (11), 5288-5300CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)
    Reinforced extracellular matrix (ECM)-based hydrogels recapitulate several mech. and biochem. features found in the tumor microenvironment (TME) in vivo. While these gels retain several crit. structural and bioactive mols. that promote cell-matrix interactivity, their mech. properties tend toward the viscous regime limiting their ability to retain ordered structural characteristics when considered as architectured scaffolds. To overcome this limitation characteristic of pure ECM hydrogels, we present a composite material contg. alginate, a seaweed-derived polysaccharide, and gelatin, denatured collagen, as rheol. modifiers which impart mech. integrity to the biol. active decellularized ECM (dECM). After an optimization process, the reinforced gel proposed is mech. stable and bioprintable and has a stiffness within the expected physiol. values. Our hydrogel's elastic modulus has no significant difference when compared to tumors induced in preclin. xenograft head and neck squamous cell carcinoma (HNSCC) mouse models. The bioprinted cell-laden model is highly reproducible and allows proliferation and reorganization of HNSCC cells while maintaining cell viability above 90% for periods of nearly 3 wk. Cells encapsulated in our bioink produce spheroids of at least 3000μm2 of cross-sectional area by day 15 of culture and are pos. for cytokeratin in immunofluorescence quantification, a common marker of HNSCC model validation in 2D and 3D models. We use this in vitro model system to evaluate the std.-of-care small mol. therapeutics used to treat HNSCC clin. and report a 4-fold increase in the IC50 of cisplatin and an 80-fold increase for 5-fluorouracil compared to monolayer cultures. Our work suggests that fabricating in vitro models using reinforced dECM provides a physiol. relevant system to evaluate malignant neoplastic phenomena in vitro due to the phys. and biol. features replicated from the source tissue microenvironment.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXit1CqsbfL&md5=fcbe70382139534a70d5ee57724e9939
  30. 30
    Vilalta, M.; Degano, I.; Bago, J.; Gould, D.; Santos, M.; Garcia-Arranz, M.; Ayats, R.; Fuster, C.; Chernajovsky, Y.; Garcia-Olmo, D.; Rubio, N.; Blanco, J. Biodistribution, Long-Term Survival, and Safety of Human Adipose Non-Invasive, Tissue-Derived Mesenchymal Stem Cells Transplanted in Nude Mice by High Sensitivity Bioluminescence Imaging. Stem Cells Dev. 2008, 17, 993– 1004,  DOI: 10.1089/scd.2007.0201
    Google Scholar
    30
    Biodistribution, long-term survival, and safety of human adipose tissue-derived mesenchymal stem cells transplanted in nude mice by high sensitivity non-invasive bioluminescence imaging
    Vilalta Marta; Degano Irene R; Bago Juli; Gould David; Santos Monica; Garcia-Arranz Mariano; Ayats Ramon; Fuster Carme; Chernajovsky Yuti; Garcia-Olmo Damian; Rubio Nuria; Blanco Jeronimo
    Stem cells and development (2008), 17 (5), 993-1003 ISSN:.
    Cultivated murine bone marrow mesenchymal stem cells (MSCs) frequently accumulate chromosome abnormalities, become oncogenically transformed, and generate sarcomas when transplanted in mice. Although human MSCs appear to be more resistant, oncogenic transformation has also been observed in MSCs cultivated past the senescence phase. Cell therapy for tissue regeneration using human autologous MSCs requires transplantation of cells previously expanded in vitro. Thus, an important concern is to determine if oncogenic transformation is a necessary outcome of the expansion procedures. We have analyzed the proliferation capacity, organ colonization, and oncogenicity of enhanced green fluorescent protein and luciferase-labeled human adipose tissue-derived mesenchymal stem cells (hAMSCs), implanted in immunocompromised mice during a prolonged time period (8 months) using a non-invasive bioluminescence imaging procedure. Our data indicates that the liver was the preferred target organ for colonization by intramuscular or intravenous implantation of hAMSCs. The implanted cells tended to maintain a steady state, population did not proliferate rapidly after implantation, and no detectable chromosomal abnormalities nor tumors formed during the 8 months of residence in the host's tissues. It would appear that hAMSCs, contrary to their murine correlatives, could be safe candidates for autologous cell therapy procedures since in our experiments they show undetectable predisposition to oncogenic transformation after cultivation in vitro and implantation in mice.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cnjsVChuw%253D%253D&md5=f77bf98021f36ea3cb8f28d6b7c487bb
  31. 31
    Arya, A. D.; Hallur, P. M.; Karkisaval, A. G.; Gudipati, A.; Rajendiran, S.; Dhavale, V.; Ramachandran, B.; Jayaprakash, A.; Gundiah, N.; Chaubey, A. Gelatin Methacrylate Hydrogels as Biomimetic Three-Dimensional Matrixes for Modeling Breast Cancer Invasion and Chemoresponse in Vitro. ACS Appl. Mater. Interfaces 2016, 8, 22005– 22017,  DOI: 10.1021/acsami.6b06309
    Google Scholar
    31
    Gelatin Methacrylate Hydrogels as Biomimetic Three-Dimensional Matrixes for Modeling Breast Cancer Invasion and Chemoresponse in Vitro
    Arya, Anuradha D.; Hallur, Pavan M.; Karkisaval, Abhijith G.; Gudipati, Aditi; Rajendiran, Satheesh; Dhavale, Vaibhav; Ramachandran, Balaji; Jayaprakash, Aravindakshan; Gundiah, Namrata; Chaubey, Aditya
    ACS Applied Materials & Interfaces (2016), 8 (34), 22005-22017CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Recent studies have shown that three-dimensional (3D) culture environments allow the study of cellular responses in a setting that more closely resembles the in vivo milieu. In this context, hydrogels have become popular scaffold options for the 3D cell culture. Because the mech. and biochem. properties of culture matrixes influence crucial cell behavior, selecting a suitable matrix for replicating in vivo cellular phenotype in vitro is essential for understanding disease progression. Gelatin methacrylate (GelMA) hydrogels have been the focus of much attention because of their inherent bioactivity, favorable hydration and diffusion properties, and ease-of-tailoring of their physicochem. characteristics. Therefore, in this study we examd. the efficacy of GelMA hydrogels as a suitable platform to model specific attributes of breast cancer. We obsd. increased invasiveness in vitro and increased tumorigenic ability in vivo in breast cancer cells cultured on GelMA hydrogels. Further, cells cultured on GelMA matrixes were more resistant to paclitaxel treatment, as shown by the results of cell-cycle anal. and gene expression. This study, therefore, validates GelMA hydrogels as inexpensive, cell-responsive 3D platforms for modeling key characteristics assocd. with breast cancer metastasis, in vitro.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht12jtr3P&md5=8cee042f009e9778fb88261d08c062b9
  32. 32
    Nguyen, A. H.; McKinney, J.; Miller, T.; Bongiorno, T.; McDevitt, T. C. Gelatin Methacrylate Microspheres for Controlled Growth Factor Release. Acta Biomater. 2015, 13, 101– 110,  DOI: 10.1016/j.actbio.2014.11.028
    Google Scholar
    32
    Gelatin methacrylate microspheres for controlled growth factor release
    Nguyen, Anh H.; McKinney, Jay; Miller, Tobias; Bongiorno, Tom; McDevitt, Todd C.
    Acta Biomaterialia (2015), 13 (), 101-110CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
    Gelatin has been commonly used as a delivery vehicle for various biomols. for tissue engineering and regenerative medicine applications due to its simple fabrication methods, inherent electrostatic binding properties, and proteolytic degradability. Compared to traditional chem. crosslinking methods, such as the use of glutaraldehyde (GA), methacrylate modification of gelatin offers an alternative method to better control the extent of hydrogel crosslinking. Here we examd. the phys. properties and growth factor delivery of gelatin methacrylate (GMA) microparticles (MPs) formulated with a wide range of different crosslinking densities (15-90%). Less methacrylated MPs had decreased elastic moduli and larger mesh sizes compared to GA MPs, with increasing methacrylation correlating to greater moduli and smaller mesh sizes. As expected, an inverse correlation between microparticle crosslinking d. and degrdn. was obsd., with the lowest crosslinked GMA MPs degrading at the fastest rate, comparable to GA MPs. Interestingly, GMA MPs at lower crosslinking densities could be loaded with up to a 10-fold higher relative amt. of growth factor than conventional GA crosslinked MPs, despite the GA MPs having an order of magnitude greater gelatin content. Moreover, a reduced GMA crosslinking d. resulted in more complete release of bone morphogenic protein 4 and basic fibroblast growth factor and accelerated release rate with collagenase treatment. These studies demonstrate that GMA MPs provide a more flexible platform for growth factor delivery by enhancing the relative binding capacity and permitting proteolytic degrdn. tunability, thereby offering a more potent controlled release system for growth factor delivery.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvF2rtb%252FP&md5=ac9c5a7f70cd67cb6d7ff23a851fccb2
  33. 33
    Li, X.; Chen, S.; Li, J.; Wang, X.; Zhang, J.; Kawazoe, N.; Chen, G. 3D Culture of Chondrocytes in Gelatin Hydrogels with Different Stiffness. Polymers 2016, 8, 269,  DOI: 10.3390/polym8080269
    Google Scholar
    33
    Culture of chondrocytes in gelatin hydrogels with different stiffness
    Li, Xiaomeng; Chen, Shangwu; Li, Jingchao; Wang, Xinlong; Zhang, Jing; Kawazoe, Naoki; Chen, Guoping
    Polymers (Basel, Switzerland) (2016), 8 (8), 269/1-269/15CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)
    Gelatin hydrogels can mimic the microenvironments of natural tissues and encapsulate cells homogeneously, which makes them attractive for cartilage tissue engineering. Both the mech. and biochem. properties of hydrogels can affect the phenotype of chondrocytes. However, the influence of each property on chondrocyte phenotype is unclear due to the difficulty in sepg. the roles of these properties. In this study, we aimed to study the influence of hydrogel stiffness on chondrocyte phenotype while excluding the role of biochem. factors, such as adhesion site d. in the hydrogels. By altering the degree of methacryloyl functionalization, gelatin hydrogels with different stiffnesses of 3.8, 17.1, and 29.9 kPa Young's modulus were prepd. from the same concn. of gelatin methacryloyl (GelMA) macromers. Bovine articular chondrocytes were encapsulated in the hydrogels and cultured for 14 days. The influence of hydrogel stiffness on the cell behaviors including cell viability, cell morphol., and maintenance of chondrogenic phenotype was evaluated. GelMA hydrogels with high stiffness (29.9 kPa) showed the best results on maintaining chondrogenic phenotype. These results will be useful for the design and prepn. of scaffolds for cartilage tissue engineering.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFKksrzE&md5=0042e1bb626ec58efdd2e283e26713ae
  34. 34
    Rajan, N.; Habermehl, J.; Coté, M.-F.; Doillon, C. J.; Mantovani, D. Preparation of Ready-to-Use, Storable and Reconstituted Type I Collagen from Rat Tail Tendon for Tissue Engineering Applications. Nat. Protoc. 2006, 1, 753– 758,  DOI: 10.1038/nprot.2006.430
    Google Scholar
    There is no corresponding record for this reference.
  35. 35
    Daly, A. C.; Critchley, S. E.; Rencsok, E. M.; Kelly, D. J. A Comparison of Different Bioinks for 3D Bioprinting of Fibrocartilage and Hyaline Cartilage. Biofabrication 2016, 8, 045002  DOI: 10.1088/1758-5090/8/4/045002
    Google Scholar
    35
    A comparison of different bioinks for 3D bioprinting of fibrocartilage and hyaline cartilage
    Daly, Andrew C.; Critchley, Susan E.; Rencsok, Emily M.; Kelly, Daniel J.
    Biofabrication (2016), 8 (4), 045002/1-045002/10CODEN: BIOFFN; ISSN:1758-5090. (IOP Publishing Ltd.)
    Cartilage is a dense connective tissue with limited self-repair capabilities. Mesenchymal stem cell (MSC) laden hydrogels are commonly used for fibrocartilage and articular cartilage tissue engineering, however they typically lack the mech. integrity for implantation into high load bearing environments. This has led to increased interested in 3D bioprinting of cell laden hydrogel bioinks reinforced with stiffer polymer fibers. The objective of this study was to compare a range of commonly used hydrogel bioinks (agarose, alginate, GelMA and BioINK) for their printing properties and capacity to support the development of either hyaline cartilage or fibrocartilage in vitro. Each hydrogel was seeded with MSCs, cultured for 28 days in the presence of TGF-β3 and then analyzed for markers indicative of differentiation towards either a fibrocartilaginous or hyaline cartilage-like phenotype. Alginate and agarose hydrogels best supported the development of hyaline-like cartilage, as evident by the development of a tissue staining predominantly for type II collagen. In contrast, GelMA and BioIN (a PEGMAbased hydrogel) supported the development of a more fibrocartilage-like tissue, as evident by the development of a tissue contg. both type I and type II collagen. GelMA demonstrated superior printability, generating structures with greater fidelity, followed by the alginate and agarose bioinks. High levels of MSC viability were obsd. in all bioinks post-printing (∼80%). Finally we demonstrate that it is possible to engineer mech. reinforced hydrogels with high cell viability by co-depositing a hydrogel bioink with polycaprolactone filaments, generating composites with bulk compressive moduli comparable to articular cartilage. This study demonstrates the importance of the choice of bioink when bioprinting different cartilaginous tissues for musculoskeletal applications.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlvFWru74%253D&md5=ed2a34e8939f4b58c6598e23ba839715
  36. 36
    Habib, A.; Sathish, V.; Mallik, S.; Khoda, B. 3D Printability of Alginate Carboxymethyl Cellulose Hydrogel. Materials 2018, 11, 454,  DOI: 10.3390/ma11030454
    Google Scholar
    36
    3D printability of alginate-carboxymethyl cellulose hydrogel
    Habib, Ahasan; Sathish, Venkatachalem; Mallik, Sanku; Khoda, Bashir
    Materials (2018), 11 (3), 454/1-454/22CODEN: MATEG9; ISSN:1996-1944. (MDPI AG)
    Three-dimensional (3D) bio-printing is a revolutionary technol. to reproduce a 3D functional living tissue scaffold in-vitro through controlled layer-by-layer deposition of biomaterials along with high precision positioning of cells. Due to its bio-compatibility, natural hydrogels are commonly considered as the scaffold material. However, the mech. integrity of a hydrogel material, esp. in 3D scaffold architecture, is an issue. In this research, a novel hybrid hydrogel, i.e., sodium alginate with CM-cellulose (CMC) is developed and systematic quant. characterization tests are conducted to validate its printability, shape fidelity and cell viability. The outcome of the rheol. and mech. test, filament collapse and fusion test demonstrate the favorable shape fidelity. Three-dimensional scaffold structures are fabricated with the pancreatic cancer cell, BxPC3 and the 86% cell viability is recorded after 23 days. This hybrid hydrogel can be a potential biomaterial in 3D bioprinting process and the outlined characterization techniques open an avenue directing reproducible printability and shape fidelity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpvFSrtrY%253D&md5=8ca9cfb6d20dbf7f28aed722125a1d5d
  37. 37
    Yin, J.; Yan, M.; Wang, Y.; Fu, J.; Suo, H. 3D Bioprinting of Low-Concentration Cell-Laden Gelatin Methacrylate (GelMA) Bioinks with a Two-Step Cross-Linking Strategy. ACS Appl. Mater. Interfaces 2018, 10, 6849– 6857,  DOI: 10.1021/acsami.7b16059
    Google Scholar
    37
    3D Bioprinting of Low-Concentration Cell-Laden Gelatin Methacrylate (GelMA) Bioinks with a Two-Step Cross-linking Strategy
    Yin, Jun; Yan, Mengling; Wang, Yancheng; Fu, Jianzhong; Suo, Hairui
    ACS Applied Materials & Interfaces (2018), 10 (8), 6849-6857CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Methacrylated gelatin (GelMA) has been widely used as a tissue-engineered scaffold material, but only low-concn. GelMA hydrogels were found to be promising cell-laden bioinks with excellent cell viability. In this work, we reported a strategy for precise deposition of 5% (w/v) cell-laden GelMA bioinks into controlled microarchitectures with high cell viability using extrusion-based three-dimensional (3D) bioprinting. By adding gelatin into GelMA bioinks, a two-step crosslinking combining the rapid and reversible thermo-crosslinking of gelatin with irreversible photo-crosslinking of GelMA was achieved. The GelMA/gelatin bioinks showed significant advantages in processability because the tunable rheol. and the rapid thermo-crosslinking of bioinks improved the shape fidelity after bioprinting. Here, the rheol., mech. properties, and swelling of GelMA/gelatin bioinks with different concn. ratios were carefully characterized to obtain the optimized bioprinting setup. We successfully printed the 5% (w/v) GelMA with 8% (w/v) gelatin into 3D structures, which had the similar geometrical resoln. as that of the structures printed by 30% (w/v) GelMA bioinks. Moreover, the cell viability of 5/8% (w/v) GelMA/gelatin bioinks was demonstrated by in vitro culture and cell printing of bone marrow stem cells (BMSCs). Larger BMSC spreading area was found on 5/8% (w/v) GelMA/gelatin scaffolds, and the BMSC viability after the printing of 5/8% (w/v) GelMA/gelatin cell-laden bioinks was more than 90%, which was very close to the viability of printing pure 5% (w/v) GelMA cell-laden bioinks. Therefore, this printing strategy of GelMA/gelatin bioinks may extensively extend the applications of GelMA hydrogels for tissue engineering, organ printing, or drug delivery.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1ylsb0%253D&md5=926ddf4272aa7923de1cf4ceb0ec5d68
  38. 38
    Schindelin, J.; Arganda-Carreras, I.; Frise, E.; Kaynig, V.; Longair, M.; Pietzsch, T.; Cardona, A. Fiji: An Open-Source Platform for Biological-Image Analysis. Nat. Methods 2012, 9, 676– 682,  DOI: 10.1038/nmeth.2019
    Google Scholar
    38
    Fiji: an open-source platform for biological-image analysis
    Schindelin, Johannes; Arganda-Carreras, Ignacio; Frise, Erwin; Kaynig, Verena; Longair, Mark; Pietzsch, Tobias; Preibisch, Stephan; Rueden, Curtis; Saalfeld, Stephan; Schmid, Benjamin; Tinevez, Jean-Yves; White, Daniel James; Hartenstein, Volker; Eliceiri, Kevin; Tomancak, Pavel; Cardona, Albert
    Nature Methods (2012), 9 (7_part1), 676-682CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
    Fiji is a distribution of the popular open-source software ImageJ focused on biol.-image anal. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biol. research communities.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVKnurbJ&md5=ad150521a33367d37a800bee853dd9db
  39. 39
    Rijal, G.; Li, W. A Versatile 3D Tissue Matrix Scaffold System for Tumor Modeling and Drug Screening. Sci. Adv. 2017, 3, 1– 17,  DOI: 10.1126/sciadv.1700764
    Google Scholar
    There is no corresponding record for this reference.
  40. 40
    Dawson, H. D. A Comparative Assessment of the Pig, Mouse and Human Genomes. In In The Minipig in Biomedical Research; CRC Press: US, 2011 pp. 323– 342,  DOI: 10.1201/b11356-28 .
    Google Scholar
    There is no corresponding record for this reference.
  41. 41
    Crapo, P. M.; Gilbert, T. W.; Badylak, S. F. An Overview of Tissue and Whole Organ Decellularization Processes. Biomaterials 2011, 32, 3233– 3243,  DOI: 10.1016/j.biomaterials.2011.01.057
    Google Scholar
    41
    An overview of tissue and whole organ decellularization processes
    Crapo, Peter M.; Gilbert, Thomas W.; Badylak, Stephen F.
    Biomaterials (2011), 32 (12), 3233-3243CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    A review. Biol. scaffold materials composed of extracellular matrix (ECM) are typically derived by processes that involve decellularization of tissues or organs. Preservation of the complex compn. and three-dimensional ultrastructure of the ECM is highly desirable but it is recognized that all methods of decellularization result in disruption of the architecture and potential loss of surface structure and compn. Phys. methods and chem. and biol. agents are used in combination to lyse cells, followed by rinsing to remove cell remnants. Effective decellularization methodol. is dictated by factors such as tissue d. and organization, geometric and biol. properties desired for the end product, and the targeted clin. application. Tissue decellularization with preservation of ECM integrity and bioactivity can be optimized by making educated decisions regarding the agents and techniques utilized during processing. An overview of decellularization methods, their effect upon resulting ECM structure and compn., and recently described perfusion techniques for whole organ decellularization techniques are presented herein.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisVOitbg%253D&md5=4759fe7e06542860b96c529c53e2806a
  42. 42
    Insua-Rodríguez, J.; Oskarsson, T. The Extracellular Matrix in Breast Cancer. Adv. Drug Delivery Rev. 2016, 97, 41– 55,  DOI: 10.1016/j.addr.2015.12.017
    Google Scholar
    42
    The extracellular matrix in breast cancer
    Insua-Rodriguez, Jacob; Oskarsson, Thordur
    Advanced Drug Delivery Reviews (2016), 97 (), 41-55CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
    The extracellular matrix (ECM) is increasingly recognized as an important regulator in breast cancer. ECM in breast cancer development features numerous changes in compn. and organization when compared to the mammary gland under homeostasis. Matrix proteins that are induced in breast cancer include fibrillar collagens, fibronectin, specific laminins and proteoglycans as well as matricellular proteins. Growing evidence suggests that many of these induced ECM proteins play a major functional role in breast cancer progression and metastasis. A no. of the induced ECM proteins have moreover been shown to be essential components of metastatic niches, promoting stem/progenitor signaling pathways and metastatic growth. ECM remodeling enzymes are also markedly increased, leading to major changes in the matrix structure and biomech. properties. Importantly, several ECM components and ECM remodeling enzymes are specifically induced in breast cancer or during tissue regeneration while healthy tissues under homeostasis express exceedingly low levels. This may indicate that ECM and ECM-assocd. functions may represent promising drug targets against breast cancer, providing important specificity that could be utilized when developing therapies.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XisleqtQ%253D%253D&md5=fe723d13450eedd105ca0b802ef0fc79
  43. 43
    Correia, A. L.; Bissell, M. J. The Tumor Microenvironment Is a Dominant Force in Multidrug Resistance. Drug Resist. Update 2012, 15, 39– 49,  DOI: 10.1016/j.drup.2012.01.006
    Google Scholar
    43
    The tumor microenvironment is a dominant force in multidrug resistance
    Correia, Ana Luisa; Bissell, Mina J.
    Drug Resistance Updates (2012), 15 (1-2), 39-49CODEN: DRUPFW; ISSN:1368-7646. (Elsevier Ltd.)
    A review. The emergence of clin. drug resistance is still one of the most challenging factors in cancer treatment effectiveness. Until more recently, the assumption has been that random genetic lesions are sufficient to explain the progression of malignancy and escape from chemotherapy. Here we propose an addnl. perspective, one in which the tumor cells despite the malignant genome could find a microenvironment either within the tumor or as a dormant cell to remain polar and blend into an organized context. Targeting this dynamic interplay could be considered a new avenue to prevent therapeutic resistance, and may even provide a promising effective cancer treatment.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xmslyns7s%253D&md5=1421f32aab73ee0ea3a4f898dd5487c1
  44. 44
    Wei, S. C.; Fattet, L.; Tsai, J. H.; Guo, Y.; Pai, V. H.; Majeski, H. E.; Chen, A. C.; Sah, R. L.; Taylor, S. S.; Engler, A. J.; Yang, J. Matrix Stiffness Drives Epithelial-Mesenchymal Transition and Tumour Metastasis through a TWIST1-G3BP2 Mechanotransduction Pathway. Nat. Cell Biol. 2015, 17, 678– 688,  DOI: 10.1038/ncb3157
    Google Scholar
    44
    Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway
    Wei, Spencer C.; Fattet, Laurent; Tsai, Jeff H.; Guo, Yurong; Pai, Vincent H.; Majeski, Hannah E.; Chen, Albert C.; Sah, Robert L.; Taylor, Susan S.; Engler, Adam J.; Yang, Jing
    Nature Cell Biology (2015), 17 (5), 678-688CODEN: NCBIFN; ISSN:1465-7392. (Nature Publishing Group)
    Matrix stiffness potently regulates cellular behavior in various biol. contexts. In breast tumors, the presence of dense clusters of collagen fibrils indicates increased matrix stiffness and correlates with poor survival. It is unclear how mech. inputs are transduced into transcriptional outputs to drive tumor progression. Here we report that TWIST1 is an essential mechanomediator that promotes epithelial-mesenchymal transition (EMT) in response to increasing matrix stiffness. High matrix stiffness promotes nuclear translocation of TWIST1 by releasing TWIST1 from its cytoplasmic binding partner G3BP2. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization and synergizes with increasing matrix stiffness to induce EMT and promote tumor invasion and metastasis. In human breast tumors, collagen fiber alignment, a marker of increasing matrix stiffness, and reduced expression of G3BP2 together predict poor survival. Our findings reveal a TWIST1-G3BP2 mechanotransduction pathway that responds to biomech. signals from the tumor microenvironment to drive EMT, invasion and metastasis.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnsVWrtLw%253D&md5=a92815227eadd28a59e440c0d3d2005d
  45. 45
    Balestrini, J. L.; Niklason, L. E. Extracellular Matrix as a Driver for Lung Regeneration. Ann. Biomed. Eng. 2015, 43, 568– 576,  DOI: 10.1007/s10439-014-1167-5
    Google Scholar
    45
    Extracellular matrix as a driver for lung regeneration
    Balestrini Jenna L; Niklason Laura E
    Annals of biomedical engineering (2015), 43 (3), 568-76 ISSN:.
    Extracellular matrix has manifold roles in tissue mechanics, guidance of cellular behavior, developmental biology, and regenerative medicine. Over the past several decades, various pre-clinical and clinical studies have shown that many connective tissues may be replaced and/or regenerated using suitable extracellular matrix scaffolds. More recently, decellularization of lung tissue has shown that gentle removal of cells can leave behind a "footprint" within the matrix that may guide cellular adhesion, differentiation and homing following cellular repopulation. Fundamental issues like understanding matrix composition and micro-mechanics remain difficult to tackle, largely because of a lack of available assays and tools for systematically characterizing intact matrix from tissues and organs. This review will critically examine the role of engineered and native extracellular matrix in tissue and lung regeneration, and provide insights into directions for future research and translation.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M3jtFCqsg%253D%253D&md5=1da133ce505afd70f8aefc712a492d1a
  46. 46
    Schwab, A.; Levato, R.; D’Este, M.; Piluso, S.; Eglin, D.; Malda, J. Printability and Shape Fidelity of Bioinks in 3D Bioprinting. Chem. Rev. 2020, 120, 11028– 11055,  DOI: 10.1021/acs.chemrev.0c00084
    Google Scholar
    46
    Printability and Shape Fidelity of Bioinks in 3D Bioprinting
    Schwab, Andrea; Levato, Riccardo; D'Este, Matteo; Piluso, Susanna; Eglin, David; Malda, Jos
    Chemical Reviews (Washington, DC, United States) (2020), 120 (19), 11028-11055CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. Three-dimensional bioprinting uses additive manufg. techniques for the automated fabrication of hierarchically organized living constructs. The building blocks are often hydrogel-based bioinks, which need to be printed into structures with high shape fidelity to the intended computer-aided design. For optimal cell performance, relatively soft and printable inks are preferred, although these undergo significant deformation during the printing process, which may impair shape fidelity. While the concept of good or poor printability seems rather intuitive, its quant. definition lacks consensus and depends on multiple rheol. and chem. parameters of the ink. This review discusses qual. and quant. methodologies to evaluate printability of bioinks for extrusion- and lithog.-based bioprinting. The physicochem. parameters influencing shape fidelity are discussed, together with their importance in establishing new models, predictive tools and printing methods that are deemed instrumental for the design of next-generation bioinks, and for reproducible comparison of their structural performance.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhs1yjt73N&md5=09c28195ff8c4992dbdba90ff583f5a7
  47. 47
    Yang, X.; Lu, Z.; Wu, H.; Li, W.; Zheng, L.; Zhao, J. Collagen-Alginate as Bioink for Three-Dimensional (3D) Cell Printing Based Cartilage Tissue Engineering. Mater. Sci. Eng., C 2018, 83, 195– 201,  DOI: 10.1016/j.msec.2017.09.002
    Google Scholar
    47
    Collagen-alginate as bioink for three-dimensional (3D) cell printing based cartilage tissue engineering
    Yang, Xingchen; Lu, Zhenhui; Wu, Huayu; Li, Wei; Zheng, Li; Zhao, Jinmin
    Materials Science & Engineering, C: Materials for Biological Applications (2018), 83 (), 195-201CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)
    Articular cartilage repair is still a huge challenge for researchers and clinicians. 3D bioprinting could be an innovative technol. for cartilage tissue engineering. In this study, we used collagen type I (COL) or agarose (AG) mixed with sodium alginate (SA) to serve as 3D bioprinting bioinks and incorporated chondrocytes to construct in vitro 3D printed cartilage tissue. Swelling ratio, mech. properties, SEM (SEM), cell viability and cytoskeleton, biochem. anal. and quant. real-time polymerase chain reaction (qRT-PCR) were performed to investigate the function of different bioinks in 3D printing cartilage tissue engineering applications. The results showed that the mech. strength was improved in both SA/COL and SA/AG groups compared to SA alone. Besides, the addn. of COL or AG has little impact on gelling behavior, demonstrating the advantage as bioinks for 3D printing. Among the three scaffolds, SA/COL could distinctly facilitated cell adhesion, accelerated cell proliferation and enhanced the expression of cartilage specific genes such as Acan, Col2al and Sox9 than the other two groups. Lower expression of Col1a1, the fibrocartilage marker, was present in SA/COL group than that in both of SA and SA/AG groups. The results indicated that SA/COL effectively suppressed dedifferentiation of chondrocytes and preserved the phenotype. In summary, 3D bioprinted SA/COL with favorable mech. strength and biol. functionality is promising in cartilage tissue engineering.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFOhsr%252FK&md5=69d2bf64c53a59d3bb065b4ef97f36d0
  48. 48
    Ying, G.; Jiang, N.; Yu, C.; Zhang, Y. S. Three-Dimensional Bioprinting of Gelatin Methacryloyl (GelMA). Bio-Des. Manuf. 2018, 1, 215– 224,  DOI: 10.1007/s42242-018-0028-8
    Google Scholar
    48
    Three-dimensional bioprinting of gelatin methacryloyl (GelMA)
    Ying, Guoliang; Jiang, Nan; Yu, Cunjiang; Zhang, Yu Shrike
    Bio-Design and Manufacturing (2018), 1 (4), 215-224CODEN: BMIAC3; ISSN:2522-8552. (Springer)
    A review. The three-dimensional (3D) bioprinting technol. has progressed tremendously over the past decade. By controlling the size, shape, and architecture of the bioprinted constructs, 3D bioprinting allows for the fabrication of tissue/organ-like constructs with strong structural-functional similarity with their in vivo counterparts at high fidelity. The bioink, a blend of biomaterials and living cells possessing both high biocompatibility and printability, is a crit. component of bioprinting. In particular, gelatin methacryloyl (GelMA) has shown its potential as a viable bioink material due to its suitable biocompatibility and readily tunable physicochem. properties. Current GelMA-based bioinks and relevant bioprinting strategies for GelMA bioprinting are briefly reviewed.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVaksbrO&md5=0f6b004663d1b554684c9a84432994bf
  49. 49
    Gao, F.; Xu, Z.; Liang, Q.; Li, H.; Peng, L.; Wu, M.; Zhao, X.; Cui, X.; Ruan, C.; Liu, W. Osteochondral Regeneration with 3D-Printed Biodegradable High-Strength Supramolecular Polymer Reinforced-Gelatin Hydrogel Scaffolds. Advanced. Science 2019, 6, 1900867,  DOI: 10.1002/advs.201900867
    Google Scholar
    49
    Osteochondral Regeneration with 3D-Printed Biodegradable High-Strength Supramolecular Polymer Reinforced-Gelatin Hydrogel Scaffolds
    Gao Fei; Xu Ziyang; Li Haofei; Liu Wenguang; Liang Qingfei; Peng Liuqi; Wu Mingming; Zhao Xiaoli; Cui Xu; Ruan Changshun
    Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2019), 6 (15), 1900867 ISSN:2198-3844.
    Biomacromolecules with poor mechanical properties cannot satisfy the stringent requirement for load-bearing as bioscaffolds. Herein, a biodegradable high-strength supramolecular polymer strengthened hydrogel composed of cleavable poly(N-acryloyl 2-glycine) (PACG) and methacrylated gelatin (GelMA) (PACG-GelMA) is successfully constructed by photo-initiated polymerization. Introducing hydrogen bond-strengthened PACG contributes to a significant increase in the mechanical strengths of gelatin hydrogel with a high tensile strength (up to 1.1 MPa), outstanding compressive strength (up to 12.4 MPa), large Young's modulus (up to 320 kPa), and high compression modulus (up to 837 kPa). In turn, the GelMA chemical crosslinking could stabilize the temporary PACG network, showing tunable biodegradability by adjusting ACG/GelMA ratios. Further, a biohybrid gradient scaffold consisting of top layer of PACG-GelMA hydrogel-Mn(2+) and bottom layer of PACG-GelMA hydrogel-bioactive glass is fabricated for repair of osteochondral defects by a 3D printing technique. In vitro biological experiments demonstrate that the biohybrid gradient hydrogel scaffold not only supports cell attachment and spreading but also enhances gene expression of chondrogenic-related and osteogenic-related differentiation of human bone marrow stem cells. Around 12 weeks after in vivo implantation, the biohybrid gradient hydrogel scaffold significantly facilitates concurrent regeneration of cartilage and subchondral bone in a rat model.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3Mvntlyluw%253D%253D&md5=23d4f3d8094e54756b27f9fd562923b3
  50. 50
    Badaoui, M.; Mimsy-Julienne, C.; Saby, C.; Van Gulick, L.; Peretti, M.; Jeannesson, P.; Morjani, H.; Ouadid-Ahidouch, H. Collagen Type 1 Promotes Survival of Human Breast Cancer Cells by Overexpressing Kv10.1 Potassium and Orai1 Calcium Channels through DDR1-Dependent Pathway. Oncotarget 2018, 9, 24653– 24671,  DOI: 10.18632/oncotarget.19065
    Google Scholar
    50
    Collagen type 1 promotes survival of human breast cancer cells by overexpressing Kv10.1 potassium and Orai1 calcium channels through DDR1-dependent pathway
    Badaoui Mehdi; Mimsy-Julienne Cloe; Peretti Marta; Ouadid-Ahidouch Halima; Saby Charles; Van Gulick Laurence; Jeannesson Pierre; Morjani Hamid
    Oncotarget (2018), 9 (37), 24653-24671 ISSN:.
    Collagen type 1 is among the tumor microenvironment (TM) factors, that regulates proliferation, survival, migration and invasion. Ion channels are key players in interactions between tumor cells and TM. Kv10.1 has been shown to play an essential role in breast cancer cell proliferation and migration by permitting Ca(2+) influx notably via Orai1. Here, we show that human breast cancer (BC) cells growing, in culture media completely devoid of the serum and seeded on collagen 1 coating, exhibited less apoptotic rate and a decrease in Bax expression when compared to those grown on plastic. The survival conferred by collagen 1 was completely abolished by removing extracellular Ca(2+) from the culture medium. In addition, Ca(2+) entry was increased in collagen 1 condition along with increased Kv10.1 and Orai1 expressions. Moreover, collagen 1 was able to increase co-localization of Kv10.1 and Orai1 on the plasma membrane. Interestingly, silencing of Kv10.1 and Orai1 reduced survival and Ca(2+)influx without any additive effect. This calcium-dependent survival is accompanied by the activation of ERK1/2, and its pharmacological inhibition completely abolished the increase in Kv10.1 and Orai1 expressions, activities, and the cell survival induced by collagen 1. Moreover, both Kv10.1 and Orai1 knockdown reduced ERK1/2 activation but not Akt. Finally, DDR1 silencing but not β1-integrin reduced the collagen induced survival, ERK1/2 phosphorylation and the expression of Kv10.1 and Orai1. Together these data show that the Kv10.1/Orai1 complex is involved in BC cell survival and this is dependent on collagen 1/DDR1 pathway. Therefore, they represent a checkpoint of tumor progression induced by the tumor microenvironment.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mbktlensw%253D%253D&md5=57be2772d343e381243a1187d467538b
  51. 51
    Chen, Z.; Wang, F.; Zhang, J.; Sun, X.; Yan, Y.; Wang, Y.; Ouyang, J.; Zhang, J.; Honore, T.; Ge, J.; Gu, Z. Study on Development of Composite Hydrogels With Tunable Structures and Properties for Tumor-on-a-Chip. Front. Bioeng. Biotechnol. 2020, 22, 611796,  DOI: 10.3389/fbioe.2020.611796
    Google Scholar
    There is no corresponding record for this reference.
  52. 52
    Berger, A. J.; Renner, C. M.; Hale, I.; Yang, X.; Ponik, S. M.; Weisman, P. S.; Masters, K. S.; Kreeger, P. K. Scaffold Stiffness Influences Breast Cancer Cell Invasion via EGFR-Linked Mena Upregulation and Matrix Remodeling. Matrix Biol. 2020, 85-86, 80– 93,  DOI: 10.1016/j.matbio.2019.07.006
    Google Scholar
    52
    Scaffold stiffness influences breast cancer cell invasion via EGFR-linked Mena upregulation and matrix remodeling
    Berger, Anthony J.; Renner, Carine M.; Hale, Isaac; Yang, Xinhai; Ponik, Suzanne M.; Weisman, Paul S.; Masters, Kristyn S.; Kreeger, Pamela K.
    Matrix Biology (2020), 85-86 (), 80-93CODEN: MTBOEC; ISSN:0945-053X. (Elsevier B.V.)
    Clin., increased breast tumor stiffness is assocd. with metastasis and poorer outcomes. Yet, in vitro studies of tumor cells in 3D scaffolds have found decreased invasion in stiffer environments. To resolve this apparent contradiction, MDA-MB-231 breast tumor spheroids were embedded in 'low' (2 kPa) and 'high' (12 kPa) stiffness 3D hydrogels comprised of methacrylated gelatin/collagen I, a material that allows for physiol.-relevant changes in stiffness while matrix d. is held const. Cells in high stiffness materials exhibited delayed invasion, but more abundant actin-enriched protrusions, compared to those in low stiffness. We find that cells in high stiffness had increased expression of Mena, an invadopodia protein assocd. with metastasis in breast cancer, as a result of EGFR and PLCγ1 activation. As invadopodia promote invasion through matrix remodeling, we examd. matrix organization and detd. that spheroids in high stiffness displayed a large fibronectin halo. Interestingly, this halo did not result from increased fibronectin prodn., but rather from Mena/α5 integrin dependent organization. In high stiffness environments, FN1 knockout inhibited invasion while addn. of exogenous cellular fibronectin lessened the invasion delay. Anal. of fibronectin isoforms demonstrated that EDA-fibronectin promoted invasion and that clin. invasive breast cancer specimens displayed elevated EDA-fibronectin. Combined, our data support a mechanism by which breast cancer cells respond to stiffness and render the environment conducive to invasion. More broadly, these findings provide important insight on the roles of matrix stiffness, compn., and organization in promoting tumor invasion.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVeltb7N&md5=62f211b1cdd3991ed931866fba8b4d23
  53. 53
    Criscitiello, C.; Esposito, A.; Curigliano, G. Tumor-Stroma Crosstalk: Targeting Stroma in Breast Cancer. Curr. Opin. Oncol. 2014, 26, 551– 555,  DOI: 10.1097/CCO.0000000000000122
    Google Scholar
    53
    Tumor-stroma crosstalk: targeting stroma in breast cancer
    Criscitiello, Carmen; Esposito, Angela; Curigliano, Giuseppe
    Current Opinion in Oncology (2014), 26 (6), 551-555CODEN: CUOOE8; ISSN:1040-8746. (Lippincott Williams & Wilkins)
    Purpose of review: Combinatorial strategies in cancer medicine will not only target cancer cell-intrinsic pathways, but also cancer cell-extrinsic cells, pathways, and mediators of the tumor microenvironment. The aim of the present review is to define the roles of the tumor microenvironment in primary and metastatic breast cancer progression. Recent findings: The cancer microenvironment is composed of nontransformed host stromal cells, such as endothelial cells, fibroblasts, various immune cells, and a complex extracellular matrix secreted by both the normal and neoplastic cells embedded in it. The stromal constituents contribute to the core and emergent hallmarks of cancer. In particular, they can boost sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metab., and evading immune destruction. Summary: The stromal cells play a role in enabling or enhancing multiple hallmark capabilities in tumor microenvironment. This is a background for therapeutic-targeting strategies aimed to abrogate the stroma's contribution. Targeting tumor-assocd. fibroblasts, macrophages, angiogenesis and enhancing immune response may represent a paradigm-shifting approach to treating human cancer in the near future.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslWitLfM&md5=88156fa1cd93e20a569ad080de2b6f4d
  54. 54
    Dias, A. S.; Almeida, C. R.; HelguerobIo, L. A.; Duarte, F. Metabolic Crosstalk in the Breast Cancer Microenvironment. Eur. J. Cancer 2019, 121, 154– 171,  DOI: 10.1016/j.ejca.2019.09.002
    Google Scholar
    54
    Metabolic crosstalk in the breast cancer microenvironment
    Dias, Ana S.; Almeida, Catarina R.; Helguero, Luisa A.; Duarte, Iola F.
    European Journal of Cancer (2019), 121 (), 154-171CODEN: EJCAEL; ISSN:0959-8049. (Elsevier Ltd.)
    A review. During tumorigenesis, breast tumor cells undergo metabolic reprogramming, which generally includes enhanced glycolysis, tricarboxylic acid cycle activity, glutaminolysis and fatty acid biosynthesis. However, the extension and functional importance of these metabolic alterations may diverge not only according to breast cancer subtypes, but also depending on the interaction of cancer cells with the complex surrounding microenvironment. This microenvironment comprises a variety of non-cancerous cells, such as immune cells (e.g. macrophages, lymphocytes, natural killer cells), fibroblasts, adipocytes and endothelial cells, together with extracellular matrix components and sol. factors, which influence cancer progression and are predictive of clin. outcome. The continuous interaction between cancer and stromal cells results in metabolic competition and symbiosis, with oncogenic-driven metabolic reprogramming of cancer cells shaping the metab. of neighboring cells and vice versa. This review addresses current knowledge on this metabolic crosstalk within the breast tumor microenvironment (TME). Improved understanding of how metab. in the TME modulates cancer development and evasion of tumor-suppressive mechanisms may provide clues for novel anticancer therapeutics directed to metabolic targets.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVKitb7N&md5=83828aafba58a4a53877a34b218127d8
  55. 55
    Raub, C.; Putnam, A.; Tromberg, B.; George, S. Predicting Bulk Mechanical Properties of Cellularized Collagen Gels Using Multiphoton Microscopy. Acta Biomater. 2010, 6, 4657– 4665,  DOI: 10.1016/j.actbio.2010.07.004
    Google Scholar
    55
    Predicting bulk mechanical properties of cellularized collagen gels using multiphoton microscopy
    Raub, C. B.; Putnam, A. J.; Tromberg, B. J.; George, S. C.
    Acta Biomaterialia (2010), 6 (12), 4657-4665CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
    Cellularized collagen gels are a common model in tissue engineering, but the relationship between the microstructure and bulk mech. properties is only partially understood. Multiphoton microscopy (MPM) is an ideal non-invasive tool for examg. collagen microstructure, cellularity and crosslink content in these gels. In order to identify robust image parameters that characterize microstructural determinants of the bulk elastic modulus, we performed serial MPM and mech. tests on acellular and cellularized (normal human lung fibroblasts) collagen hydrogels, before and after glutaraldehyde crosslinking. Following gel contraction over 16 days, cellularized collagen gel content approached that of native connective tissues (∼200 mg ml-1). Young's modulus (E) measurements from acellular collagen gels (range 0.5-12 kPa) exhibited a power-law concn. dependence (range 3-9 mg ml-1) with exponents from 2.1 to 2.2, similar to other semiflexible biopolymer networks such as fibrin and actin. In contrast, cellularized collagen gel stiffness (range 0.5-27 kPa) produced concn.-dependent exponents of 0.7 uncrosslinked and 1.1 crosslinked (range ∼5-200 mg ml-1). The variation in E of cellularized collagen hydrogels can be explained by a power-law dependence on robust image parameters: either the second harmonic generation (SHG) and two-photon fluorescence (TPF) (matrix component) skewness (R 2 = 0.75, exponents of -1.0 and -0.6, resp.); or alternatively the SHG and TPF (matrix component) speckle contrast (R 2 = 0.83, exponents of -0.7 and -1.8, resp.). Image parameters based on the cellular component of TPF signal did not improve the fits. The concn. dependence of E suggests enhanced stress relaxation in cellularized vs. acellular gels. SHG and TPF image skewness and speckle contrast from cellularized collagen gels can predict E by capturing mech. relevant information on collagen fiber, cell and crosslink d.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht12ktr7L&md5=c857761720d110525d54d207d40cf579
  56. 56
    Singhai, R.; Patil, V. W.; Jaiswal, S. R.; Patil, S. D.; Tayade, M. B.; Patil, A. V. E-Cadherin as a Diagnostic Biomarker in Breast Cancer. N. Am. J. Med. Sci. 2011, 3, 227– 233,  DOI: 10.4297/najms.2011.3227
    Google Scholar
    56
    E-Cadherin as a diagnostic biomarker in breast cancer
    Singhai Rajeev; Patil Vinayak W; Jaiswal Sanjog R; Patil Shital D; Tayade Mukund B; Patil Amit V
    North American journal of medical sciences (2011), 3 (5), 227-33 ISSN:.
    BACKGROUND: E-cadherin is expressed in most normal epithelial tissues. Selective loss of E-cadherin can cause dedifferentiation and invasiveness in human carcinomas, leading E-cadherin to be classified as a tumor suppressor. Loss of E-cadherin has been demonstrated in invasive lobular carcinoma of the breast, but the relationship between E-cadherin expression and breast cancer histopathology and prognosis is less clear. AIM: Our objective was to assess loss of E-cadherin as a diagnostic breast cancer biomarker and as an aid to the sub-classification of invasive breast cancer. We also correlated the loss of expression of E-cadherin with various clinical and pathologic prognostic factors. MATERIAL AND METHODS: Breast cancer specimens after modified radical mastectomy were obtained from women who underwent surgery at Grant Medical College and Sir J.J Group of Hospitals, Mumbai, India between May 2007 and October 2010. We stained 276 breast cancers specimens with monoclonal antibodies to E-cadherin. The breast cancers were classified by histopathological type. RESULTS: A statistical correlation of E-cadherin loss with a positive diagnosis of invasive lobular carcinoma was found, but there was no correlation with any prognostic tumor variables. A negative E-cadherin stain was a sensitive and specific biomarker to confirm the diagnosis of invasive lobular carcinoma (specificity 97.7%; negative predictive value 96.8%; sensitivity 88.1%; and positive predictive value 91.2%). Positive E-cadherin expression was also associated with tubulolobular carcinomas. CONCLUSIONS: E-cadherin immunohistochemistry is helpful in classifying breast cancer cases with indeterminate histopathologic features. E-cadherin loss is uncommon in non-lobular carcinomas but shows no correlation to currently established prognostic variables.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38ngsVOksQ%253D%253D&md5=5a1ff41f511de33f5f741ba0d75d8a79
  57. 57
    Liu, J.; Shen, J.; Wu, H.; Li, X.; Wen, X.; Du, C.; Zhang, G. Collagen 1A1 (COL1A1) Promotes Metastasis of Breast Cancer and Is a Potential Therapeutic Target. Discov. Med. 2018, 25, 211– 223
    Google Scholar
    57
    Collagen 1A1 (COL1A1) promotes metastasis of breast cancer and is a potential therapeutic target
    Liu Jing; Shen Jia-Xin; Li Xiao-Li; Wen Xiao-Fen; Du Cai-Wen; Zhang Guo-Jun; Shen Jia-Xin; Zhang Guo-Jun; Wu Hua-Tao; Li Xiao-Li; Wen Xiao-Fen; Du Cai-Wen
    Discovery medicine (2018), 25 (139), 211-223 ISSN:.
    PURPOSE: Extracellular matrix (ECM) is an important component of tumor microenvironment and plays critical roles in cancer development and metastasis, in which collagen is the major structural protein. Collagen type I alpha 1 (COL1A1) is reportedly associated with the development of several human diseases. However, the functions and mechanisms of cellular expression of COL1A1 in breast cancer remain unknown. The purpose of this study is to investigate the cellular expression of COL1A1 in breast cancer cells and patients, and its role in the development and metastasis of breast cancer. METHODS: The immunofluorescence staining was used to identify the cellular location of COL1A1 in breast cancer cell lines. Real-time PCR was applied to measuring the mRNA levels of COL1A1 and genes of interest. Wound healing and transwell assay were performed to evaluate the effect of COL1A1 on metastasis of breast cancer cells. 97 patients with breast cancer were recruited in this study for evaluating the correlation of COL1A1 with survival and clinicopathological parameters. RESULTS: COL1A1 was expressed in all examined breast cancer cells. Knockdown of COL1A1 inhibited metastasis of breast cancer cells, with a low-level of CXCR4, independent of the epithelial-mesenchymal transition (EMT) process. In patients with breast cancer, cellular expression of COL1A1 was associated with ER/PR expression and metastasis status. The increased COL1A1 level was associated with poor survival, especially in patients with ER+ breast cancer. Patients with a high-level of COL1A1 showed better cisplatin-based chemotherapy response. CONCLUSION: Cellular expression of COL1A1 could promote breast cancer metastasis. COL1A1 is a new prognostic biomarker and a potential therapeutic target for breast cancer, especially in ER+ patients.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MbnslWjsw%253D%253D&md5=5d0707b0ab32cbac3d4c8b71c90c8c49
  58. 58
    Xu, S.; Xu, H.; Wang, W.; Li, S.; Li, H.; Li, T.; Zhang, W.; Yu, X.; Liu, L. The Role of Collagen in Cancer: From Bench to Bedside. J. Trans. Med. 2019, 17, 309,  DOI: 10.1186/s12967-019-2058-1
    Google Scholar
    There is no corresponding record for this reference.
  59. 59
    Barcus, C.; O’Leary, K.; Brockman, J.; Rugowski, D.; Liu, Y.; Garcia, N.; Yu, M.; Keely, P.; Eliceiri, K.; Schuler, L. Elevated Collagen-I Augments Tumor Progressive Signals, Intravasation and Metastasis of Prolactin-Induced Estrogen Receptor Alpha Positive Mammary Tumor Cells. Breast Cancer Res. 2017, 19, 9,  DOI: 10.1186/s13058-017-0801-1
    Google Scholar
    59
    Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells
    Barcus, Craig E.; O'Leary, Kathleen A.; Brockman, Jennifer L.; Rugowski, Debra E.; Liu, Yuming; Garcia, Nancy; Yu, Menggang; Keely, Patricia J.; Eliceiri, Kevin W.; Schuler, Linda A.
    Breast Cancer Research (2017), 19 (), 9/1-9/13CODEN: BRCRFS; ISSN:1465-542X. (BioMed Central Ltd.)
    Background: The development and progression of estrogen receptor alpha pos. (ERα+) breast cancer has been linked epidemiol. to prolactin. However, activation of the canonical mediator of prolactin, STAT5, is assocd. with more differentiated cancers and better prognoses. We have reported that d./stiffness of the extracellular matrix potently modulates the repertoire of prolactin signals in human ERα + breast cancer cells in vitro: stiff matrixes shift the balance from the Janus kinase (JAK)2/STAT5 cascade toward pro-tumor progressive extracellular regulated kinase (ERK)1/2 signals, driving invasion. However, the consequences for behavior of ERα + cancers in vivo are not known. Methods: In order to investigate the importance of matrix d./stiffness in progression of ERα + cancers, we examd. tumor development and progression following orthotopic transplantation of two clonal green fluorescent protein (GFP) + ERα + tumor cell lines derived from prolactin-induced tumors to 8-wk-old wild-type FVB/N (WT) or collagen-dense (col1a1tm1Jae/+) female mice. The latter express a mutant non-cleavable allele of collagen 1a1 "knocked-in" to the col1a1 gene locus, permitting COL1A1 accumulation. We evaluated the effect of the collagen environment on tumor progression by examg. circulating tumor cells and lung metastases, activated signaling pathways by immunohistochem. anal. and immunoblotting, and collagen structure by second harmonic generation microscopy. Results: ERα + primary tumors did not differ in growth rate, histol. type, ERα, or prolactin receptor (PRLR) expression between col1a1tm1Jae/+ and WT recipients. However, the col1a1tm1Jae/+ environment significantly increased circulating tumor cells and the no. and size of lung metastases at end stage. Tumors in col1a1tm1Jae/+ recipients displayed reduced STAT5 activation, and higher phosphorylation of ERK1/2 and AKT. Moreover, intratumoral collagen fibers in col1a1tm1Jae/+ recipients were aligned with tumor projections into the adjacent fat pad, perpendicular to the bulk of the tumor, in contrast to the collagen fibers wrapped around the more uniformly expansive tumors in WT recipients. Conclusions: A collagen-dense extracellular matrix can potently interact with hormonal signals to drive metastasis of ERα +breast cancers.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXivVWmtLg%253D&md5=a9f5609ba1df744ea7180ee276ab9254
  60. 60
    Cheng, Q.; Chang, J.; Geradts, J.; Neckers, L.; Haystead, T.; Spector, N.; Lyerly, H. Amplification and High-Level Expression of Heat Shock Protein 90 Marks Aggressive Phenotypes of Human Epidermal Growth Factor Receptor 2 Negative Breast Cancer. Breast Cancer Res. 2012, 14, R62,  DOI: 10.1186/bcr3168
    Google Scholar
    60
    Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer
    Cheng, Qing; Chang, Jeffrey T.; Geradts, Joseph; Neckers, Leonard M.; Haystead, Timothy; Spector, Neil L.; Lyerly, H. Kim
    Breast Cancer Research (2012), 14 (), R62CODEN: BRCRFS; ISSN:1465-542X. (BioMed Central Ltd.)
    Introduction: Although human epidermal growth factor receptor 2 (HER2) pos. or estrogen receptor (ER) pos. breast cancers are treated with clin. validated anti-HER2 or anti-estrogen therapies, intrinsic and acquired resistance to these therapies appears in a substantial proportion of breast cancer patients and new therapies are needed. Identification of addnl. mol. factors, esp. those characterized by aggressive behavior and poor prognosis, could prioritize interventional opportunities to improve the diagnosis and treatment of breast cancer. Methods: We compiled a collection of 4,010 breast tumor gene expression data derived from 23 datasets that have been posted on the National Center for Biotechnol. Information (NCBI) Gene Expression Omnibus (GEO) database. We performed a genome-scale survival anal. using Cox-regression survival analyses, and validated using Kaplan-Meier Ests. survival and Cox Proportional-Hazards Regression survival analyses. We conducted a genome-scale anal. of chromosome alteration using 481 breast cancer samples obtained from The Cancer Genome Atlas (TCGA), from which combined expression and copy no. data were available. We assessed the correlation between somatic copy no. alterations and gene expression using anal. of variance (ANOVA). Results: Increased expression of each of the heat shock protein (HSP) 90 isoforms, as well as HSP transcriptional factor 1 (HSF1), was correlated with poor prognosis in different subtypes of breast cancer. High-level expression of HSP90AA1 and HSP90AB1, two cytoplasmic HSP90 isoforms, was driven by chromosome coding region amplifications and were independent factors that led to death from breast cancer among patients with triple-neg. (TNBC) and HER2-/ER+ subtypes, resp. Furthermore, amplification of HSF1 was correlated with higher HSP90AA1 and HSP90AB1 mRNA expression among the breast cancer cells without amplifications of these two genes. A collection of HSP90AA1, HSP90AB1 and HSF1 amplifications defined a subpopulation of breast cancer with up-regulated HSP90 gene expression, and up-regulated HSP90 expression independently elevated the risk of recurrence of TNBC and poor prognosis of HER2-/ER+ breast cancer. Conclusions: Up-regulated HSP90 mRNA expression represents a confluence of genomic vulnerability that renders HER2 neg. breast cancers more aggressive, resulting in poor prognosis. Targeting breast cancer with up-regulated HSP90 may potentially improve the effectiveness of clin. intervention in this disease.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotVyrtrg%253D&md5=4e2c4ac0e924277c07af327f81a9ef31
  61. 61
    Hong, D.; Banerji, U.; Tavana, B.; George, G.; Aaron, J.; Kurzrock, R. Targeting the Molecular Chaperone Heat Shock Protein 90 (HSP90): Lessons Learned and Future Directions. Cancer Treat. Rev. 2013, 39, 375– 387,  DOI: 10.1016/j.ctrv.2012.10.001
    Google Scholar
    61
    Targeting the molecular chaperone heat shock protein 90 (HSP90): Lessons learned and future directions
    Hong, David S.; Banerji, Udai; Tavana, Bahareh; George, Goldy C.; Aaron, Joann; Kurzrock, Razelle
    Cancer Treatment Reviews (2013), 39 (4), 375-387CODEN: CTREDJ; ISSN:0305-7372. (Elsevier Ltd.)
    A review. Due to the crit. role of heat shock protein 90 (HSP90) in regulating the stability, activity and intracellular sorting of its client proteins involved in multiple oncogenic processes, HSP90 inhibitors are promising therapeutic agents for cancer treatment. In cancer cells, HSP90 client proteins play a major role in oncogenic signal transduction (i.e., mutant epidermal growth factor receptor), angiogenesis (i.e., vascular endothelial growth factor), anti-apoptosis (i.e., AKT), and metastasis (i.e., matrix metalloproteinase 2 and CD91), processes central to maintaining the cancer phenotype. Thus, HSP90 has emerged as a viable target for antitumor drug development, and several HSP90 inhibitors have transitioned to clin. trials. HSP90 inhibitors include geldanamycin and its derivs. (i.e., tanespimycin, alvespimycin, IPI-504), synthetic and small mol. inhibitors (i.e., AUY922, AT13387, STA9090, MPC3100), other inhibitors of HSP90 and its isoforms (i.e., shepherdin and 5'-N-ethylcarboxamideadenosine). With more than 200 "client" proteins, many of them meta-stable and oncogenic, HSP90 inhibition can affect an array of tumors. Here we review the mol. structure of HSP90, structural features of HSP90 inhibition, pharmacodynamic effects and tumor responses in clin. trials of HSP90 inhibitors. We also discuss lessons learned from completed clin. trials of HSP90 inhibitors, and future directions for these promising therapeutic agents.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslGjsLvM&md5=485735cfb38cb7113648b54e2ec99426
  62. 62
    Parkash, J. A. K.; Asotra, K. Calcium Wave Signaling in Cancer Cells. Life Sci. 2010, 87, 587– 595,  DOI: 10.1016/j.lfs.2010.09.013
    Google Scholar
    62
    Calcium wave signaling in cancer cells
    Parkash, Jai; Asotra, Kamlesh
    Life Sciences (2010), 87 (19-22), 587-595CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)
    A review. Ca2+ functions as an important signaling messenger right from beginning of life to the final moments of the end of life. Ca2+ is needed at several steps of the cell cycle such as early G1, at the G1/S, and G2/M transitions. The Ca2+ signals in the form of time-dependent changes in intracellular Ca2+ concns., [Ca2+]i, are presented as brief spikes organized into regenerative Ca2+ waves. Ca2+-mediated signaling pathways have also been shown to play important roles in carcinogenesis such as transformation of normal cells to cancerous cells, tumor formation and growth, invasion, angiogenesis and metastasis. Since the global Ca2+ oscillations arise from Ca2+ waves initiated locally, it results in stochastic oscillations because although each cell has many IP3Rs and Ca2+ ions, the law of large nos. does not apply to the initiating event which is restricted to very few IP3Rs due to steep Ca2+ concn. gradients. The specific Ca2+ signaling information is likely to be encoded in a calcium code as the amplitude, duration, frequency, waveform or timing of Ca2+ oscillations and decoded again at a later stage. Since Ca2+ channels or pumps involved in regulating Ca2+ signaling pathways show altered expression in cancer, one can target these Ca2+ channels and pumps as therapeutic options to decrease proliferation of cancer cells and to promote their apoptosis. These studies can provide novel insights into alterations in Ca2+ wave patterns in carcinogenesis and lead to the development of newer technologies based on Ca2+ waves for the diagnosis and therapy of cancer.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlyrsL7N&md5=af1b4b6b150398756fd56267e884e8d3
  63. 63
    Ohkubo, T.; Yamazaki, J. T-Type Voltage-Activated Calcium Channel Cav3.1, but Not Cav3.2, Is Involved in the Inhibition of Proliferation and Apoptosis in MCF-7 Human Breast Cancer Cells. Int. J. Oncol. 2012, 41, 267– 275,  DOI: 10.3892/ijo.2012.1422
    Google Scholar
    63
    T-type voltage-activated calcium channel Cav3.1, but not Cav3.2, is involved in the inhibition of proliferation and apoptosis in MCF-7 human breast cancer cells
    Ohkubo, Tsuyako; Yamazaki, Jun
    International Journal of Oncology (2012), 41 (1), 267-275CODEN: IJONES; ISSN:1019-6439. (International Journal of Oncology)
    T-type voltage-gated Ca2+ channels have unique electrophysiol. properties, suitable for generating Ca2+ oscillations and waves and thus controlling the proliferation of various tumor cells. In the present study, we investigated the role of Cav3.1, a candidate tumor suppressor gene, in neoplastic processes, and compared the differences between Cav3.1 with Cav3.2 channels. While the overexpression of a full-length Cav3.1 clone suppressed cell proliferation, the knockdown of the Cav3.1 gene by siRNA, or treatment with ProTx-I, a relatively selective inhibitor for Cav3.1, promoted the cell proliferation of MCF-7 cells (a human breast adenocarcinoma cell line). Although Cav3.1 and Cav3.2 channels possess comparable biophys. properties and are often co-expressed in various tissues, gene knockdown or the overexpression of Cav3.2 channels exhibited no effect on cell proliferation. Using immunocytochem. co-staining, the Cav3.1 channels were specifically visualized in the plasma membranes of apoptotic cells, identified by Annexin V and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assays and nuclear condensation. On the contrary, Cav3.2 channels were expressed at the membrane of large portions of cells, with no likely relation to Cav3.1 expression or apoptosis. An apoptosis assay revealed that the overexpression of the Cav3.1 clone caused an increase in the no. of apoptotic cells. Furthermore, Cav3.1 knockdown blocked cyclophosphamide-induced apoptosis. These results suggest that Cav3.1 channels may contribute to the repression of tumor proliferation and the promotion of apoptosis mediated via Cav3.1-specific Ca2+ influx.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xptl2lu70%253D&md5=41e795de3daa07a10623522b410a61fa
  64. 64
    Wang, C.; Lai, M. D.; Phan, N. N.; Sun, Z.; Lin, Y. C. Meta-Analysis of Public Microarray Datasets Reveals Voltage-Gated Calcium Gene Signatures in Clinical Cancer Patients. PLoS ONE 10 2015, 10, e0125766  DOI: 10.1371/journal.pone.0125766
    Google Scholar
    There is no corresponding record for this reference.
  65. 65
    Comes, N.; Serrano-Albarrás, A.; Capera, J.; Serrano-Novillo, C.; Condom, E.; Ramón y Cajal, S.; Ferreres, J.; Felipe, A. Involvement of Potassium Channels in the Progression of Cancer to a More Malignant Phenotype. Biochim. Biophys. Acta, Biomembr. 2015, 1848, 2477– 2492,  DOI: 10.1016/j.bbamem.2014.12.008
    Google Scholar
    65
    Involvement of potassium channels in the progression of cancer to a more malignant phenotype
    Comes, Nuria; Serrano-Albarras, Antonio; Capera, Jesusa; Serrano-Novillo, Clara; Condom, Enric; Ramon y Cajal, Santiago; Ferreres, Joan Carles; Felipe, Antonio
    Biochimica et Biophysica Acta, Biomembranes (2015), 1848 (10_Part_B), 2477-2492CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
    A review. Potassium channels are a diverse group of pore-forming transmembrane proteins that selectively facilitate potassium flow through an electrochem. gradient. They participate in the control of the membrane potential and cell excitability in addn. to different cell functions such as cell vol. regulation, proliferation, cell migration, angiogenesis as well as apoptosis. Because these physiol. processes are essential for the correct cell function, K + channels have been assocd. with a growing no. of diseases including cancer. In fact, different K + channel families such as the voltage-gated K + channels, the ether ´a-go-go K + channels, the two pore domain K + channels and the Ca2+-activated K + channels have been assocd. to tumor biol. Potassium channels have a role in neoplastic cell-cycle progression and their expression has been found abnormal in many types of tumors and cancer cells. In addn., the expression and activity of specific K + channels have shown a significant correlation with the tumor malignancy grade. The aim of this overview is to summarize published data on K + channels that exhibit oncogenic properties and have been linked to a more malignant cancer phenotype. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVansw%253D%253D&md5=ff2a87329344104e1fd1e21e074abe13
  66. 66
    Brevet, M.; Ahidouch, A.; Sevestre, H.; Merviel, P.; el Hiani, Y.; Micheline Robbe, M.; Ouadid-Ahidouch, H. Expression of K+ Channels in Normal and Cancerous Human Breast. Histol. Histopathol. 2008, 23, 965– 972,  DOI: 10.14670/HH-23.965
    Google Scholar
    66
    Expression of K+ channels in normal and cancerous human breast
    Brevet Marie; Ahidouch Ahmed; Sevestre Henri; Merviel Philippe; El Hiani Yassine; Robbe Micheline; Ouadid-Ahidouch Halima
    Histology and histopathology (2008), 23 (8), 965-72 ISSN:.
    Potassium (K+) channels contribute to the regulation of cell proliferation and apoptosis and are also involved in tumor generation and malignant growth. Using immunohistochemical analysis, we investigated the expression of four K+ channels GIRK1 (G-Protein Inwardly Rectifying Potassium Channel 1), Ca2+-activated K channel (K Ca 1.1), voltage activated K+ channels (KV 1.1 and KV 1.3) and of the anti-apoptotic protein Bcl2 in normal and cancerous breast tissues and compared their expression with clinicopathological data. GIRK1 was overexpressed in carcinomatous tissues. In contrast, K V 1.1 and K V 1.3 were less expressed in cancerous tissue. The expression of Bcl-2 was similar in both tissues. As to the clinicopathological data, a correlation between K Ca 1.1 channel and estrogen receptor (ER) expression was observed. GIRK1 was overexpressed in breast carcinoma suggesting its involvement in proliferation and oncogenesis and its possible use as a putative pharmaceutical target. The correlation between K Ca 1.1 channel and ER suggests the involvement of this channel in proliferation. The loss of expression of the two channels K V 1.1 and K V 1.3 may correspond to their role in apoptosis.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1czjsFSjug%253D%253D&md5=4cdc13d7c67685d9574a5e9da303ec1a
  67. 67
    Hassan, M. S. U.; Ansari, J.; Spooner, D.; Hussain, S. A. Chemotherapy for Breast Cancer (Review). Oncol. Rep. 2010, 24, 1121– 1131,  DOI: 10.3892/or_00000963
    Google Scholar
    67
    Chemotherapy for breast cancer (review)
    Hassan, M. S. U.; Ansari, J.; Spooner, D.; Hussain, S. A.
    Oncology Reports (2010), 24 (5), 1121-1131CODEN: OCRPEW; ISSN:1021-335X. (Oncology Reports)
    A review. The use of cytotoxic chemotherapy in both advanced and early stage breast cancer has made significant progress in the last 10 years with several landmark studies identifying clear survival benefits for newer therapies. In spite of these developments the optimal approach for any specific patient can not be detd. from a literature review or decision-making algorithm alone. Treatment choices are predominantly based on practice detd. by individual or collective experience and the historical development of treatment within a locality. The improvement in the understanding of the mol. biol. basis of breast cancer provides possible targets for novel therapies. Personalised therapies for breast cancer based on the mol. characteristics of the tumor could improve the risk:benefit ratio of current therapies. Increased improvements in the use of a panel of biomarkers will thus not only move us towards tailored therapies but will also spare a group of patients that do not benefit from adjuvant chemotherapy. At the same time a better understanding of tumor biol. will also streamline the development of new regimens for those who are unlikely to benefit from existing drugs. This review will focus on the evidence for the use of chemotherapy and highlight advances in chemotherapy treatments with the addn. of new and novel drugs marching into our clinics as std. treatments based on evidence from clin. trials and from a better understanding of tumor biol. that has transformed the outlook in breast cancer in both the adjuvant and metastatic setting.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVegsbrM&md5=70ca40ffc1ef655e3b64c58b63a2e602
  68. 68
    Muranen, T.; Selfors, L. M.; Worster, D. T.; Iwanicki, M. P.; Song, L.; Morales, F. C.; Gao, S.; Mills, G. B.; Brugge, J. S. Inhibition of PI3K/MTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells. Cancer Cell 2012, 21, 227– 239,  DOI: 10.1016/j.ccr.2011.12.024
    Google Scholar
    68
    Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells
    Muranen, Taru; Selfors, Laura M.; Worster, Devin T.; Iwanicki, Marcin P.; Song, Loling; Morales, Fabiana C.; Gao, Sizhen; Mills, Gordon B.; Brugge, Joan S.
    Cancer Cell (2012), 21 (2), 227-239CODEN: CCAECI; ISSN:1535-6108. (Elsevier Inc.)
    The PI3K/mTOR-pathway is the most commonly dysregulated pathway in epithelial cancers and represents an important target for cancer therapeutics. Here, we show that dual inhibition of PI3K/mTOR in ovarian cancer-spheroids leads to death of inner matrix-deprived cells, whereas matrix-attached cells are resistant. This matrix-assocd. resistance is mediated by drug-induced upregulation of cellular survival programs that involve both FOXO-regulated transcription and cap-independent translation. Inhibition of any one of several upregulated proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to PI3K/mTOR inhibition. These results demonstrate that acute adaptive responses to PI3K/mTOR inhibition in matrix-attached cells resemble well-conserved stress responses to nutrient and growth factor deprivation. Bypass of this resistance mechanism through rational design of drug combinations could significantly enhance PI3K-targeted drug efficacy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xit12jt70%253D&md5=78ff56774f7e2588a1c8ffbce49ad8a2
  69. 69
    Campiglio, M.; Somenzi, G.; Olgiati, C.; Beretta, G.; Balsari, A.; Zaffaroni, N.; Valagussa, P.; Ménard, S. Role of Proliferation in HER2 Status Predicted Response to Doxorubicin. Int. J. Cancer 2003, 105, 568– 573,  DOI: 10.1002/ijc.11113
    Google Scholar
    69
    Role of proliferation in HER2 status predicted response to doxorubicin
    Campiglio, Manuela; Somenzi, Giulia; Olgiati, Clelia; Beretta, Giovanni; Balsari, Andrea; Zaffaroni, Nadia; Valagussa, Pinuccia; Menard, Sylvie
    International Journal of Cancer (2003), 105 (4), 568-573CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)
    The role of HER2 in predicting response to doxorubicin (DXR) therapy in breast cancer was evaluated in vivo in a series of breast carcinomas from 220 patients with tumors larger than 2.5 cm and treated with 3 cycles of DXR (75 mg/m2) as neoadjuvant chemotherapy. Patients with HER2-pos. tumors were more frequently responsive to DXR treatment compared with HER2-neg. patients (p = 0.05; Mantel-Haenszel X2 = 0.009). Progesterone receptor (PgR) negativity, but not mutated p53, was also assocd. with response to DXR (p = 0.05; Mantel-Haenszel X2 = 0.004). Further anal. of those correlations using breast carcinoma cell lines characterized for different biol. parameters revealed a trend between HER2 positivity/PgR negativity and greater DXR sensitivity, but the strongest direct correlation was found between the proliferation rate and sensitivity to DXR (r = 0.82, p = 0.00009). Neither p53 nor the DXR target mol. topoisomerase-II-α was significantly assocd. with in vitro sensitivity to DXR. Thus, whereas data showed that the major biol. parameter assocd. with in vitro response to DXR in breast cancer cells appears to be the tumor proliferation rate, HER2 expression together with PgR negativity may serve as the counterpart of the proliferation marker in predicting the in vivo response to DXR.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktlOqsbY%253D&md5=2dcdfcda5e2e08428584f20521b2ab24
  70. 70
    Yu, D.; Huynh, T.; Truong, A.; Haber, M.; Norris, M. Chapter Five - ABC Transporters and Neuroblastoma. In Advances in Cancer Research; Schuetz, J.; Ishikawa, T., Eds.; Academic Press, 2015, Vol. 125, p 139– 170.
    Google Scholar
    There is no corresponding record for this reference.
  71. 71
    Calcagno, A.; Fostel, J.; To, K.; Salcido, C.; Martin, S.; Chewning, K.; Wu, C.; Varticovski, L.; Bates, S.; Caplen, N.; Ambudkar, S. Single-Step Doxorubicin-Selected Cancer Cells Overexpress the ABCG2 Drug Transporter through Epigenetic Changes. Br. J. Cancer 2008, 98, 1515– 1524,  DOI: 10.1038/sj.bjc.6604334
    Google Scholar
    71
    Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes
    Calcagno, A. M.; Fostel, J. M.; To, K. K. W.; Salcido, C. D.; Martin, S. E.; Chewning, K. J.; Wu, C.-P.; Varticovski, L.; Bates, S. E.; Caplen, N. J.; Ambudkar, S. V.
    British Journal of Cancer (2008), 98 (9), 1515-1524CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)
    Understanding the mechanisms of multidrug resistance (MDR) could improve clin. drug efficacy. Multidrug resistance is assocd. with ATP binding cassette (ABC) transporters, but the factors that regulate their expression at clin. relevant drug concns. are poorly understood. We report that a single-step selection with low doses of anti-cancer agents, similar to concns. reported in vivo, induces MDR that is mediated exclusively by ABCG2. We selected breast, ovarian and colon cancer cells (MCF-7, IGROV-1 and S-1) after exposure to 14 or 21 n doxorubicin for only 10 days. We found that these cells overexpress ABCG2 at the mRNA and protein levels. RNA interference anal. confirmed that ABCG2 confers drug resistance. Furthermore, ABCG2 upregulation was facilitated by histone hyperacetylation due to weaker histone deacetylase 1-promoter assocn., indicating that these epigenetic changes elicit changes in ABCG2 gene expression. These studies indicate that the MDR phenotype arises following low-dose, single-step exposure to doxorubicin, and further suggest that ABCG2 may mediate early stages of MDR development. This is the first report to our knowledge of single-step, low-dose selection leading to overexpression of ABCG2 by epigenetic changes in multiple cancer cell lines.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXltl2it7g%253D&md5=c83033d75c6cf30c8e40f13155307b3e

Cited By

ARTICLE SECTIONS
Jump To

This article is cited by 13 publications.

  1. Dongliang Chen, Yonggang Li, Xiaoqiu Liu, Yali Zhao, Tianying Ren, Jing Guo, Dawei Yang, Shenghai Li. Multi-DNA-Modified Double-Network Hydrogel with Customized Microstructure: A Novel System for Living Circulating Tumor Cells Capture and Real-Time Detection. ACS Applied Materials & Interfaces 2024, 16 (7) , 8301-8309. https://doi.org/10.1021/acsami.3c15432
  2. Fang Zhang, Huimin Gao, Xuefeng Jiang, Fang Yang, Jun Zhang, Saijie Song, Jian Shen. Biomedical Application of Decellularized Scaffolds. ACS Applied Bio Materials 2023, 6 (12) , 5145-5168. https://doi.org/10.1021/acsabm.3c00778
  3. Barbara Blanco-Fernandez, Arturo Ibañez-Fonseca, Doriana Orbanic, Celia Ximenes-Carballo, Soledad Perez-Amodio, Jose Carlos Rodríguez-Cabello, Elisabeth Engel. Elastin-like Recombinamer Hydrogels as Platforms for Breast Cancer Modeling. Biomacromolecules 2023, 24 (10) , 4408-4418. https://doi.org/10.1021/acs.biomac.2c01080
  4. Sytze Buwalda. Advanced Functional Polymers for Unmet Medical Challenges. Biomacromolecules 2023, 24 (10) , 4329-4332. https://doi.org/10.1021/acs.biomac.3c00332
  5. Sriram Bharath Gugulothu, Sonal Asthana, Shervanthi Homer-Vanniasinkam, Kaushik Chatterjee. Trends in Photopolymerizable Bioinks for 3D Bioprinting of Tumor Models. JACS Au 2023, 3 (8) , 2086-2106. https://doi.org/10.1021/jacsau.3c00281
  6. Manqing Lin, Mengyi Tang, Wenzhe Duan, Shengkai Xia, Wenwen Liu, Qi Wang. 3D Bioprinting for Tumor Metastasis Research. ACS Biomaterials Science & Engineering 2023, 9 (6) , 3116-3133. https://doi.org/10.1021/acsbiomaterials.3c00239
  7. Sera Hong, Joon Myong Song. High-Resolution In Situ High-Content Imaging of 3D-Bioprinted Single Breast Cancer Spheroids for Advanced Quantification of Benzo(a)pyrene Carcinogen-Induced Breast Cancer Stem Cells. ACS Applied Materials & Interfaces 2023, 15 (9) , 11416-11430. https://doi.org/10.1021/acsami.2c17877
  8. Rui-Zhi Tang, Xi-Qiu Liu. Biophysical cues of in vitro biomaterials-based artificial extracellular matrix guide cancer cell plasticity. Materials Today Bio 2023, 19 , 100607. https://doi.org/10.1016/j.mtbio.2023.100607
  9. Dániel Sztankovics, Dorottya Moldvai, Gábor Petővári, Rebeka Gelencsér, Ildikó Krencz, Regina Raffay, Titanilla Dankó, Anna Sebestyén. 3D bioprinting and the revolution in experimental cancer model systems—A review of developing new models and experiences with in vitro 3D bioprinted breast cancer tissue-mimetic structures. Pathology and Oncology Research 2023, 29 https://doi.org/10.3389/pore.2023.1610996
  10. Maritza Londoño-Berrio, Cristina Castro, Ana Cañas, Isabel Ortiz, Marlon Osorio. Advances in Tumor Organoids for the Evaluation of Drugs: A Bibliographic Review. Pharmaceutics 2022, 14 (12) , 2709. https://doi.org/10.3390/pharmaceutics14122709
  11. Evelin Pellegrini, Giovanna Desando, Mauro Petretta, Antonella Cellamare, Camilla Cristalli, Michela Pasello, Maria Cristina Manara, Brunella Grigolo, Katia Scotlandi. A 3D Collagen-Based Bioprinted Model to Study Osteosarcoma Invasiveness and Drug Response. Polymers 2022, 14 (19) , 4070. https://doi.org/10.3390/polym14194070
  12. Xiaoyong Guan, Shigao Huang. Advances in the application of 3D tumor models in precision oncology and drug screening. Frontiers in Bioengineering and Biotechnology 2022, 10 https://doi.org/10.3389/fbioe.2022.1021966
  13. Gülsün Bağcı, Celia Ximenes-Carballo, Soledad Perez-Amodio, Oscar Castaño, Elisabeth Engel, Barbara Blanco-Fernandez. Advanced 3D In Vitro Models to Recapitulate the Breast Tumor Microenvironment. 2022https://doi.org/10.1007/16833_2022_56
Download PDF

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 1

    Scheme 1. Schematic Illustration Showing the Workflow of the TDM Hydrogel Fabrication
    High Resolution Image
    Download MS PowerPoint Slide

    Figure 1

    Figure 1. (A) Histological comparison of the native porcine breast tissue (left) and the decellularized breast tissue (TDM, right). Hematoxylin and eosin staining of tissue sections (scale bar of 100 μm), oil red O staining (scale bar of 200 μm), and picrosirius red staining (scale bar of 100 μm). (B) Total collagen and GAG contents in the porcine breast tissue and the decellularized breast tissue (TDM).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 2

    Figure 2. (A) Hydrogel formation from TDMs of various sources. Mouse, rat, and porcine breast tissues (first column) were decellularized (second column), lyophilized, cryomilled, and enzymatically digested (third column), and pre-gel solutions were used to prepare TDM hydrogels (fourth column). (B) Rheological properties of T2 at different temperatures. (C) Young’s moduli of T2 and T3 hydrogels.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 3

    Figure 3. MCF-7 viability, proliferation, and organization in TDM hydrogels at 2%. (A) Cellular organization over time (cell cytoskeletons stained with phalloidin (red) and nuclei stained with DAPI (blue), scale bar of 100 μm). (B) MCF-7 viability over time (viable cells stained with calcein AM in green and dead cells stained with PI in red, scale bar of 100 μm). (C) Cellular proliferation over time by alamarBlue.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 4

    Figure 4. (A,B) Formation of linear and continuous filaments of TDM bioinks containing 20 mg/mL TDM, 0.5% alginate, and 2.5 (A, TGA bioink) or 4% (B, T2_G4_A0.5) GelMA. (C,D) Temperature sweeps of TGA (C) and TGAC (D) bioinks. (E) Young’s moduli of TGA, TGAC, T2_A0.5, T2_A1, G2.5_A0.5, and G2.5_A0.5_Col1 hydrogels.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 5

    Figure 5. (A) Design of the bioprinted scaffolds to study the printability and shape fidelity. (B) Bioprinted scaffolds to determine the printability and shape fidelity of the bioinks. (1,5) Filaments of 14 mm in length, (2,6) filaments with an L shape (3,7) scaffolds with pores of 3 × 3 mm (4,8), and scaffolds for the filament fusion test. (C) Length and diameter of bioprinted filaments (theoretical sizes: 14 mm length, 0.51 mm diameter). (D) Diffusion rate of both bioinks. (E) Printability of both bioinks.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 6

    Figure 6. MCF-7- and hAMSC-laden bioprinted scaffolds. (A) Architecture of the bioprinted scaffolds with BCC- and stromal-cell-laden hydrogels (diameter, D; interline distance, di; height, h). (B) Bioprinted scaffolds (without cells) with a white core (1,5) recreating the tumor and an outer layer in pink (2,3,6,7) mimicking the stromal layer and cut in half (4,8). (C) Bioprinted hydrogels consisting of a core of MCF-7 (in red) and an outer layer of hAMSCs (in green). On the left is the hydrogel view from the bottom of the hydrogel, and on the right is the hydrogel view from the middle after slicing it in half.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 7

    Figure 7. MCF-7-laden bioprinted scaffolds. (A) Architecture of the scaffolds (diameter, D; interline distance, di; height, h). (B) Cell viability after 1, 7, and 14 days in culture (in green are cells stained with calcein AM (alive), and in red are cells dyed with PI (dead)). (C) MCF-7 proliferation by alamarBlue.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 8

    Figure 8. MCF-7-laden bioprinted scaffolds. (A) MCF-7 stained with phalloidin–rhodamine (red) and DAPI (blue) at day 1, 7, and 14. (B) Expression of E-cadherin (green) in MCF-7 clusters after 14 days in culture.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 9

    Figure 9. COL1A1, FN1, HSP90AA1, HSP90AB1, ABCC1, and ABCG2 expressions in MCF-7 cells cultured in TGA, TGAC, or Col1 for 14 days. 2–ΔΔCt values were calculated with the ΔCts from 2D cultures.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 10

    Figure 10. (A) MCF-7 viability after incubating the cell-laden hydrogels with doxorubicin for 48 h (a: p < 0.001 for TGA or TGAC vs the 2D control, b: p < 0.001 for Col1 vs the 2D control, c: p < 0.0011 for TGA vs TGAC, d: p < 0.0011 for TGA vs Col1, and e: p < 0.0011 for TGAC vs Col1). (B) COL1A1, FN1, HSP90AA1, HSP90AB1, ABCC1, and ABCG2 fold expressions in MCF-7 cells cultured in TGA, TGAC, Col1, or 2D and treated for 2 days with doxorubicin at 0.1 μM, after 14 days in culture for hydrogels and 7 days for 2D. 2–ΔΔCt values of each sample were calculated with the ΔCts of cell-laden hydrogels or 2D cultures for 16 or 9 days, respectively. (C–E) MCF-7 viability after incubating the TGA (C), TGAC (D), and Col1 (E) nonbioprinted cell-laden hydrogels with two cell densities with doxorubicin for 48 h. (F) Fluorescence intensity of the negative controls (cell-laden hydrogels not treated with doxorubicin) used for the calculation of the cell viability in C–E).

    High Resolution Image
    Download MS PowerPoint Slide

  • References

    ARTICLE SECTIONS
    Jump To

    This article references 71 other publications.

    1. 1
      Bahcecioglu, G.; Basara, G.; Ellis, B. W.; Ren, X.; Zorlutuna, P. Breast Cancer Models: Engineering the Tumor Microenvironment. Acta Biomater. 2020, 106, 1– 21,  DOI: 10.1016/j.actbio.2020.02.006
      1
      Breast cancer models: Engineering the tumor microenvironment
      Bahcecioglu, Gokhan; Basara, Gozde; Ellis, Bradley W.; Ren, Xiang; Zorlutuna, Pinar
      Acta Biomaterialia (2020), 106 (), 1-21CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
      A review. The mechanisms behind cancer initiation and progression are not clear. Therefore, development of clin. relevant models to study cancer biol. and drug response in tumors is essential. In vivo models are very valuable tools for studying cancer biol. and for testing drugs; however, they often suffer from not accurately representing the clin. scenario because they lack either human cells or a functional immune system. On the other hand, two-dimensional (2D) in vitro models lack the three-dimensional (3D) network of cells and extracellular matrix (ECM) and thus do not represent the tumor microenvironment (TME). As an alternative approach, 3D models have started to gain more attention, as such models offer a platform with the ability to study cell-cell and cell-material interactions parametrically, and possibly include all the components present in the TME. Here, we first give an overview of the breast cancer TME, and then discuss the current state of the pre-clin. breast cancer models, with a focus on the engineered 3D tissue models. We also highlight two engineering approaches that we think are promising in constructing models representative of human tumors: 3D printing and microfluidics. In addn. to giving basic information about the TME in the breast tissue, this review article presents the state-of-the-art tissue engineered breast cancer models. Involvement of biomaterials and tissue engineering fields in cancer research enables realistic mimicry of the cell-cell and cell-extracellular matrix (ECM) interactions in the tumor microenvironment (TME), and thus creation of better models that reflect the tumor response against drugs. Engineering the 3D in vitro models also requires a good understanding of the TME. Here, an overview of the breast cancer TME is given, and the current state of the pre-clin. breast cancer models, with a focus on the engineered 3D tissue models is discussed. This review article is useful not only for biomaterials scientists aiming to engineer 3D in vitro TME models, but also for cancer researchers willing to use these models for studying cancer biol. and drug testing.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjsFSrsrw%253D&md5=1c27cf2ab68188e5a18f6c0217bb6c45
    2. 2
      Winkler, J.; Abisoye-Ogunniyan, A.; Metcalf, K. J.; Werb, Z. Concepts of Extracellular Matrix Remodelling in Tumour Progression and Metastasis. Nat. Commun. 2020, 11, 1– 19,  DOI: 10.1038/s41467-020-18794-x
      There is no corresponding record for this reference.
    3. 3
      Jena, M. K.; Janjanam, J. Role of Extracellular Matrix in Breast Cancer Development: A Brief Update. F1000Res 2018, 7, 274,  DOI: 10.12688/f1000research.14133.2
      3
      Role of extracellular matrix in breast cancer development: a brief update
      Jena Manoj Kumar; Janjanam Jagadeesh
      F1000Research (2018), 7 (), 274 ISSN:2046-1402.
      Evidence is increasing on the crucial role of the extracellular matrix (ECM) in breast cancer progression, invasion and metastasis with almost all mortality cases owing to metastasis. The epithelial-mesenchymal transition is the first signal of metastasis involving different transcription factors such as Snail, TWIST, and ZEB1. ECM remodeling is a major event promoting cancer invasion and metastasis; where matrix metalloproteinases (MMPs) such as MMP-2, -9, -11, and -14 play vital roles degrading the matrix proteins for cancer spread. The β-D mannuronic acid (MMP inhibitor) has anti-metastatic properties through inhibition of MMP-2, and -9 and could be a potential therapeutic agent. Besides the MMPs, the enzymes such as LOXL2, LOXL4, procollagen lysyl hydroxylase-2, and heparanase also regulate breast cancer progression. The important ECM proteins like integrins (b1-, b5-, and b6- integrins), ECM1 protein, and Hic-5 protein are also actively involved in breast cancer development. The stromal cells such as tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and adipocytes also contribute in tumor development through different processes. The TAMs become proangiogenic through secretion of VEGF-A and building vessel network for nourishment and invasion of the tumor mass. The latest developments of ECM involvement in breast cancer progression has been discussed in this review and this study will help researchers in designing future work on breast cancer pathogenesis and developing therapy targeted to the ECM components.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FlvFajtA%253D%253D&md5=f528ea31ddab81c6b08b7d56d5d9dad5
    4. 4
      Quail, D.; Joyce, J. Microenvironmental Regulation of Tumor Progression and Metastasis. Nat. Med. 2013, 19, 1423– 1437,  DOI: 10.1038/nm.3394
      4
      Microenvironmental regulation of tumor progression and metastasis
      Quail, Daniela F.; Joyce, Johanna A.
      Nature Medicine (New York, NY, United States) (2013), 19 (11), 1423-1437CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
      A review. Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslCmsrjL&md5=52d5ff0b56fb4749d0a42fedb3b83eb2
    5. 5
      Nallanthighal, S.; Heiserman, J.; Cheon, D. The Role of the Extracellular Matrix in Cancer Stemness. Front Cell Dev. Biol. 2019, 7, 86,  DOI: 10.3389/fcell.2019.00086
      5
      The Role of the Extracellular Matrix in Cancer Stemness
      Nallanthighal Sameera; Heiserman James Patrick; Cheon Dong-Joo
      Frontiers in cell and developmental biology (2019), 7 (), 86 ISSN:2296-634X.
      As our understanding of cancer cell biology progresses, it has become clear that tumors are a heterogenous mixture of different cell populations, some of which contain so called "cancer stem cells" (CSCs). Hallmarks of CSCs include self-renewing capability, tumor-initiating capacity and chemoresistance. The extracellular matrix (ECM), a major structural component of the tumor microenvironment, is a highly dynamic structure and increasing evidence suggests that ECM proteins establish a physical and biochemical niche for CSCs. In cancer, abnormal ECM dynamics occur due to disrupted balance between ECM synthesis and secretion and altered expression of matrix-remodeling enzymes. Tumor-derived ECM is biochemically distinct in its composition and is stiffer compared to normal ECM. In this review, we will provide a brief overview of how different components of the ECM modulate CSC properties then discuss how physical, mechanical, and biochemical cues from the ECM drive cancer stemness. Given the fact that current CSC targeting therapies face many challenges, a better understanding of CSC-ECM interactions will be crucial to identify more effective therapeutic strategies to eliminate CSCs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MvgtF2jtg%253D%253D&md5=1f33e808fbbdb1fa20ef3b9cac2aef0c
    6. 6
      Filipe, E. C.; Chitty, J. L.; Cox, T. R. Charting the Unexplored Extracellular Matrix in Cancer. Int. J. Exp. Pathol. 2018, 99, 58– 76,  DOI: 10.1111/iep.12269
      6
      Charting the unexplored extracellular matrix in cancer
      Filipe Elysse C; Chitty Jessica L; Cox Thomas R; Cox Thomas R
      International journal of experimental pathology (2018), 99 (2), 58-76 ISSN:.
      The extracellular matrix (ECM) is present in all solid tissues and considered a master regulator of cell behaviour and phenotype. The importance of maintaining the correct biochemical and biophysical properties of the ECM, and the subsequent regulation of cell and tissue homeostasis, is illustrated by the simple fact that the ECM is highly dysregulated in many different types of disease, especially cancer. The loss of tissue ECM homeostasis and integrity is seen as one of the hallmarks of cancer and typically defines transitional events in progression and metastasis. The vast majority of cancer studies place an emphasis on exploring the behaviour and intrinsic signalling pathways of tumour cells. Their goal was to identify ways to target intracellular pathways regulating cancer. Cancer progression and metastasis are powerfully influenced by the ECM and thus present a vast, unexplored repository of anticancer targets that we are only just beginning to tap into. Deconstructing the complexity of the tumour ECM landscape and identifying the interactions between the many cell types, soluble factors and extracellular-matrix proteins have proved challenging. Here, we discuss some of the emerging tools and platforms being used to catalogue and chart the ECM in cancer.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MjktlGhsw%253D%253D&md5=3bb538d5d6f8d4653ea588bfcaef1ad0
    7. 7
      Blanco-Fernandez, B.; Gaspar, V. M.; Engel, E.; Mano, J. F. Proteinaceous Hydrogels for Bioengineering Advanced 3D Tumor Models. Adv. Sci. 2021, 2003129, 1– 38,  DOI: 10.1002/advs.202003129
      There is no corresponding record for this reference.
    8. 8
      Mantha, S.; Pillai, S.; Khayambashi, P.; Upadhyay, A.; Zhang, Y.; Tao, O.; Pham, H. M.; Tran, S. D. Smart Hydrogels in Tissue Engineering and Regenerative Medicine. Materials 2019, 12, 3323,  DOI: 10.3390/ma12203323
      8
      Smart hydrogels in tissue engineering and regenerative medicine
      Mantha, Somasundar; Pillai, Sangeeth; Khayambashi, Parisa; Upadhyay, Akshaya; Zhang, Yuli; Tao, Owen; Pham, Hieu M.; Tran, Simon D.
      Materials (2019), 12 (20), 3323CODEN: MATEG9; ISSN:1996-1944. (MDPI AG)
      The field of regenerative medicine has tremendous potential for improved treatment outcomes and has been stimulated by advances made in bioengineering over the last few decades. The strategies of engineering tissues and assembling functional constructs that are capable of restoring, retaining, and revitalizing lost tissues and organs have impacted the whole spectrum of medicine and health care. Techniques to combine biomimetic materials, cells, and bioactive mols. play a decisive role in promoting the regeneration of damaged tissues or as therapeutic systems. Hydrogels have been used as one of the most common tissue engineering scaffolds over the past two decades due to their ability to maintain a distinct 3D structure, to provide mech. support for the cells in the engineered tissues, and to simulate the native extracellular matrix. The high water content of hydrogels can provide an ideal environment for cell survival, and structure which mimics the native tissues. Hydrogel systems have been serving as a supportive matrix for cell immobilization and growth factor delivery. This review outlines a brief description of the properties, structure, synthesis and fabrication methods, applications, and future perspectives of smart hydrogels in tissue engineering.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXotFGkt7c%253D&md5=d6cf64ff65b28e2d447e196b5e468a52
    9. 9
      Horning, J. L.; Sahoo, S. K.; Vijayaraghavalu, S.; Dimitrijevic, S.; Vasir, J. K.; Jain, T. K.; Panda, A. K.; Labhasetwar, V. 3-D Tumor Model for In Vitro Evaluation of Anticancer Drugs. Mol. Pharmaceutics 2008, 5, 849– 862,  DOI: 10.1021/mp800047v
      9
      3-D Tumor Model for In Vitro Evaluation of Anticancer Drugs
      Horning, Jayme L.; Sahoo, Sanjeeb K.; Vijayaraghavalu, Sivakumar; Dimitrijevic, Sanja; Vasir, Jaspreet K.; Jain, Tapan K.; Panda, Amulya K.; Labhasetwar, Vinod
      Molecular Pharmaceutics (2008), 5 (5), 849-862CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      The efficacy of potential anticancer drugs during preclin. development is generally tested in vitro using cancer cells grown in monolayer; however, a significant discrepancy in their efficacy is obsd. when these drugs are evaluated in vivo. This discrepancy, in part, could be due to the three-dimensional (3-D) nature of tumors as compared to the two-dimensional (2-D) nature of monolayer cultures. Therefore, there is a need for an in vitro model that would mimic the 3-D nature of tumors. With this objective, we have developed surface-engineered, large and porous biodegradable polymeric microparticles as a scaffold for 3-D growth of cancer cells. Using the MCF-7 cell line as model breast cancer cells, we evaluated the antiproliferative effect of three anticancer drugs: doxorubicin, paclitaxel and tamoxifen in 3-D model vs in 2-D monolayer. With optimized compn. of microparticles and cell culture conditions, a d. of 4.5 × 106 MCF-7 cells/mg of microparticles, which is an 18-fold increase from the seeding d., was achieved in six days of culture. Cells were obsd. to have grown in clumps on the microparticle surface as well as in their interior matrix structure. The antiproliferative effect of the drugs in 3-D model was significantly lower than in 2-D monolayer, which was evident from the 12- to 23-fold differences in their IC50 values. Using doxorubicin, the flow cytometry data demonstrated ∼2.6-fold lower drug accumulation in the cells grown in 3-D model than in the cells grown as 2-D monolayer. Further, only 26% of the cells in 3-D model had the same concn. of drug as the cells in monolayer, thus explaining the reduced activity of the drugs in 3-D model. The collagen content of the cells grown in 3-D model was 2-fold greater than that of the cells grown in 2-D, suggesting greater synthesis of extracellular matrix in 3-D model, which acted as a barrier to drug diffusion. The microarray anal. showed changes in several genes in cells grown in 3-D, which could also influence the drug effect. In conclusion, the cells grown in 3-D are more resistant to chemotherapy than those grown in 2-D culture, suggesting the significant roles of cellular architecture, phenotypic variations, and extracellular matrix barrier to drug transport in drug efficacy. We propose that our model provides a better assessment of drug efficacy than the currently used 2-D monolayer as many of its characteristic features are similar to an actual tumor. A well-characterized 3-D model can particularly be useful for rapid screening of a large no. of therapeutics for their efficacy during the drug discovery phase.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptlejs7o%253D&md5=87f323b84674ba0ab5bbe1c5d799e281
    10. 10
      Shekhar, M. P.; Werdell, J.; Santner, S. J.; Pauley, R. J.; Tait, L. Breast Stroma Plays a Dominant Regulatory Role in Breast Epithelial Growth and Differentiation: Implications for Tumor Development and Progression. Cancer Res. 2001, 61, 1320– 1326
      10
      Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: implications for tumor development and progression
      Shekhar, Malathy P. V.; Werdell, Jill; Santner, Steve J.; Pauley, Robert J.; Tait, Larry
      Cancer Research (2001), 61 (4), 1320-1326CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
      Although growth factors and extracellular matrix (ECM) are recognized as important contributors to breast epithelial growth, morphogenesis, hormone responsiveness, and neoplastic progression, the influence of functional interactions between breast stromal and epithelial cells on these processes has not been defined. Using a novel three-dimensional cell-cell interaction model, the authors have compared the abilities of different mesenchymal cell types, including breast fibroblasts derived from redn. mammoplasty and tumor tissues, and human umbilical endothelial cells (HUVECs) to induce three-dimensional morphogenesis and growth of normal MCF10A and preneoplastic MCF10AT1-EIII8 (referred as EIII8) human breast epithelial cells. The authors' data demonstrate a requirement for organ-specific fibroblasts in the induction of epithelial morphogenesis. Whereas inclusion of normal redn. mammoplasty fibroblasts inhibit or retard morphol. conversion and growth of MCF10A and EIII8 cells, resp., tumor-derived breast fibroblasts evoke ductal-alveolar morphogenesis of both MCF10A and EIII8 cells. The growth and morphogenesis inhibitory effects of normal fibroblasts remain even in the presence of estrogen because they are able to suppress the estrogen-induced growth of EIII8 cells, whereas tumor fibroblasts support and maintain estrogen responsiveness of EIII8 cells. The inductive morphogenic effects of tumor fibroblasts on EIII8 cells is further augmented by the inclusion of HUVECs because these cocultures undergo a dramatic increase in proliferation and branching ductal-alveolar morphogenesis that is accompanied by an increase in invasion, degrdn. of coincident ECM, and expression of MMP-9. Therefore, tumor fibroblasts confer morphogenic and mitogenic induction of epithelial cells, and further enhancement of growth and progression requires active angiogenesis. These data illustrate the importance of structural and functional interactions between breast stromal and epithelial cells in the regulation of breast epithelial growth and progression.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhvVelsbY%253D&md5=5cbe47c6ef81f610a42e8ede4ba3de57
    11. 11
      Cavo, M.; Caria, M.; Pulsoni, I.; Beltrame, F.; Fato, M.; Scaglione, S. A New Cell-Laden 3D Alginate-Matrigel Hydrogel Resembles Human Breast Cancer Cell Malignant Morphology, Spread and Invasion Capability Observed “in Vivo.”. Sci. Rep. 2018, 8, 1– 12,  DOI: 10.1038/s41598-018-23250-4
      11
      A new cell-laden 3D Alginate-Matrigel hydrogel resembles human breast cancer cell malignant morphology, spread and invasion capability observed ''in vivo''
      Cavo, Marta; Caria, Marco; Pulsoni, Ilaria; Beltrame, Francesco; Fato, Marco; Scaglione, Silvia
      Scientific Reports (2018), 8 (1), 1-12CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
      Purpose of this study was the development of a 3D material to be used as substrate for breast cancer cell culture. We developed composite gels constituted by different concns. of Alginate (A) and Matrigel (M) to obtain a structurally stable-in-time and biol. active substrate. Human aggressive breast cancer cells (i.e. MDA-MB-231) were cultured within the gels. Known the link between cell morphol. and malignancy, cells were morphol. characterized and their invasiveness correlated through an innovative bioreactor-based invasion assay. A particular type of gel (i.e. 50% Alginate, 50% Matrigel) emerged thanks to a series of significant results: 1. cells exhibited peculiar cytoskeleton shapes and nuclear fragmentation characteristic of their malignancy; 2. cells expressed the formation of the so-called invadopodia, actin-based protrusion of the plasma membrane through which cells anchor to the extracellular matrix; 3. cells were able to migrate through the gels and attach to an engineered membrane mimicking the vascular walls hosted within bioreactor, providing a completely new 3D in vitro model of the very precursor steps of metastasis.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1yktrrK&md5=06bd01d9da7b51e9381f274f2b4810bd
    12. 12
      Ferreira, L. P.; Gaspar, V. M.; Mano, J. F. Decellularized Extracellular Matrix for Bioengineering Physiomimetic 3D in Vitro Tumor Models. Trends Biotechnol. 2020, 38, 1397– 1414,  DOI: 10.1016/j.tibtech.2020.04.006
      12
      Decellularized Extracellular Matrix for Bioengineering Physiomimetic 3D in Vitro Tumor Models
      Ferreira, Luis P.; Gaspar, Vitor M.; Mano, Joao F.
      Trends in Biotechnology (2020), 38 (12), 1397-1414CODEN: TRBIDM; ISSN:0167-7799. (Elsevier Ltd.)
      A review. Recent advances in the extn. and purifn. of decellularized extracellular matrix (dECM) obtained from healthy or malignant tissues open new avenues for engineering physiomimetic 3D in vitro tumor models, which closely recapitulate key biomol. hallmarks and the dynamic cancer cell-ECM interactions in the tumor microenvironment. We review current and upcoming methodologies for chem. modification of dECM-based biomaterials and advanced bioprocessing into organotypic 3D solid tumor models. A comprehensive review of disruptive advances and shortcomings of exploring dECM-based biomaterials for recapitulating the native tumor-supporting matrix is also provided. We hope to drive the discussion on how 3D dECM testing platforms can be leveraged for generating microphysiol. tumor surrogates that generate more robust and predictive data on therapeutic bioperformance.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXovVCht7k%253D&md5=01da7431f6c4f1bbc5d2f7b3719e61e2
    13. 13
      Saldin, L. T.; Cramer, M. C.; Velankar, S. S.; White, L. J.; Badylaka, S. F. Extracellular Matrix Hydrogels from Decellularized Tissues: Structure and Function. Acta Biomater. 2017, 49, 1– 15,  DOI: 10.1016/j.actbio.2016.11.068
      13
      Extracellular matrix hydrogels from decellularized tissues: Structure and function
      Saldin, Lindsey T.; Cramer, Madeline C.; Velankar, Sachin S.; White, Lisa J.; Badylak, Stephen F.
      Acta Biomaterialia (2017), 49 (), 1-15CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
      A review. Extracellular matrix (ECM) bioscaffolds prepd. from decellularized tissues have been used to facilitate constructive and functional tissue remodeling in a variety of clin. applications. The discovery that these ECM materials could be solubilized and subsequently manipulated to form hydrogels expanded their potential in vitro and in vivo utility; i.e. as culture substrates comparable to collagen or Matrigel, and as injectable materials that fill irregularly-shaped defects. The mechanisms by which ECM hydrogels direct cell behavior and influence remodeling outcomes are only partially understood, but likely include structural and biol. signals retained from the native source tissue. The present review describes the utility, formation, and phys. and biol. characterization of ECM hydrogels. Two examples of clin. application are presented to demonstrate in vivo utility of ECM hydrogels in different organ systems. Finally, new research directions and clin. translation of ECM hydrogels are discussed. More than 70 papers have been published on extracellular matrix (ECM) hydrogels created from source tissue in almost every organ system. The present manuscript represents a review of ECM hydrogels and attempts to identify structure-function relationships that influence the tissue remodeling outcomes and gaps in the understanding thereof. There is a Phase 1 clin. trial now in progress for an ECM hydrogel.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFKqsrzF&md5=61a751f33ddaa825cd19400a094f1c17
    14. 14
      Pati, F.; Jang, J.; Ha, D.-H.; Kim, S. W.; Rhie, J.-W.; Shim, J.-H.; Kim, D.-H.; Cho, D.-W. Printing Three-Dimensional Tissue Analogues with Decellularized Extracellular Matrix Bioink. Nat. Commun. 2014, 5, 3935,  DOI: 10.1038/ncomms4935
      14
      Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink
      Pati, Falguni; Jang, Jinah; Ha, Dong-Heon; Won Kim, Sung; Rhie, Jong-Won; Shim, Jin-Hyung; Kim, Deok-Ho; Cho, Dong-Woo
      Nature Communications (2014), 5 (), 3935CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      The ability to print and pattern all the components that make up a tissue (cells and matrix materials) in three dimensions to generate structures similar to tissues is an exciting prospect of bioprinting. However, the majority of the matrix materials used so far for bioprinting cannot represent the complexity of natural extracellular matrix (ECM) and thus are unable to reconstitute the intrinsic cellular morphologies and functions. Here, we develop a method for the bioprinting of cell-laden constructs with novel decellularized extracellular matrix (dECM) bioink capable of providing an optimized microenvironment conducive to the growth of three-dimensional structured tissue. We show the versatility and flexibility of the developed bioprinting process using tissue-specific dECM bioinks, including adipose, cartilage and heart tissues, capable of providing crucial cues for cells engraftment, survival and long-term function. We achieve high cell viability and functionality of the printed dECM structures using our bioprinting method.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvF2mu77P&md5=bf583e49f37c1ec2bb11657dc85522f8
    15. 15
      Dunne, L. W.; Huang, Z.; Meng, W. X.; Fan, X. J.; Zhang, N. Y.; Zhang, Q. X.; An, Z. G. Human Decellularized Adipose Tissue Scaffold as a Model for Breast Cancer Cell Growth and Drug Treatments. Biomaterials 2014, 35, 4940– 4949,  DOI: 10.1016/j.biomaterials.2014.03.003
      15
      Human decellularized adipose tissue scaffold as a model for breast cancer cell growth and drug treatments
      Dunne, Lina W.; Huang, Zhao; Meng, Weixu; Fan, Xuejun; Zhang, Ningyan; Zhang, Qixu; An, Zhiqiang
      Biomaterials (2014), 35 (18), 4940-4949CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Human adipose tissue extracellular matrix, derived through decellularization processing, has been shown to provide a biomimetic microenvironment for adipose tissue regeneration. This study reports the use of human adipose tissue-derived extracellular matrix (hDAM) scaffolds as a three-dimensional cell culturing system for the investigation of breast cancer growth and drug treatments. The hDAM scaffolds have similar extracellular matrix compn. to the microenvironment of breast tissues. Breast cancer cells were cultured in hDAM scaffolds, and cell proliferation, migration, morphol., and drug responses were investigated. The growth profiles of multiple breast cancer cell lines cultured in hDAM scaffolds differed from the growth of those cultured on two-dimensional surfaces and more closely resembled the growth of xenografts. HDAM-cultured breast cancer cells also differed from those cultured on two-dimensional surfaces in terms of cell morphol., migration, expression of adhesion mols., and sensitivity to drug treatment. Our results demonstrated that the hDAM system provides breast cancer cells with a biomimetic microenvironment in vitro that more closely mimics the in vivo microenvironment than existing two-dimensional and Matrigel three-dimensional cultures do, and thus can provide vital information for the characterization of cancer cells and screening of cancer therapeutics.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXksleku70%253D&md5=9e9dfcde46cc19180dd9a648087152d1
    16. 16
      Liu, G.; Wang, B.; Li, S.; Jin, Q.; Dai, Y. Human Breast Cancer Decellularized Scaffolds Promote Epithelial-to-Mesenchymal Transitions and Stemness of Breast Cancer Cells in Vitro. J. Cell. Physiol. 2019, 234, 9447– 9456,  DOI: 10.1002/jcp.27630
      16
      Human breast cancer decellularized scaffolds promote epithelial-to-mesenchymal transitions and stemness of breast cancer cells in vitro
      Liu, Gang; Wang, Biao; Li, Shubin; Jin, Qin; Dai, Yanfeng
      Journal of Cellular Physiology (2019), 234 (6), 9447-9456CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)
      Breast cancer, with unsatisfactory survival rates, is the leading cause of cancer-related death in women worldwide. Recent advances in the genetic basis of breast cancer have benefitted the development of gene-based medicines and therapies. Tissue engineering technologies, including tissue decellularizations and reconstructions, are potential therapeutic alternatives for cancer research and tissue regeneration. In our study, human breast cancer biopsies were decellularized by a detergent technique, with sodium lauryl ether sulfate (SLES) soln., for the first time. And the decellularization process was optimized to maximally maintain tissue microarchitectures and extracellular matrix (ECM) components with minimal DNA compds. preserved. Histol. anal. and DNA quantification results confirmed the decellularization effect with maximal genetic compds. removal. Quantification, immunofluorescence, and histol. analyses demonstrated better preservation of ECM components in 0.5% SLES-treated scaffolds. Scaffolds seeded with MCF-7 cells demonstrated the process of cell recellularization in vitro, with increased cell migration, proliferation, and epithelial-to-mesenchymal transition (EMT) process. When treated with 5-fluorouracil, the expressions of stem cell markers, including Oct4, Sox2, and CD49F, were maximally maintained in the recellularized scaffold with decreased apoptosis rates compared with monolayer cells. These results showed that the decellularized breast scaffold model with SLES treatments would help to simulate the pathogenesis of breast cancer in vitro. And we hope that this model could further accelerate the development of effective therapies for breast cancer and benefit drug screenings.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlSgs7%252FO&md5=318fe70c0f4c5a5d915b30895064054f
    17. 17
      Mollica, P.; Booth-Creech, E.; Reid, J.; Zamponi, M.; Sullivan, S.; Palmer, X.; Sachs, P.; Robert, D. 3D Bioprinted Mammary Organoids and Tumoroids in Human Mammary Derived ECM Hydrogels. Acta Biomater. 2019, 95, 201– 213,  DOI: 10.1016/j.actbio.2019.06.017
      17
      3D bioprinted mammary organoids and tumoroids in human mammary derived ECM hydrogels
      Mollica, Peter A.; Booth-Creech, Elizabeth N.; Reid, John A.; Zamponi, Martina; Sullivan, Shea M.; Palmer, Xavier-Lewis; Sachs, Patrick C.; Bruno, Robert D.
      Acta Biomaterialia (2019), 95 (), 201-213CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
      The extracellular matrix (ECM) of tissues is an important mediator of cell function. Moreover, understanding cellular dynamics within their specific tissue context is also important for developmental biol., cancer research, and regenerative medicine. However, robust in vitro models that incorporate tissue-specific microenvironments are lacking. Here we describe a novel mammary-specific culture protocol that combines a self-gelling hydrogel comprised solely of ECM from decellularized rat or human breast tissue with the use of our previously described 3D bioprinting platform. We initially demonstrate that undigested and decellularized mammary tissue can support mammary epithelial and tumor cell growth. We then describe a methodol. for generating mammary ECM exts. that can spontaneously gel to form hydrogels. These ECM hydrogels retain unique structural and signaling profiles that elicit differential responses when normal mammary and breast cancer cells are cultured within them. Using our bioprinter, we establish that we can generate large organoids/tumoroids in the all mammary-derived hydrogel. These findings demonstrate that our system allows for growth of organoids/tumoroids in a tissue-specific matrix with unique properties, thus providing a suitable platform for ECM and epithelial/cancer cell studies. Factors within extracellular matrixes (ECMs) are specific to their tissue of origin. It has been shown that tissue specific factors within the mammary gland's ECM have pronounced effects on cellular differentiation and cancer behavior. Understanding the role of the ECM in controlling cell fate has major implications for developmental biol., tissue engineering, and cancer therapy. However, in vitro models to study cellular interactions with tissue specific ECM are lacking. Here we describe the generation of 3D hydrogels consisting solely of human or mouse mammary ECM. We demonstrate that these novel 3D culture substrates can sustain large 3D bioprinted organoid and tumoroid formation. This is the first demonstration of an all mammary ECM culture system capable of sustaining large structural growths.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht1yitLfI&md5=52b6c9b874e5129fb96a34965523072a
    18. 18
      Rijal, G.; Wang, J.; Yu, I.; Gang, D. R.; Chen, R. K.; Li, W. Porcine Breast Extracellular Matrix Hydrogel for Spatial Tissue Culture. Int. J. Mol. Sci. 2018, 19, 2912,  DOI: 10.3390/ijms19102912
      18
      Porcine breast extracellular matrix hydrogel for spatial tissue culture
      Rijal, Girdhari; Wang, Jing; Yu, Ilhan; Gang, David R.; Chen, Roland K.; Li, Weimin
      International Journal of Molecular Sciences (2018), 19 (10), 2912/1-2912/13CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      Porcine mammary fatty tissues represent an abundant source of natural biomaterial for generation of breast-specific extracellular matrix (ECM). Here we report the extn. of total ECM proteins from pig breast fatty tissues, the fabrication of hydrogel and porous scaffolds from the extd. ECM proteins, the structural properties of the scaffolds (tissue matrix scaffold, TMS), and the applications of the hydrogel in human mammary epithelial cell spatial cultures for cell surface receptor expression, metabolomics characterization, acini formation, proliferation, migration between different scaffolding compartments, and in vivo tumor formation. This model system provides an addnl. option for studying human breast diseases such as breast cancer.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntVKqtrw%253D&md5=30f34bdc2bf94772b7101bb5415c845d
    19. 19
      Ruud, K. F.; Hiscox, W. C.; Yu, I.; Chen, R. K.; Li, W. Distinct Phenotypes of Cancer Cells on Tissue Matrix Gel. Breast Cancer Res. 2020, 22, 82,  DOI: 10.1186/s13058-020-01321-7
      19
      Distinct phenotypes of cancer cells on tissue matrix gel
      Ruud, Kelsey F.; Hiscox, William C.; Yu, Ilhan; Chen, Roland K.; Li, Weimin
      Breast Cancer Research (2020), 22 (1), 82CODEN: BRCRFS; ISSN:1465-542X. (BioMed Central Ltd.)
      Breast cancer cells invading the connective tissues outside the mammary lobule or duct immerse in a reservoir of extracellular matrix (ECM) that is structurally and biochem. distinct from that of their site of origin. The ECM is a spatial network of matrix proteins, which not only provide phys. support but also serve as bioactive ligands to the cells. It becomes evident that the dimensional, mech., structural, and biochem. properties of ECM are all essential mediators of many cellular functions. To better understand breast cancer development and cancer cell biol. in native tissue environment, various tissue-mimicking culture models such as hydrogel have been developed. Collagen I (Col I) and Matrigel are the most common hydrogels used in cancer research and have opened opportunities for addressing biol. questions beyond the two-dimensional (2D) cell cultures. Yet, it remains unclear whether these broadly used hydrogels can recapitulate the environmental properties of tissue ECM, and whether breast cancer cells grown on CoI I or Matrigel display similar phenotypes as they would on their native ECM. We investigated mammary epithelial cell phenotypes and metabolic profiles on animal breast ECM-derived tissue matrix gel (TMG), Col I, and Matrigel. Atomic force microscopy (AFM), fluorescence microscopy, acini formation assay, differentiation expts., spatial migration/invasion assays, proliferation assay, and NMR (NMR) spectroscopy were used to examine biol. phenotypes and metabolic changes. Student's t test was applied for statistical analyses. Our data showed that under a similar physiol. stiffness, the three types of hydrogels exhibited distinct microstructures. Breast cancer cells grown on TMG displayed quite different morphologies, surface receptor expression, differentiation status, migration and invasion, and metabolic profiles compared to those cultured on Col I and Matrigel. Depleting lactate produced by glycolytic metab. of cancer cells abolished the cell proliferation promoted by the non-tissue-specific hydrogel. The full ECM protein-based hydrogel system may serve as a biol. relevant model system to study tissue- and disease-specific pathol. questions. This work provides insights into tissue matrix regulation of cancer cell biomarker expression and identification of novel therapeutic targets for the treatment of human cancers based on tissue-specific disease modeling.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFejs77N&md5=eff0b71bb4e851ad47ae3f61488d98a9
    20. 20
      Landberg, G.; Landberg, P.; Fitzpatrick, P.; Jonasson, J.; Jonasson, E.; Karlsson, J.; Larsson, E.; Svanström, A.; Rafnsdottir, S.; Persson, E.; Gustafsson, A.; Andersson, D.; Rosendah, J.; Petronis, S.; Panji, P.; Gregersson, P.; Magnusson, Y.; Håkansson, J.; Ståhlberg, A. Patient-Derived Scaffolds Uncover Breast Cancer Promoting Properties of the Microenvironment. Biomaterials 2020, 235, 119705,  DOI: 10.1016/j.biomaterials.2019.119705
      20
      Patient-derived scaffolds uncover breast cancer promoting properties of the microenvironment
      Landberg, Goeran; Fitzpatrick, Paul; Isakson, Pauline; Jonasson, Emma; Karlsson, Joakim; Larsson, Erik; Svanstroem, Andreas; Rafnsdottir, Svanheidur; Persson, Emma; Gustafsson, Anna; Andersson, Daniel; Rosendahl, Jennifer; Petronis, Sarunas; Ranji, Parmida; Gregersson, Pernilla; Magnusson, Ylva; Haakansson, Joakim; Staahlberg, Anders
      Biomaterials (2020), 235 (), 119705CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Tumor cells interact with the microenvironment that specifically supports and promotes tumor development. Key components in the tumor environment have been linked to various aggressive cancer features and can further influence the presence of subpopulations of cancer cells with specific functions, including cancer stem cells and migratory cells. To model and further understand the influence of specific microenvironments we have developed an exptl. platform using cell-free patient-derived scaffolds (PDSs) from primary breast cancers infiltrated with standardized breast cancer cell lines. This PDS culture system induced a series of orchestrated changes in differentiation, epithelial-mesenchymal transition, stemness and proliferation of the cancer cell population, where an increased cancer stem cell pool was confirmed using functional assays. Furthermore, global gene expression profiling showed that PDS cultures were similar to xenograft cultures. Mass spectrometry analyses of cell-free PDSs identified subgroups based on their protein compn. that were linked to clin. properties, including tumor grade. Finally, we obsd. that an induction of epithelial-mesenchymal transition-related genes in cancer cells growing on the PDSs were significantly assocd. with clin. disease recurrences in breast cancer patients. Patient-derived scaffolds thus mimics in vivo-like growth conditions and uncovers unique information about the malignancy-inducing properties of tumor microenvironment.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlajsLs%253D&md5=d3ba9113dd3ea82e0483532873a073c3
    21. 21
      Monteiro, M. v.; Zhang, Y. S.; Gaspar, V. M.; Mano, J. F. 3D-Bioprinted Cancer-on-a-Chip: Level-up Organotypic in Vitro Models. In Trends in Biotechnology; Elsevier Ltd 2021.
      There is no corresponding record for this reference.
    22. 22
      Langer, E. M.; Allen-Petersen, B. L.; King, S. M.; Kendsersky, N. D.; Turnidge, M. A.; Kuziel, G. M.; Riggers, R.; Samatham, R.; Amery, T. S.; Jacques, S. L.; Sheppard, B. C.; Korkola, J. E.; Muschler, J. L.; Thibault, G.; Chang, Y. H.; Gray, J. W.; Presnell, S. C.; Nguyen, D. G.; Sears, R. C. Modeling Tumor Phenotypes In Vitro with Three-Dimensional Bioprinting. Cell Rep. 2019, 26, 608– 623.e6,  DOI: 10.1016/j.celrep.2018.12.090
      22
      Modeling Tumor Phenotypes In Vitro with Three-Dimensional Bioprinting
      Langer, Ellen M.; Allen-Petersen, Brittany L.; King, Shelby M.; Kendsersky, Nicholas D.; Turnidge, Megan A.; Kuziel, Genevra M.; Riggers, Rachelle; Samatham, Ravi; Amery, Taylor S.; Jacques, Steven L.; Sheppard, Brett C.; Korkola, James E.; Muschler, John L.; Thibault, Guillaume; Chang, Young Hwan; Gray, Joe W.; Presnell, Sharon C.; Nguyen, Deborah G.; Sears, Rosalie C.
      Cell Reports (2019), 26 (3), 608-623.e6CODEN: CREED8; ISSN:2211-1247. (Cell Press)
      The tumor microenvironment plays a crit. role in tumor growth, progression, and therapeutic resistance, but interrogating the role of specific tumor-stromal interactions on tumorigenic phenotypes is challenging within in vivo tissues. Here, we tested whether three-dimensional (3D) bioprinting could improve in vitro models by incorporating multiple cell types into scaffold-free tumor tissues with defined architecture. We generated tumor tissues from distinct subtypes of breast or pancreatic cancer in relevant microenvironments and demonstrate that this technique can model patient-specific tumors by using primary patient tissue. We assess intrinsic, extrinsic, and spatial tumorigenic phenotypes in bioprinted tissues and find that cellular proliferation, extracellular matrix deposition, and cellular migration are altered in response to extrinsic signals or therapies. Together, this work demonstrates that multi-cell-type bioprinted tissues can recapitulate aspects of in vivo neoplastic tissues and provide a manipulable system for the interrogation of multiple tumorigenic endpoints in the context of distinct tumor microenvironments.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht1egt78%253D&md5=d00d3e243296ac49df727528b89a9ebf
    23. 23
      Datta, P.; Dey, M.; Ataie, Z.; Unutmaz, D.; Ozbolat, I. T. 3D Bioprinting for Reconstituting the Cancer Microenvironment. npj Precis. Oncol. 2020, 4, 18,  DOI: 10.1038/s41698-020-0121-2
      23
      3D bioprinting for reconstituting the cancer microenvironment
      Datta Pallab; Dey Madhuri; Ataie Zaman; Ozbolat Ibrahim T; Unutmaz Derya; Ozbolat Ibrahim T; Ozbolat Ibrahim T; Ozbolat Ibrahim T
      NPJ precision oncology (2020), 4 (), 18 ISSN:2397-768X.
      The cancer microenvironment is known for its complexity, both in its content as well as its dynamic nature, which is difficult to study using two-dimensional (2D) cell culture models. Several advances in tissue engineering have allowed more physiologically relevant three-dimensional (3D) in vitro cancer models, such as spheroid cultures, biopolymer scaffolds, and cancer-on-a-chip devices. Although these models serve as powerful tools for dissecting the roles of various biochemical and biophysical cues in carcinoma initiation and progression, they lack the ability to control the organization of multiple cell types in a complex dynamic 3D architecture. By virtue of its ability to precisely define perfusable networks and position of various cell types in a high-throughput manner, 3D bioprinting has the potential to more closely recapitulate the cancer microenvironment, relative to current methods. In this review, we discuss the applications of 3D bioprinting in mimicking cancer microenvironment, their use in immunotherapy as prescreening tools, and overview of current bioprinted cancer models.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38fltlejug%253D%253D&md5=e865b51d9160bad39d35627109289326
    24. 24
      Sharifi, M.; Baia, Q.; Babadaei, M. M. N.; Chowdhury, F.; Hassan, M.; Taghizadeh, A.; Derakhshankhah, H.; Khan, S.; Hasan, A.; Falahati, M. 3D Bioprinting of Engineered Breast Cancer Constructs for Personalized and Targeted Cancer Therapy. J. Control Rel. 2021, 333, 91– 106,  DOI: 10.1016/j.jconrel.2021.03.026
      There is no corresponding record for this reference.
    25. 25
      Zhou, X.; Zhu, W.; Nowicki, M.; Miao, S.; Cui, H.; Holmes, B.; Glazer, R. I.; Zhang, L. G. 3D Bioprinting a Cell-Laden Bone Matrix for Breast Cancer Metastasis Study. ACS Appl. Mater. Interfaces 2016, 8, 30017– 30026,  DOI: 10.1021/acsami.6b10673
      25
      3D Bioprinting a Cell-Laden Bone Matrix for Breast Cancer Metastasis Study
      Zhou, Xuan; Zhu, Wei; Nowicki, Margaret; Miao, Shida; Cui, Haitao; Holmes, Benjamin; Glazer, Robert I.; Zhang, Lijie Grace
      ACS Applied Materials & Interfaces (2016), 8 (44), 30017-30026CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Metastasis is one of the deadliest consequences of breast cancer, with bone being one of the primary sites of occurrence. Insufficient 3D biomimetic models currently exist to replicate this process in vitro. In this study, we developed a biomimetic bone matrix using 3D bioprinting technol. to investigate the interaction between breast cancer (BrCa) cells and bone stromal cells (fetal osteoblasts and human bone marrow mesenchymal stem cells (MSCs)). A tabletop stereolithog. 3D bioprinter was employed to fabricate a series of bone matrixes consisting of osteoblasts or MSCs encapsulated in gelatin methacrylate (GelMA) hydrogel with nanocryst. hydroxyapatite (nHA). When BrCa cells were introduced into the stromal cell-laden bioprinted matrixes, we found that the growth of BrCa cells was enhanced by the presence of osteoblasts or MSCs, whereas the proliferation of the osteoblasts or MSCs was inhibited by the BrCa cells. The BrCa cells co-cultured with MSCs or osteoblasts presented increased vascular endothelial growth factor (VEGF) secretion in comparison to that of monocultured BrCa cells. Addnl., the alk. phosphatase activity of MSCs or osteoblasts was reduced after BrCa cell co-culture. These results demonstrate that the 3D bioprinted matrix, with BrCa cells and bone stromal cells, provides a suitable model with which to study the interactive effects of cells in the context of an artificial bone microenvironment and thus may serve as a valuable tool for the investigation of postmetastatic breast cancer progression in bone.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslWjsL3N&md5=727074490fefdd2e67cb7428c6123250
    26. 26
      Wang, Y.; Shi, W.; Kuss, M.; Mirza, S.; Qi, D.; Krasnoslobodtsev, A.; Zeng, J.; Band, H.; Band, V.; Duan, B. 3D Bioprinting of Breast Cancer Models for Drug Resistance Study. ACS Biomater. Sci. Eng. 2018, 4, 4401– 4411,  DOI: 10.1021/acsbiomaterials.8b01277
      26
      3D Bioprinting of Breast Cancer Models for Drug Resistance Study
      Wang, Ying; Shi, Wen; Kuss, Mitchell; Mirza, Sameer; Qi, Dianjun; Krasnoslobodtsev, Alexey; Zeng, Jiping; Band, Hamid; Band, Vimla; Duan, Bin
      ACS Biomaterials Science & Engineering (2018), 4 (12), 4401-4411CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)
      Adipose-derived mesenchymal stem/stromal cells (ADMSC) are one of the major stromal cells in the breast cancer microenvironment that promote cancer progression. Previous studies on the effects of ADMSC on breast cancer metastasis and drug resistance, using two-dimensional (2D) cultures, remained inconclusive. In the present study, we compared cocultured ADMSC and human epidermal receptor 2 pos. breast primary breast cancer cells (21PT) in 2D and three-dimensional (3D) cultures and then examd. their response to doxorubicin (DOX). We examd. 3D bioprinted constructs with breast cancer cells in the middle and ADMSC in the edge region, which were made by using dual hydrogel-based bioinks. We found that the percentage of cleaved Caspase-3 pos. cells was significantly lower in the bioprinted constructs with ADMSC and 21PT than that in the cancer cell alone constructs, in response to low DOX dose. We further increased the thickness of the ADMSC layers to mimic the status of obesity and then examd. the effect of ADMSC thickness on DOX resistance and lysyl oxidase (LOX) secretion. In the moderate and thick-layered ADMSC constructs, significantly more cells were stained neg. for cleaved Caspase-3, indicating less apoptosis. Both ADMSC and 21PT intrinsically expressed LOX, regardless of changes in thickness or DOX administration. Notably, treatment with a LOX inhibitor significantly decreased the stiffness in the ADMSC region but did not affect the stiffness in the 21PT region. In addn., LOX inhibitor treatment enhanced DOX sensitivity of 21PT in the bioprinted constructs, as seen by a decrease in LOX secretion and downregulation of ATP-binding cassette transporter gene expression. Taken together, we demonstrate that 3D bioprinted these breast cancer models faithfully reproduce in vivo conditions and should provide better models for examg. breast cancer biol. and for screening for drug discoveries.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1SgsbfO&md5=a79510a12bde91f7726c0bcb0857f2c5
    27. 27
      Badylak, S. F.; Freytes, D. O.; Gilbert, T. W. Reprint of: Extracellular Matrix as a Biological Scaffold Material: Structure and Function. Acta Biomater. 2015, 23, S17– S26,  DOI: 10.1016/j.actbio.2015.07.016
      There is no corresponding record for this reference.
    28. 28
      Skardal, A.; Devarasetty, M.; Kang, H.; Mead, I.; Bishop, C.; Shupe, T.; Lee, S.; Jackson, J.; Yoo, J.; Soker, S.; Atala, A. A Hydrogel Bioink Toolkit for Mimicking Native Tissue Biochemical and Mechanical Properties in Bioprinted Tissue Constructs. Acta Biomater. 2015, 25, 24– 34,  DOI: 10.1016/j.actbio.2015.07.030
      28
      A hydrogel bioink toolkit for mimicking native tissue biochemical and mechanical properties in bioprinted tissue constructs
      Skardal, Aleksander; Devarasetty, Mahesh; Kang, Hyun-Wook; Mead, Ivy; Bishop, Colin; Shupe, Thomas; Lee, Sang Jin; Jackson, John; Yoo, James; Soker, Shay; Atala, Anthony
      Acta Biomaterialia (2015), 25 (), 24-34CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
      Advancement of bioprinting technol. is limited by the availability of materials that both facilitate bioprinting logistics as well as support cell viability and function by providing tissue-specific cues. Herein we describe a modular hyaluronic acid (HA) and gelatin-based hydrogel toolbox comprised of a 2-crosslinker, 2-stage polymn. technique, and the capability to provide tissue specific biochem. and mech. accurate signals to cells within biofabricated tissue constructs. First, we prepd. and characterized several tissue-derived decellularized extracellular matrix-based solns., which contain complex combinations of growth factors, collagens, glycosaminoglycans, and elastin. These solns. can be incorporated into bioinks to provide the important biochem. cues of different tissue types. Second, we employed combinations of PEG-based crosslinkers with varying mol. wts., geometries (linear, 4-arm, and 8-arm), and functional groups to yield hydrogel bioinks that supported extrusion bioprinting and the capability to achieve final construct shear stiffness values ranging from approx. 100 Pa to 20 kPa. Lastly, we integrated these hydrogel bioinks with a 3-D bioprinting platform, and validated their use by bioprinting primary liver spheroids in a liver-specific bioink to create in vitro liver constructs with high cell viability and measurable functional albumin and urea output. This hydrogel bioink system has the potential to be a versatile tool for biofabrication of a wide range of tissue construct types. Biochem. and mech. factors both have important implications in guiding the behavior of cells in vivo, yet both realms are rarely considered together in the context of biofabrication in vitro tissue construct models. We describe a modular hydrogel system that (1) facilitates extrusion bioprinting of cell-laden hydrogels, (2) incorporates tissue-specific factors derived from decellularized tissue extracellular matrix, thus mimicking biochem. tissue profile, and (3) allows control over mech. properties to mimic the tissue stiffness. We believe that employing this technol. to attend to both the biochem. and mech. profiles of tissues, will allow us to more accurately recapitulate the in vivo environment of tissues while creating functional 3-D in vitro tissue constructs that can be used as disease models, personalized medicine, and in vitro drug and toxicol. screening systems.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1GrurnL&md5=c3e7f1490962d6ec2e9bba3fd49b0747
    29. 29
      Kort-Mascort, J.; Bao, G.; Elkashty, O.; Flores-Torres, S.; Munguia-Lopez, J. G.; Jiang, T.; Ehrlicher, A. J.; Mongeau, L.; Tran, S. D.; Kinsella, J. M. Decellularized Extracellular Matrix Composite Hydrogel Bioinks for the Development of 3D Bioprinted Head and Neck in Vitro Tumor Models. ACS Biomater. Sci. Eng. 2021, 5288,  DOI: 10.1021/acsbiomaterials.1c00812
      29
      Decellularized Extracellular Matrix Composite Hydrogel Bioinks for the Development of 3D Bioprinted Head and Neck in Vitro Tumor Models
      Kort-Mascort, Jacqueline; Bao, Guangyu; Elkashty, Osama; Flores-Torres, Salvador; Munguia-Lopez, Jose G.; Jiang, Tao; Ehrlicher, Allen J.; Mongeau, Luc; Tran, Simon D.; Kinsella, Joseph M.
      ACS Biomaterials Science & Engineering (2021), 7 (11), 5288-5300CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)
      Reinforced extracellular matrix (ECM)-based hydrogels recapitulate several mech. and biochem. features found in the tumor microenvironment (TME) in vivo. While these gels retain several crit. structural and bioactive mols. that promote cell-matrix interactivity, their mech. properties tend toward the viscous regime limiting their ability to retain ordered structural characteristics when considered as architectured scaffolds. To overcome this limitation characteristic of pure ECM hydrogels, we present a composite material contg. alginate, a seaweed-derived polysaccharide, and gelatin, denatured collagen, as rheol. modifiers which impart mech. integrity to the biol. active decellularized ECM (dECM). After an optimization process, the reinforced gel proposed is mech. stable and bioprintable and has a stiffness within the expected physiol. values. Our hydrogel's elastic modulus has no significant difference when compared to tumors induced in preclin. xenograft head and neck squamous cell carcinoma (HNSCC) mouse models. The bioprinted cell-laden model is highly reproducible and allows proliferation and reorganization of HNSCC cells while maintaining cell viability above 90% for periods of nearly 3 wk. Cells encapsulated in our bioink produce spheroids of at least 3000μm2 of cross-sectional area by day 15 of culture and are pos. for cytokeratin in immunofluorescence quantification, a common marker of HNSCC model validation in 2D and 3D models. We use this in vitro model system to evaluate the std.-of-care small mol. therapeutics used to treat HNSCC clin. and report a 4-fold increase in the IC50 of cisplatin and an 80-fold increase for 5-fluorouracil compared to monolayer cultures. Our work suggests that fabricating in vitro models using reinforced dECM provides a physiol. relevant system to evaluate malignant neoplastic phenomena in vitro due to the phys. and biol. features replicated from the source tissue microenvironment.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXit1CqsbfL&md5=fcbe70382139534a70d5ee57724e9939
    30. 30
      Vilalta, M.; Degano, I.; Bago, J.; Gould, D.; Santos, M.; Garcia-Arranz, M.; Ayats, R.; Fuster, C.; Chernajovsky, Y.; Garcia-Olmo, D.; Rubio, N.; Blanco, J. Biodistribution, Long-Term Survival, and Safety of Human Adipose Non-Invasive, Tissue-Derived Mesenchymal Stem Cells Transplanted in Nude Mice by High Sensitivity Bioluminescence Imaging. Stem Cells Dev. 2008, 17, 993– 1004,  DOI: 10.1089/scd.2007.0201
      30
      Biodistribution, long-term survival, and safety of human adipose tissue-derived mesenchymal stem cells transplanted in nude mice by high sensitivity non-invasive bioluminescence imaging
      Vilalta Marta; Degano Irene R; Bago Juli; Gould David; Santos Monica; Garcia-Arranz Mariano; Ayats Ramon; Fuster Carme; Chernajovsky Yuti; Garcia-Olmo Damian; Rubio Nuria; Blanco Jeronimo
      Stem cells and development (2008), 17 (5), 993-1003 ISSN:.
      Cultivated murine bone marrow mesenchymal stem cells (MSCs) frequently accumulate chromosome abnormalities, become oncogenically transformed, and generate sarcomas when transplanted in mice. Although human MSCs appear to be more resistant, oncogenic transformation has also been observed in MSCs cultivated past the senescence phase. Cell therapy for tissue regeneration using human autologous MSCs requires transplantation of cells previously expanded in vitro. Thus, an important concern is to determine if oncogenic transformation is a necessary outcome of the expansion procedures. We have analyzed the proliferation capacity, organ colonization, and oncogenicity of enhanced green fluorescent protein and luciferase-labeled human adipose tissue-derived mesenchymal stem cells (hAMSCs), implanted in immunocompromised mice during a prolonged time period (8 months) using a non-invasive bioluminescence imaging procedure. Our data indicates that the liver was the preferred target organ for colonization by intramuscular or intravenous implantation of hAMSCs. The implanted cells tended to maintain a steady state, population did not proliferate rapidly after implantation, and no detectable chromosomal abnormalities nor tumors formed during the 8 months of residence in the host's tissues. It would appear that hAMSCs, contrary to their murine correlatives, could be safe candidates for autologous cell therapy procedures since in our experiments they show undetectable predisposition to oncogenic transformation after cultivation in vitro and implantation in mice.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cnjsVChuw%253D%253D&md5=f77bf98021f36ea3cb8f28d6b7c487bb
    31. 31
      Arya, A. D.; Hallur, P. M.; Karkisaval, A. G.; Gudipati, A.; Rajendiran, S.; Dhavale, V.; Ramachandran, B.; Jayaprakash, A.; Gundiah, N.; Chaubey, A. Gelatin Methacrylate Hydrogels as Biomimetic Three-Dimensional Matrixes for Modeling Breast Cancer Invasion and Chemoresponse in Vitro. ACS Appl. Mater. Interfaces 2016, 8, 22005– 22017,  DOI: 10.1021/acsami.6b06309
      31
      Gelatin Methacrylate Hydrogels as Biomimetic Three-Dimensional Matrixes for Modeling Breast Cancer Invasion and Chemoresponse in Vitro
      Arya, Anuradha D.; Hallur, Pavan M.; Karkisaval, Abhijith G.; Gudipati, Aditi; Rajendiran, Satheesh; Dhavale, Vaibhav; Ramachandran, Balaji; Jayaprakash, Aravindakshan; Gundiah, Namrata; Chaubey, Aditya
      ACS Applied Materials & Interfaces (2016), 8 (34), 22005-22017CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Recent studies have shown that three-dimensional (3D) culture environments allow the study of cellular responses in a setting that more closely resembles the in vivo milieu. In this context, hydrogels have become popular scaffold options for the 3D cell culture. Because the mech. and biochem. properties of culture matrixes influence crucial cell behavior, selecting a suitable matrix for replicating in vivo cellular phenotype in vitro is essential for understanding disease progression. Gelatin methacrylate (GelMA) hydrogels have been the focus of much attention because of their inherent bioactivity, favorable hydration and diffusion properties, and ease-of-tailoring of their physicochem. characteristics. Therefore, in this study we examd. the efficacy of GelMA hydrogels as a suitable platform to model specific attributes of breast cancer. We obsd. increased invasiveness in vitro and increased tumorigenic ability in vivo in breast cancer cells cultured on GelMA hydrogels. Further, cells cultured on GelMA matrixes were more resistant to paclitaxel treatment, as shown by the results of cell-cycle anal. and gene expression. This study, therefore, validates GelMA hydrogels as inexpensive, cell-responsive 3D platforms for modeling key characteristics assocd. with breast cancer metastasis, in vitro.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht12jtr3P&md5=8cee042f009e9778fb88261d08c062b9
    32. 32
      Nguyen, A. H.; McKinney, J.; Miller, T.; Bongiorno, T.; McDevitt, T. C. Gelatin Methacrylate Microspheres for Controlled Growth Factor Release. Acta Biomater. 2015, 13, 101– 110,  DOI: 10.1016/j.actbio.2014.11.028
      32
      Gelatin methacrylate microspheres for controlled growth factor release
      Nguyen, Anh H.; McKinney, Jay; Miller, Tobias; Bongiorno, Tom; McDevitt, Todd C.
      Acta Biomaterialia (2015), 13 (), 101-110CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
      Gelatin has been commonly used as a delivery vehicle for various biomols. for tissue engineering and regenerative medicine applications due to its simple fabrication methods, inherent electrostatic binding properties, and proteolytic degradability. Compared to traditional chem. crosslinking methods, such as the use of glutaraldehyde (GA), methacrylate modification of gelatin offers an alternative method to better control the extent of hydrogel crosslinking. Here we examd. the phys. properties and growth factor delivery of gelatin methacrylate (GMA) microparticles (MPs) formulated with a wide range of different crosslinking densities (15-90%). Less methacrylated MPs had decreased elastic moduli and larger mesh sizes compared to GA MPs, with increasing methacrylation correlating to greater moduli and smaller mesh sizes. As expected, an inverse correlation between microparticle crosslinking d. and degrdn. was obsd., with the lowest crosslinked GMA MPs degrading at the fastest rate, comparable to GA MPs. Interestingly, GMA MPs at lower crosslinking densities could be loaded with up to a 10-fold higher relative amt. of growth factor than conventional GA crosslinked MPs, despite the GA MPs having an order of magnitude greater gelatin content. Moreover, a reduced GMA crosslinking d. resulted in more complete release of bone morphogenic protein 4 and basic fibroblast growth factor and accelerated release rate with collagenase treatment. These studies demonstrate that GMA MPs provide a more flexible platform for growth factor delivery by enhancing the relative binding capacity and permitting proteolytic degrdn. tunability, thereby offering a more potent controlled release system for growth factor delivery.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvF2rtb%252FP&md5=ac9c5a7f70cd67cb6d7ff23a851fccb2
    33. 33
      Li, X.; Chen, S.; Li, J.; Wang, X.; Zhang, J.; Kawazoe, N.; Chen, G. 3D Culture of Chondrocytes in Gelatin Hydrogels with Different Stiffness. Polymers 2016, 8, 269,  DOI: 10.3390/polym8080269
      33
      Culture of chondrocytes in gelatin hydrogels with different stiffness
      Li, Xiaomeng; Chen, Shangwu; Li, Jingchao; Wang, Xinlong; Zhang, Jing; Kawazoe, Naoki; Chen, Guoping
      Polymers (Basel, Switzerland) (2016), 8 (8), 269/1-269/15CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)
      Gelatin hydrogels can mimic the microenvironments of natural tissues and encapsulate cells homogeneously, which makes them attractive for cartilage tissue engineering. Both the mech. and biochem. properties of hydrogels can affect the phenotype of chondrocytes. However, the influence of each property on chondrocyte phenotype is unclear due to the difficulty in sepg. the roles of these properties. In this study, we aimed to study the influence of hydrogel stiffness on chondrocyte phenotype while excluding the role of biochem. factors, such as adhesion site d. in the hydrogels. By altering the degree of methacryloyl functionalization, gelatin hydrogels with different stiffnesses of 3.8, 17.1, and 29.9 kPa Young's modulus were prepd. from the same concn. of gelatin methacryloyl (GelMA) macromers. Bovine articular chondrocytes were encapsulated in the hydrogels and cultured for 14 days. The influence of hydrogel stiffness on the cell behaviors including cell viability, cell morphol., and maintenance of chondrogenic phenotype was evaluated. GelMA hydrogels with high stiffness (29.9 kPa) showed the best results on maintaining chondrogenic phenotype. These results will be useful for the design and prepn. of scaffolds for cartilage tissue engineering.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFKksrzE&md5=0042e1bb626ec58efdd2e283e26713ae
    34. 34
      Rajan, N.; Habermehl, J.; Coté, M.-F.; Doillon, C. J.; Mantovani, D. Preparation of Ready-to-Use, Storable and Reconstituted Type I Collagen from Rat Tail Tendon for Tissue Engineering Applications. Nat. Protoc. 2006, 1, 753– 758,  DOI: 10.1038/nprot.2006.430
      There is no corresponding record for this reference.
    35. 35
      Daly, A. C.; Critchley, S. E.; Rencsok, E. M.; Kelly, D. J. A Comparison of Different Bioinks for 3D Bioprinting of Fibrocartilage and Hyaline Cartilage. Biofabrication 2016, 8, 045002  DOI: 10.1088/1758-5090/8/4/045002
      35
      A comparison of different bioinks for 3D bioprinting of fibrocartilage and hyaline cartilage
      Daly, Andrew C.; Critchley, Susan E.; Rencsok, Emily M.; Kelly, Daniel J.
      Biofabrication (2016), 8 (4), 045002/1-045002/10CODEN: BIOFFN; ISSN:1758-5090. (IOP Publishing Ltd.)
      Cartilage is a dense connective tissue with limited self-repair capabilities. Mesenchymal stem cell (MSC) laden hydrogels are commonly used for fibrocartilage and articular cartilage tissue engineering, however they typically lack the mech. integrity for implantation into high load bearing environments. This has led to increased interested in 3D bioprinting of cell laden hydrogel bioinks reinforced with stiffer polymer fibers. The objective of this study was to compare a range of commonly used hydrogel bioinks (agarose, alginate, GelMA and BioINK) for their printing properties and capacity to support the development of either hyaline cartilage or fibrocartilage in vitro. Each hydrogel was seeded with MSCs, cultured for 28 days in the presence of TGF-β3 and then analyzed for markers indicative of differentiation towards either a fibrocartilaginous or hyaline cartilage-like phenotype. Alginate and agarose hydrogels best supported the development of hyaline-like cartilage, as evident by the development of a tissue staining predominantly for type II collagen. In contrast, GelMA and BioIN (a PEGMAbased hydrogel) supported the development of a more fibrocartilage-like tissue, as evident by the development of a tissue contg. both type I and type II collagen. GelMA demonstrated superior printability, generating structures with greater fidelity, followed by the alginate and agarose bioinks. High levels of MSC viability were obsd. in all bioinks post-printing (∼80%). Finally we demonstrate that it is possible to engineer mech. reinforced hydrogels with high cell viability by co-depositing a hydrogel bioink with polycaprolactone filaments, generating composites with bulk compressive moduli comparable to articular cartilage. This study demonstrates the importance of the choice of bioink when bioprinting different cartilaginous tissues for musculoskeletal applications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlvFWru74%253D&md5=ed2a34e8939f4b58c6598e23ba839715
    36. 36
      Habib, A.; Sathish, V.; Mallik, S.; Khoda, B. 3D Printability of Alginate Carboxymethyl Cellulose Hydrogel. Materials 2018, 11, 454,  DOI: 10.3390/ma11030454
      36
      3D printability of alginate-carboxymethyl cellulose hydrogel
      Habib, Ahasan; Sathish, Venkatachalem; Mallik, Sanku; Khoda, Bashir
      Materials (2018), 11 (3), 454/1-454/22CODEN: MATEG9; ISSN:1996-1944. (MDPI AG)
      Three-dimensional (3D) bio-printing is a revolutionary technol. to reproduce a 3D functional living tissue scaffold in-vitro through controlled layer-by-layer deposition of biomaterials along with high precision positioning of cells. Due to its bio-compatibility, natural hydrogels are commonly considered as the scaffold material. However, the mech. integrity of a hydrogel material, esp. in 3D scaffold architecture, is an issue. In this research, a novel hybrid hydrogel, i.e., sodium alginate with CM-cellulose (CMC) is developed and systematic quant. characterization tests are conducted to validate its printability, shape fidelity and cell viability. The outcome of the rheol. and mech. test, filament collapse and fusion test demonstrate the favorable shape fidelity. Three-dimensional scaffold structures are fabricated with the pancreatic cancer cell, BxPC3 and the 86% cell viability is recorded after 23 days. This hybrid hydrogel can be a potential biomaterial in 3D bioprinting process and the outlined characterization techniques open an avenue directing reproducible printability and shape fidelity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpvFSrtrY%253D&md5=8ca9cfb6d20dbf7f28aed722125a1d5d
    37. 37
      Yin, J.; Yan, M.; Wang, Y.; Fu, J.; Suo, H. 3D Bioprinting of Low-Concentration Cell-Laden Gelatin Methacrylate (GelMA) Bioinks with a Two-Step Cross-Linking Strategy. ACS Appl. Mater. Interfaces 2018, 10, 6849– 6857,  DOI: 10.1021/acsami.7b16059
      37
      3D Bioprinting of Low-Concentration Cell-Laden Gelatin Methacrylate (GelMA) Bioinks with a Two-Step Cross-linking Strategy
      Yin, Jun; Yan, Mengling; Wang, Yancheng; Fu, Jianzhong; Suo, Hairui
      ACS Applied Materials & Interfaces (2018), 10 (8), 6849-6857CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Methacrylated gelatin (GelMA) has been widely used as a tissue-engineered scaffold material, but only low-concn. GelMA hydrogels were found to be promising cell-laden bioinks with excellent cell viability. In this work, we reported a strategy for precise deposition of 5% (w/v) cell-laden GelMA bioinks into controlled microarchitectures with high cell viability using extrusion-based three-dimensional (3D) bioprinting. By adding gelatin into GelMA bioinks, a two-step crosslinking combining the rapid and reversible thermo-crosslinking of gelatin with irreversible photo-crosslinking of GelMA was achieved. The GelMA/gelatin bioinks showed significant advantages in processability because the tunable rheol. and the rapid thermo-crosslinking of bioinks improved the shape fidelity after bioprinting. Here, the rheol., mech. properties, and swelling of GelMA/gelatin bioinks with different concn. ratios were carefully characterized to obtain the optimized bioprinting setup. We successfully printed the 5% (w/v) GelMA with 8% (w/v) gelatin into 3D structures, which had the similar geometrical resoln. as that of the structures printed by 30% (w/v) GelMA bioinks. Moreover, the cell viability of 5/8% (w/v) GelMA/gelatin bioinks was demonstrated by in vitro culture and cell printing of bone marrow stem cells (BMSCs). Larger BMSC spreading area was found on 5/8% (w/v) GelMA/gelatin scaffolds, and the BMSC viability after the printing of 5/8% (w/v) GelMA/gelatin cell-laden bioinks was more than 90%, which was very close to the viability of printing pure 5% (w/v) GelMA cell-laden bioinks. Therefore, this printing strategy of GelMA/gelatin bioinks may extensively extend the applications of GelMA hydrogels for tissue engineering, organ printing, or drug delivery.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1ylsb0%253D&md5=926ddf4272aa7923de1cf4ceb0ec5d68
    38. 38
      Schindelin, J.; Arganda-Carreras, I.; Frise, E.; Kaynig, V.; Longair, M.; Pietzsch, T.; Cardona, A. Fiji: An Open-Source Platform for Biological-Image Analysis. Nat. Methods 2012, 9, 676– 682,  DOI: 10.1038/nmeth.2019
      38
      Fiji: an open-source platform for biological-image analysis
      Schindelin, Johannes; Arganda-Carreras, Ignacio; Frise, Erwin; Kaynig, Verena; Longair, Mark; Pietzsch, Tobias; Preibisch, Stephan; Rueden, Curtis; Saalfeld, Stephan; Schmid, Benjamin; Tinevez, Jean-Yves; White, Daniel James; Hartenstein, Volker; Eliceiri, Kevin; Tomancak, Pavel; Cardona, Albert
      Nature Methods (2012), 9 (7_part1), 676-682CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
      Fiji is a distribution of the popular open-source software ImageJ focused on biol.-image anal. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biol. research communities.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVKnurbJ&md5=ad150521a33367d37a800bee853dd9db
    39. 39
      Rijal, G.; Li, W. A Versatile 3D Tissue Matrix Scaffold System for Tumor Modeling and Drug Screening. Sci. Adv. 2017, 3, 1– 17,  DOI: 10.1126/sciadv.1700764
      There is no corresponding record for this reference.
    40. 40
      Dawson, H. D. A Comparative Assessment of the Pig, Mouse and Human Genomes. In In The Minipig in Biomedical Research; CRC Press: US, 2011 pp. 323– 342,  DOI: 10.1201/b11356-28 .
      There is no corresponding record for this reference.
    41. 41
      Crapo, P. M.; Gilbert, T. W.; Badylak, S. F. An Overview of Tissue and Whole Organ Decellularization Processes. Biomaterials 2011, 32, 3233– 3243,  DOI: 10.1016/j.biomaterials.2011.01.057
      41
      An overview of tissue and whole organ decellularization processes
      Crapo, Peter M.; Gilbert, Thomas W.; Badylak, Stephen F.
      Biomaterials (2011), 32 (12), 3233-3243CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      A review. Biol. scaffold materials composed of extracellular matrix (ECM) are typically derived by processes that involve decellularization of tissues or organs. Preservation of the complex compn. and three-dimensional ultrastructure of the ECM is highly desirable but it is recognized that all methods of decellularization result in disruption of the architecture and potential loss of surface structure and compn. Phys. methods and chem. and biol. agents are used in combination to lyse cells, followed by rinsing to remove cell remnants. Effective decellularization methodol. is dictated by factors such as tissue d. and organization, geometric and biol. properties desired for the end product, and the targeted clin. application. Tissue decellularization with preservation of ECM integrity and bioactivity can be optimized by making educated decisions regarding the agents and techniques utilized during processing. An overview of decellularization methods, their effect upon resulting ECM structure and compn., and recently described perfusion techniques for whole organ decellularization techniques are presented herein.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisVOitbg%253D&md5=4759fe7e06542860b96c529c53e2806a
    42. 42
      Insua-Rodríguez, J.; Oskarsson, T. The Extracellular Matrix in Breast Cancer. Adv. Drug Delivery Rev. 2016, 97, 41– 55,  DOI: 10.1016/j.addr.2015.12.017
      42
      The extracellular matrix in breast cancer
      Insua-Rodriguez, Jacob; Oskarsson, Thordur
      Advanced Drug Delivery Reviews (2016), 97 (), 41-55CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
      The extracellular matrix (ECM) is increasingly recognized as an important regulator in breast cancer. ECM in breast cancer development features numerous changes in compn. and organization when compared to the mammary gland under homeostasis. Matrix proteins that are induced in breast cancer include fibrillar collagens, fibronectin, specific laminins and proteoglycans as well as matricellular proteins. Growing evidence suggests that many of these induced ECM proteins play a major functional role in breast cancer progression and metastasis. A no. of the induced ECM proteins have moreover been shown to be essential components of metastatic niches, promoting stem/progenitor signaling pathways and metastatic growth. ECM remodeling enzymes are also markedly increased, leading to major changes in the matrix structure and biomech. properties. Importantly, several ECM components and ECM remodeling enzymes are specifically induced in breast cancer or during tissue regeneration while healthy tissues under homeostasis express exceedingly low levels. This may indicate that ECM and ECM-assocd. functions may represent promising drug targets against breast cancer, providing important specificity that could be utilized when developing therapies.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XisleqtQ%253D%253D&md5=fe723d13450eedd105ca0b802ef0fc79
    43. 43
      Correia, A. L.; Bissell, M. J. The Tumor Microenvironment Is a Dominant Force in Multidrug Resistance. Drug Resist. Update 2012, 15, 39– 49,  DOI: 10.1016/j.drup.2012.01.006
      43
      The tumor microenvironment is a dominant force in multidrug resistance
      Correia, Ana Luisa; Bissell, Mina J.
      Drug Resistance Updates (2012), 15 (1-2), 39-49CODEN: DRUPFW; ISSN:1368-7646. (Elsevier Ltd.)
      A review. The emergence of clin. drug resistance is still one of the most challenging factors in cancer treatment effectiveness. Until more recently, the assumption has been that random genetic lesions are sufficient to explain the progression of malignancy and escape from chemotherapy. Here we propose an addnl. perspective, one in which the tumor cells despite the malignant genome could find a microenvironment either within the tumor or as a dormant cell to remain polar and blend into an organized context. Targeting this dynamic interplay could be considered a new avenue to prevent therapeutic resistance, and may even provide a promising effective cancer treatment.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xmslyns7s%253D&md5=1421f32aab73ee0ea3a4f898dd5487c1
    44. 44
      Wei, S. C.; Fattet, L.; Tsai, J. H.; Guo, Y.; Pai, V. H.; Majeski, H. E.; Chen, A. C.; Sah, R. L.; Taylor, S. S.; Engler, A. J.; Yang, J. Matrix Stiffness Drives Epithelial-Mesenchymal Transition and Tumour Metastasis through a TWIST1-G3BP2 Mechanotransduction Pathway. Nat. Cell Biol. 2015, 17, 678– 688,  DOI: 10.1038/ncb3157
      44
      Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway
      Wei, Spencer C.; Fattet, Laurent; Tsai, Jeff H.; Guo, Yurong; Pai, Vincent H.; Majeski, Hannah E.; Chen, Albert C.; Sah, Robert L.; Taylor, Susan S.; Engler, Adam J.; Yang, Jing
      Nature Cell Biology (2015), 17 (5), 678-688CODEN: NCBIFN; ISSN:1465-7392. (Nature Publishing Group)
      Matrix stiffness potently regulates cellular behavior in various biol. contexts. In breast tumors, the presence of dense clusters of collagen fibrils indicates increased matrix stiffness and correlates with poor survival. It is unclear how mech. inputs are transduced into transcriptional outputs to drive tumor progression. Here we report that TWIST1 is an essential mechanomediator that promotes epithelial-mesenchymal transition (EMT) in response to increasing matrix stiffness. High matrix stiffness promotes nuclear translocation of TWIST1 by releasing TWIST1 from its cytoplasmic binding partner G3BP2. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization and synergizes with increasing matrix stiffness to induce EMT and promote tumor invasion and metastasis. In human breast tumors, collagen fiber alignment, a marker of increasing matrix stiffness, and reduced expression of G3BP2 together predict poor survival. Our findings reveal a TWIST1-G3BP2 mechanotransduction pathway that responds to biomech. signals from the tumor microenvironment to drive EMT, invasion and metastasis.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnsVWrtLw%253D&md5=a92815227eadd28a59e440c0d3d2005d
    45. 45
      Balestrini, J. L.; Niklason, L. E. Extracellular Matrix as a Driver for Lung Regeneration. Ann. Biomed. Eng. 2015, 43, 568– 576,  DOI: 10.1007/s10439-014-1167-5
      45
      Extracellular matrix as a driver for lung regeneration
      Balestrini Jenna L; Niklason Laura E
      Annals of biomedical engineering (2015), 43 (3), 568-76 ISSN:.
      Extracellular matrix has manifold roles in tissue mechanics, guidance of cellular behavior, developmental biology, and regenerative medicine. Over the past several decades, various pre-clinical and clinical studies have shown that many connective tissues may be replaced and/or regenerated using suitable extracellular matrix scaffolds. More recently, decellularization of lung tissue has shown that gentle removal of cells can leave behind a "footprint" within the matrix that may guide cellular adhesion, differentiation and homing following cellular repopulation. Fundamental issues like understanding matrix composition and micro-mechanics remain difficult to tackle, largely because of a lack of available assays and tools for systematically characterizing intact matrix from tissues and organs. This review will critically examine the role of engineered and native extracellular matrix in tissue and lung regeneration, and provide insights into directions for future research and translation.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M3jtFCqsg%253D%253D&md5=1da133ce505afd70f8aefc712a492d1a
    46. 46
      Schwab, A.; Levato, R.; D’Este, M.; Piluso, S.; Eglin, D.; Malda, J. Printability and Shape Fidelity of Bioinks in 3D Bioprinting. Chem. Rev. 2020, 120, 11028– 11055,  DOI: 10.1021/acs.chemrev.0c00084
      46
      Printability and Shape Fidelity of Bioinks in 3D Bioprinting
      Schwab, Andrea; Levato, Riccardo; D'Este, Matteo; Piluso, Susanna; Eglin, David; Malda, Jos
      Chemical Reviews (Washington, DC, United States) (2020), 120 (19), 11028-11055CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. Three-dimensional bioprinting uses additive manufg. techniques for the automated fabrication of hierarchically organized living constructs. The building blocks are often hydrogel-based bioinks, which need to be printed into structures with high shape fidelity to the intended computer-aided design. For optimal cell performance, relatively soft and printable inks are preferred, although these undergo significant deformation during the printing process, which may impair shape fidelity. While the concept of good or poor printability seems rather intuitive, its quant. definition lacks consensus and depends on multiple rheol. and chem. parameters of the ink. This review discusses qual. and quant. methodologies to evaluate printability of bioinks for extrusion- and lithog.-based bioprinting. The physicochem. parameters influencing shape fidelity are discussed, together with their importance in establishing new models, predictive tools and printing methods that are deemed instrumental for the design of next-generation bioinks, and for reproducible comparison of their structural performance.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhs1yjt73N&md5=09c28195ff8c4992dbdba90ff583f5a7
    47. 47
      Yang, X.; Lu, Z.; Wu, H.; Li, W.; Zheng, L.; Zhao, J. Collagen-Alginate as Bioink for Three-Dimensional (3D) Cell Printing Based Cartilage Tissue Engineering. Mater. Sci. Eng., C 2018, 83, 195– 201,  DOI: 10.1016/j.msec.2017.09.002
      47
      Collagen-alginate as bioink for three-dimensional (3D) cell printing based cartilage tissue engineering
      Yang, Xingchen; Lu, Zhenhui; Wu, Huayu; Li, Wei; Zheng, Li; Zhao, Jinmin
      Materials Science & Engineering, C: Materials for Biological Applications (2018), 83 (), 195-201CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)
      Articular cartilage repair is still a huge challenge for researchers and clinicians. 3D bioprinting could be an innovative technol. for cartilage tissue engineering. In this study, we used collagen type I (COL) or agarose (AG) mixed with sodium alginate (SA) to serve as 3D bioprinting bioinks and incorporated chondrocytes to construct in vitro 3D printed cartilage tissue. Swelling ratio, mech. properties, SEM (SEM), cell viability and cytoskeleton, biochem. anal. and quant. real-time polymerase chain reaction (qRT-PCR) were performed to investigate the function of different bioinks in 3D printing cartilage tissue engineering applications. The results showed that the mech. strength was improved in both SA/COL and SA/AG groups compared to SA alone. Besides, the addn. of COL or AG has little impact on gelling behavior, demonstrating the advantage as bioinks for 3D printing. Among the three scaffolds, SA/COL could distinctly facilitated cell adhesion, accelerated cell proliferation and enhanced the expression of cartilage specific genes such as Acan, Col2al and Sox9 than the other two groups. Lower expression of Col1a1, the fibrocartilage marker, was present in SA/COL group than that in both of SA and SA/AG groups. The results indicated that SA/COL effectively suppressed dedifferentiation of chondrocytes and preserved the phenotype. In summary, 3D bioprinted SA/COL with favorable mech. strength and biol. functionality is promising in cartilage tissue engineering.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFOhsr%252FK&md5=69d2bf64c53a59d3bb065b4ef97f36d0
    48. 48
      Ying, G.; Jiang, N.; Yu, C.; Zhang, Y. S. Three-Dimensional Bioprinting of Gelatin Methacryloyl (GelMA). Bio-Des. Manuf. 2018, 1, 215– 224,  DOI: 10.1007/s42242-018-0028-8
      48
      Three-dimensional bioprinting of gelatin methacryloyl (GelMA)
      Ying, Guoliang; Jiang, Nan; Yu, Cunjiang; Zhang, Yu Shrike
      Bio-Design and Manufacturing (2018), 1 (4), 215-224CODEN: BMIAC3; ISSN:2522-8552. (Springer)
      A review. The three-dimensional (3D) bioprinting technol. has progressed tremendously over the past decade. By controlling the size, shape, and architecture of the bioprinted constructs, 3D bioprinting allows for the fabrication of tissue/organ-like constructs with strong structural-functional similarity with their in vivo counterparts at high fidelity. The bioink, a blend of biomaterials and living cells possessing both high biocompatibility and printability, is a crit. component of bioprinting. In particular, gelatin methacryloyl (GelMA) has shown its potential as a viable bioink material due to its suitable biocompatibility and readily tunable physicochem. properties. Current GelMA-based bioinks and relevant bioprinting strategies for GelMA bioprinting are briefly reviewed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVaksbrO&md5=0f6b004663d1b554684c9a84432994bf
    49. 49
      Gao, F.; Xu, Z.; Liang, Q.; Li, H.; Peng, L.; Wu, M.; Zhao, X.; Cui, X.; Ruan, C.; Liu, W. Osteochondral Regeneration with 3D-Printed Biodegradable High-Strength Supramolecular Polymer Reinforced-Gelatin Hydrogel Scaffolds. Advanced. Science 2019, 6, 1900867,  DOI: 10.1002/advs.201900867
      49
      Osteochondral Regeneration with 3D-Printed Biodegradable High-Strength Supramolecular Polymer Reinforced-Gelatin Hydrogel Scaffolds
      Gao Fei; Xu Ziyang; Li Haofei; Liu Wenguang; Liang Qingfei; Peng Liuqi; Wu Mingming; Zhao Xiaoli; Cui Xu; Ruan Changshun
      Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2019), 6 (15), 1900867 ISSN:2198-3844.
      Biomacromolecules with poor mechanical properties cannot satisfy the stringent requirement for load-bearing as bioscaffolds. Herein, a biodegradable high-strength supramolecular polymer strengthened hydrogel composed of cleavable poly(N-acryloyl 2-glycine) (PACG) and methacrylated gelatin (GelMA) (PACG-GelMA) is successfully constructed by photo-initiated polymerization. Introducing hydrogen bond-strengthened PACG contributes to a significant increase in the mechanical strengths of gelatin hydrogel with a high tensile strength (up to 1.1 MPa), outstanding compressive strength (up to 12.4 MPa), large Young's modulus (up to 320 kPa), and high compression modulus (up to 837 kPa). In turn, the GelMA chemical crosslinking could stabilize the temporary PACG network, showing tunable biodegradability by adjusting ACG/GelMA ratios. Further, a biohybrid gradient scaffold consisting of top layer of PACG-GelMA hydrogel-Mn(2+) and bottom layer of PACG-GelMA hydrogel-bioactive glass is fabricated for repair of osteochondral defects by a 3D printing technique. In vitro biological experiments demonstrate that the biohybrid gradient hydrogel scaffold not only supports cell attachment and spreading but also enhances gene expression of chondrogenic-related and osteogenic-related differentiation of human bone marrow stem cells. Around 12 weeks after in vivo implantation, the biohybrid gradient hydrogel scaffold significantly facilitates concurrent regeneration of cartilage and subchondral bone in a rat model.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3Mvntlyluw%253D%253D&md5=23d4f3d8094e54756b27f9fd562923b3
    50. 50
      Badaoui, M.; Mimsy-Julienne, C.; Saby, C.; Van Gulick, L.; Peretti, M.; Jeannesson, P.; Morjani, H.; Ouadid-Ahidouch, H. Collagen Type 1 Promotes Survival of Human Breast Cancer Cells by Overexpressing Kv10.1 Potassium and Orai1 Calcium Channels through DDR1-Dependent Pathway. Oncotarget 2018, 9, 24653– 24671,  DOI: 10.18632/oncotarget.19065
      50
      Collagen type 1 promotes survival of human breast cancer cells by overexpressing Kv10.1 potassium and Orai1 calcium channels through DDR1-dependent pathway
      Badaoui Mehdi; Mimsy-Julienne Cloe; Peretti Marta; Ouadid-Ahidouch Halima; Saby Charles; Van Gulick Laurence; Jeannesson Pierre; Morjani Hamid
      Oncotarget (2018), 9 (37), 24653-24671 ISSN:.
      Collagen type 1 is among the tumor microenvironment (TM) factors, that regulates proliferation, survival, migration and invasion. Ion channels are key players in interactions between tumor cells and TM. Kv10.1 has been shown to play an essential role in breast cancer cell proliferation and migration by permitting Ca(2+) influx notably via Orai1. Here, we show that human breast cancer (BC) cells growing, in culture media completely devoid of the serum and seeded on collagen 1 coating, exhibited less apoptotic rate and a decrease in Bax expression when compared to those grown on plastic. The survival conferred by collagen 1 was completely abolished by removing extracellular Ca(2+) from the culture medium. In addition, Ca(2+) entry was increased in collagen 1 condition along with increased Kv10.1 and Orai1 expressions. Moreover, collagen 1 was able to increase co-localization of Kv10.1 and Orai1 on the plasma membrane. Interestingly, silencing of Kv10.1 and Orai1 reduced survival and Ca(2+)influx without any additive effect. This calcium-dependent survival is accompanied by the activation of ERK1/2, and its pharmacological inhibition completely abolished the increase in Kv10.1 and Orai1 expressions, activities, and the cell survival induced by collagen 1. Moreover, both Kv10.1 and Orai1 knockdown reduced ERK1/2 activation but not Akt. Finally, DDR1 silencing but not β1-integrin reduced the collagen induced survival, ERK1/2 phosphorylation and the expression of Kv10.1 and Orai1. Together these data show that the Kv10.1/Orai1 complex is involved in BC cell survival and this is dependent on collagen 1/DDR1 pathway. Therefore, they represent a checkpoint of tumor progression induced by the tumor microenvironment.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mbktlensw%253D%253D&md5=57be2772d343e381243a1187d467538b
    51. 51
      Chen, Z.; Wang, F.; Zhang, J.; Sun, X.; Yan, Y.; Wang, Y.; Ouyang, J.; Zhang, J.; Honore, T.; Ge, J.; Gu, Z. Study on Development of Composite Hydrogels With Tunable Structures and Properties for Tumor-on-a-Chip. Front. Bioeng. Biotechnol. 2020, 22, 611796,  DOI: 10.3389/fbioe.2020.611796
      There is no corresponding record for this reference.
    52. 52
      Berger, A. J.; Renner, C. M.; Hale, I.; Yang, X.; Ponik, S. M.; Weisman, P. S.; Masters, K. S.; Kreeger, P. K. Scaffold Stiffness Influences Breast Cancer Cell Invasion via EGFR-Linked Mena Upregulation and Matrix Remodeling. Matrix Biol. 2020, 85-86, 80– 93,  DOI: 10.1016/j.matbio.2019.07.006
      52
      Scaffold stiffness influences breast cancer cell invasion via EGFR-linked Mena upregulation and matrix remodeling
      Berger, Anthony J.; Renner, Carine M.; Hale, Isaac; Yang, Xinhai; Ponik, Suzanne M.; Weisman, Paul S.; Masters, Kristyn S.; Kreeger, Pamela K.
      Matrix Biology (2020), 85-86 (), 80-93CODEN: MTBOEC; ISSN:0945-053X. (Elsevier B.V.)
      Clin., increased breast tumor stiffness is assocd. with metastasis and poorer outcomes. Yet, in vitro studies of tumor cells in 3D scaffolds have found decreased invasion in stiffer environments. To resolve this apparent contradiction, MDA-MB-231 breast tumor spheroids were embedded in 'low' (2 kPa) and 'high' (12 kPa) stiffness 3D hydrogels comprised of methacrylated gelatin/collagen I, a material that allows for physiol.-relevant changes in stiffness while matrix d. is held const. Cells in high stiffness materials exhibited delayed invasion, but more abundant actin-enriched protrusions, compared to those in low stiffness. We find that cells in high stiffness had increased expression of Mena, an invadopodia protein assocd. with metastasis in breast cancer, as a result of EGFR and PLCγ1 activation. As invadopodia promote invasion through matrix remodeling, we examd. matrix organization and detd. that spheroids in high stiffness displayed a large fibronectin halo. Interestingly, this halo did not result from increased fibronectin prodn., but rather from Mena/α5 integrin dependent organization. In high stiffness environments, FN1 knockout inhibited invasion while addn. of exogenous cellular fibronectin lessened the invasion delay. Anal. of fibronectin isoforms demonstrated that EDA-fibronectin promoted invasion and that clin. invasive breast cancer specimens displayed elevated EDA-fibronectin. Combined, our data support a mechanism by which breast cancer cells respond to stiffness and render the environment conducive to invasion. More broadly, these findings provide important insight on the roles of matrix stiffness, compn., and organization in promoting tumor invasion.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVeltb7N&md5=62f211b1cdd3991ed931866fba8b4d23
    53. 53
      Criscitiello, C.; Esposito, A.; Curigliano, G. Tumor-Stroma Crosstalk: Targeting Stroma in Breast Cancer. Curr. Opin. Oncol. 2014, 26, 551– 555,  DOI: 10.1097/CCO.0000000000000122
      53
      Tumor-stroma crosstalk: targeting stroma in breast cancer
      Criscitiello, Carmen; Esposito, Angela; Curigliano, Giuseppe
      Current Opinion in Oncology (2014), 26 (6), 551-555CODEN: CUOOE8; ISSN:1040-8746. (Lippincott Williams & Wilkins)
      Purpose of review: Combinatorial strategies in cancer medicine will not only target cancer cell-intrinsic pathways, but also cancer cell-extrinsic cells, pathways, and mediators of the tumor microenvironment. The aim of the present review is to define the roles of the tumor microenvironment in primary and metastatic breast cancer progression. Recent findings: The cancer microenvironment is composed of nontransformed host stromal cells, such as endothelial cells, fibroblasts, various immune cells, and a complex extracellular matrix secreted by both the normal and neoplastic cells embedded in it. The stromal constituents contribute to the core and emergent hallmarks of cancer. In particular, they can boost sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metab., and evading immune destruction. Summary: The stromal cells play a role in enabling or enhancing multiple hallmark capabilities in tumor microenvironment. This is a background for therapeutic-targeting strategies aimed to abrogate the stroma's contribution. Targeting tumor-assocd. fibroblasts, macrophages, angiogenesis and enhancing immune response may represent a paradigm-shifting approach to treating human cancer in the near future.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslWitLfM&md5=88156fa1cd93e20a569ad080de2b6f4d
    54. 54
      Dias, A. S.; Almeida, C. R.; HelguerobIo, L. A.; Duarte, F. Metabolic Crosstalk in the Breast Cancer Microenvironment. Eur. J. Cancer 2019, 121, 154– 171,  DOI: 10.1016/j.ejca.2019.09.002
      54
      Metabolic crosstalk in the breast cancer microenvironment
      Dias, Ana S.; Almeida, Catarina R.; Helguero, Luisa A.; Duarte, Iola F.
      European Journal of Cancer (2019), 121 (), 154-171CODEN: EJCAEL; ISSN:0959-8049. (Elsevier Ltd.)
      A review. During tumorigenesis, breast tumor cells undergo metabolic reprogramming, which generally includes enhanced glycolysis, tricarboxylic acid cycle activity, glutaminolysis and fatty acid biosynthesis. However, the extension and functional importance of these metabolic alterations may diverge not only according to breast cancer subtypes, but also depending on the interaction of cancer cells with the complex surrounding microenvironment. This microenvironment comprises a variety of non-cancerous cells, such as immune cells (e.g. macrophages, lymphocytes, natural killer cells), fibroblasts, adipocytes and endothelial cells, together with extracellular matrix components and sol. factors, which influence cancer progression and are predictive of clin. outcome. The continuous interaction between cancer and stromal cells results in metabolic competition and symbiosis, with oncogenic-driven metabolic reprogramming of cancer cells shaping the metab. of neighboring cells and vice versa. This review addresses current knowledge on this metabolic crosstalk within the breast tumor microenvironment (TME). Improved understanding of how metab. in the TME modulates cancer development and evasion of tumor-suppressive mechanisms may provide clues for novel anticancer therapeutics directed to metabolic targets.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVKitb7N&md5=83828aafba58a4a53877a34b218127d8
    55. 55
      Raub, C.; Putnam, A.; Tromberg, B.; George, S. Predicting Bulk Mechanical Properties of Cellularized Collagen Gels Using Multiphoton Microscopy. Acta Biomater. 2010, 6, 4657– 4665,  DOI: 10.1016/j.actbio.2010.07.004
      55
      Predicting bulk mechanical properties of cellularized collagen gels using multiphoton microscopy
      Raub, C. B.; Putnam, A. J.; Tromberg, B. J.; George, S. C.
      Acta Biomaterialia (2010), 6 (12), 4657-4665CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
      Cellularized collagen gels are a common model in tissue engineering, but the relationship between the microstructure and bulk mech. properties is only partially understood. Multiphoton microscopy (MPM) is an ideal non-invasive tool for examg. collagen microstructure, cellularity and crosslink content in these gels. In order to identify robust image parameters that characterize microstructural determinants of the bulk elastic modulus, we performed serial MPM and mech. tests on acellular and cellularized (normal human lung fibroblasts) collagen hydrogels, before and after glutaraldehyde crosslinking. Following gel contraction over 16 days, cellularized collagen gel content approached that of native connective tissues (∼200 mg ml-1). Young's modulus (E) measurements from acellular collagen gels (range 0.5-12 kPa) exhibited a power-law concn. dependence (range 3-9 mg ml-1) with exponents from 2.1 to 2.2, similar to other semiflexible biopolymer networks such as fibrin and actin. In contrast, cellularized collagen gel stiffness (range 0.5-27 kPa) produced concn.-dependent exponents of 0.7 uncrosslinked and 1.1 crosslinked (range ∼5-200 mg ml-1). The variation in E of cellularized collagen hydrogels can be explained by a power-law dependence on robust image parameters: either the second harmonic generation (SHG) and two-photon fluorescence (TPF) (matrix component) skewness (R 2 = 0.75, exponents of -1.0 and -0.6, resp.); or alternatively the SHG and TPF (matrix component) speckle contrast (R 2 = 0.83, exponents of -0.7 and -1.8, resp.). Image parameters based on the cellular component of TPF signal did not improve the fits. The concn. dependence of E suggests enhanced stress relaxation in cellularized vs. acellular gels. SHG and TPF image skewness and speckle contrast from cellularized collagen gels can predict E by capturing mech. relevant information on collagen fiber, cell and crosslink d.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht12ktr7L&md5=c857761720d110525d54d207d40cf579
    56. 56
      Singhai, R.; Patil, V. W.; Jaiswal, S. R.; Patil, S. D.; Tayade, M. B.; Patil, A. V. E-Cadherin as a Diagnostic Biomarker in Breast Cancer. N. Am. J. Med. Sci. 2011, 3, 227– 233,  DOI: 10.4297/najms.2011.3227
      56
      E-Cadherin as a diagnostic biomarker in breast cancer
      Singhai Rajeev; Patil Vinayak W; Jaiswal Sanjog R; Patil Shital D; Tayade Mukund B; Patil Amit V
      North American journal of medical sciences (2011), 3 (5), 227-33 ISSN:.
      BACKGROUND: E-cadherin is expressed in most normal epithelial tissues. Selective loss of E-cadherin can cause dedifferentiation and invasiveness in human carcinomas, leading E-cadherin to be classified as a tumor suppressor. Loss of E-cadherin has been demonstrated in invasive lobular carcinoma of the breast, but the relationship between E-cadherin expression and breast cancer histopathology and prognosis is less clear. AIM: Our objective was to assess loss of E-cadherin as a diagnostic breast cancer biomarker and as an aid to the sub-classification of invasive breast cancer. We also correlated the loss of expression of E-cadherin with various clinical and pathologic prognostic factors. MATERIAL AND METHODS: Breast cancer specimens after modified radical mastectomy were obtained from women who underwent surgery at Grant Medical College and Sir J.J Group of Hospitals, Mumbai, India between May 2007 and October 2010. We stained 276 breast cancers specimens with monoclonal antibodies to E-cadherin. The breast cancers were classified by histopathological type. RESULTS: A statistical correlation of E-cadherin loss with a positive diagnosis of invasive lobular carcinoma was found, but there was no correlation with any prognostic tumor variables. A negative E-cadherin stain was a sensitive and specific biomarker to confirm the diagnosis of invasive lobular carcinoma (specificity 97.7%; negative predictive value 96.8%; sensitivity 88.1%; and positive predictive value 91.2%). Positive E-cadherin expression was also associated with tubulolobular carcinomas. CONCLUSIONS: E-cadherin immunohistochemistry is helpful in classifying breast cancer cases with indeterminate histopathologic features. E-cadherin loss is uncommon in non-lobular carcinomas but shows no correlation to currently established prognostic variables.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38ngsVOksQ%253D%253D&md5=5a1ff41f511de33f5f741ba0d75d8a79
    57. 57
      Liu, J.; Shen, J.; Wu, H.; Li, X.; Wen, X.; Du, C.; Zhang, G. Collagen 1A1 (COL1A1) Promotes Metastasis of Breast Cancer and Is a Potential Therapeutic Target. Discov. Med. 2018, 25, 211– 223
      57
      Collagen 1A1 (COL1A1) promotes metastasis of breast cancer and is a potential therapeutic target
      Liu Jing; Shen Jia-Xin; Li Xiao-Li; Wen Xiao-Fen; Du Cai-Wen; Zhang Guo-Jun; Shen Jia-Xin; Zhang Guo-Jun; Wu Hua-Tao; Li Xiao-Li; Wen Xiao-Fen; Du Cai-Wen
      Discovery medicine (2018), 25 (139), 211-223 ISSN:.
      PURPOSE: Extracellular matrix (ECM) is an important component of tumor microenvironment and plays critical roles in cancer development and metastasis, in which collagen is the major structural protein. Collagen type I alpha 1 (COL1A1) is reportedly associated with the development of several human diseases. However, the functions and mechanisms of cellular expression of COL1A1 in breast cancer remain unknown. The purpose of this study is to investigate the cellular expression of COL1A1 in breast cancer cells and patients, and its role in the development and metastasis of breast cancer. METHODS: The immunofluorescence staining was used to identify the cellular location of COL1A1 in breast cancer cell lines. Real-time PCR was applied to measuring the mRNA levels of COL1A1 and genes of interest. Wound healing and transwell assay were performed to evaluate the effect of COL1A1 on metastasis of breast cancer cells. 97 patients with breast cancer were recruited in this study for evaluating the correlation of COL1A1 with survival and clinicopathological parameters. RESULTS: COL1A1 was expressed in all examined breast cancer cells. Knockdown of COL1A1 inhibited metastasis of breast cancer cells, with a low-level of CXCR4, independent of the epithelial-mesenchymal transition (EMT) process. In patients with breast cancer, cellular expression of COL1A1 was associated with ER/PR expression and metastasis status. The increased COL1A1 level was associated with poor survival, especially in patients with ER+ breast cancer. Patients with a high-level of COL1A1 showed better cisplatin-based chemotherapy response. CONCLUSION: Cellular expression of COL1A1 could promote breast cancer metastasis. COL1A1 is a new prognostic biomarker and a potential therapeutic target for breast cancer, especially in ER+ patients.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MbnslWjsw%253D%253D&md5=5d0707b0ab32cbac3d4c8b71c90c8c49
    58. 58
      Xu, S.; Xu, H.; Wang, W.; Li, S.; Li, H.; Li, T.; Zhang, W.; Yu, X.; Liu, L. The Role of Collagen in Cancer: From Bench to Bedside. J. Trans. Med. 2019, 17, 309,  DOI: 10.1186/s12967-019-2058-1
      There is no corresponding record for this reference.
    59. 59
      Barcus, C.; O’Leary, K.; Brockman, J.; Rugowski, D.; Liu, Y.; Garcia, N.; Yu, M.; Keely, P.; Eliceiri, K.; Schuler, L. Elevated Collagen-I Augments Tumor Progressive Signals, Intravasation and Metastasis of Prolactin-Induced Estrogen Receptor Alpha Positive Mammary Tumor Cells. Breast Cancer Res. 2017, 19, 9,  DOI: 10.1186/s13058-017-0801-1
      59
      Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells
      Barcus, Craig E.; O'Leary, Kathleen A.; Brockman, Jennifer L.; Rugowski, Debra E.; Liu, Yuming; Garcia, Nancy; Yu, Menggang; Keely, Patricia J.; Eliceiri, Kevin W.; Schuler, Linda A.
      Breast Cancer Research (2017), 19 (), 9/1-9/13CODEN: BRCRFS; ISSN:1465-542X. (BioMed Central Ltd.)
      Background: The development and progression of estrogen receptor alpha pos. (ERα+) breast cancer has been linked epidemiol. to prolactin. However, activation of the canonical mediator of prolactin, STAT5, is assocd. with more differentiated cancers and better prognoses. We have reported that d./stiffness of the extracellular matrix potently modulates the repertoire of prolactin signals in human ERα + breast cancer cells in vitro: stiff matrixes shift the balance from the Janus kinase (JAK)2/STAT5 cascade toward pro-tumor progressive extracellular regulated kinase (ERK)1/2 signals, driving invasion. However, the consequences for behavior of ERα + cancers in vivo are not known. Methods: In order to investigate the importance of matrix d./stiffness in progression of ERα + cancers, we examd. tumor development and progression following orthotopic transplantation of two clonal green fluorescent protein (GFP) + ERα + tumor cell lines derived from prolactin-induced tumors to 8-wk-old wild-type FVB/N (WT) or collagen-dense (col1a1tm1Jae/+) female mice. The latter express a mutant non-cleavable allele of collagen 1a1 "knocked-in" to the col1a1 gene locus, permitting COL1A1 accumulation. We evaluated the effect of the collagen environment on tumor progression by examg. circulating tumor cells and lung metastases, activated signaling pathways by immunohistochem. anal. and immunoblotting, and collagen structure by second harmonic generation microscopy. Results: ERα + primary tumors did not differ in growth rate, histol. type, ERα, or prolactin receptor (PRLR) expression between col1a1tm1Jae/+ and WT recipients. However, the col1a1tm1Jae/+ environment significantly increased circulating tumor cells and the no. and size of lung metastases at end stage. Tumors in col1a1tm1Jae/+ recipients displayed reduced STAT5 activation, and higher phosphorylation of ERK1/2 and AKT. Moreover, intratumoral collagen fibers in col1a1tm1Jae/+ recipients were aligned with tumor projections into the adjacent fat pad, perpendicular to the bulk of the tumor, in contrast to the collagen fibers wrapped around the more uniformly expansive tumors in WT recipients. Conclusions: A collagen-dense extracellular matrix can potently interact with hormonal signals to drive metastasis of ERα +breast cancers.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXivVWmtLg%253D&md5=a9f5609ba1df744ea7180ee276ab9254
    60. 60
      Cheng, Q.; Chang, J.; Geradts, J.; Neckers, L.; Haystead, T.; Spector, N.; Lyerly, H. Amplification and High-Level Expression of Heat Shock Protein 90 Marks Aggressive Phenotypes of Human Epidermal Growth Factor Receptor 2 Negative Breast Cancer. Breast Cancer Res. 2012, 14, R62,  DOI: 10.1186/bcr3168
      60
      Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer
      Cheng, Qing; Chang, Jeffrey T.; Geradts, Joseph; Neckers, Leonard M.; Haystead, Timothy; Spector, Neil L.; Lyerly, H. Kim
      Breast Cancer Research (2012), 14 (), R62CODEN: BRCRFS; ISSN:1465-542X. (BioMed Central Ltd.)
      Introduction: Although human epidermal growth factor receptor 2 (HER2) pos. or estrogen receptor (ER) pos. breast cancers are treated with clin. validated anti-HER2 or anti-estrogen therapies, intrinsic and acquired resistance to these therapies appears in a substantial proportion of breast cancer patients and new therapies are needed. Identification of addnl. mol. factors, esp. those characterized by aggressive behavior and poor prognosis, could prioritize interventional opportunities to improve the diagnosis and treatment of breast cancer. Methods: We compiled a collection of 4,010 breast tumor gene expression data derived from 23 datasets that have been posted on the National Center for Biotechnol. Information (NCBI) Gene Expression Omnibus (GEO) database. We performed a genome-scale survival anal. using Cox-regression survival analyses, and validated using Kaplan-Meier Ests. survival and Cox Proportional-Hazards Regression survival analyses. We conducted a genome-scale anal. of chromosome alteration using 481 breast cancer samples obtained from The Cancer Genome Atlas (TCGA), from which combined expression and copy no. data were available. We assessed the correlation between somatic copy no. alterations and gene expression using anal. of variance (ANOVA). Results: Increased expression of each of the heat shock protein (HSP) 90 isoforms, as well as HSP transcriptional factor 1 (HSF1), was correlated with poor prognosis in different subtypes of breast cancer. High-level expression of HSP90AA1 and HSP90AB1, two cytoplasmic HSP90 isoforms, was driven by chromosome coding region amplifications and were independent factors that led to death from breast cancer among patients with triple-neg. (TNBC) and HER2-/ER+ subtypes, resp. Furthermore, amplification of HSF1 was correlated with higher HSP90AA1 and HSP90AB1 mRNA expression among the breast cancer cells without amplifications of these two genes. A collection of HSP90AA1, HSP90AB1 and HSF1 amplifications defined a subpopulation of breast cancer with up-regulated HSP90 gene expression, and up-regulated HSP90 expression independently elevated the risk of recurrence of TNBC and poor prognosis of HER2-/ER+ breast cancer. Conclusions: Up-regulated HSP90 mRNA expression represents a confluence of genomic vulnerability that renders HER2 neg. breast cancers more aggressive, resulting in poor prognosis. Targeting breast cancer with up-regulated HSP90 may potentially improve the effectiveness of clin. intervention in this disease.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotVyrtrg%253D&md5=4e2c4ac0e924277c07af327f81a9ef31
    61. 61
      Hong, D.; Banerji, U.; Tavana, B.; George, G.; Aaron, J.; Kurzrock, R. Targeting the Molecular Chaperone Heat Shock Protein 90 (HSP90): Lessons Learned and Future Directions. Cancer Treat. Rev. 2013, 39, 375– 387,  DOI: 10.1016/j.ctrv.2012.10.001
      61
      Targeting the molecular chaperone heat shock protein 90 (HSP90): Lessons learned and future directions
      Hong, David S.; Banerji, Udai; Tavana, Bahareh; George, Goldy C.; Aaron, Joann; Kurzrock, Razelle
      Cancer Treatment Reviews (2013), 39 (4), 375-387CODEN: CTREDJ; ISSN:0305-7372. (Elsevier Ltd.)
      A review. Due to the crit. role of heat shock protein 90 (HSP90) in regulating the stability, activity and intracellular sorting of its client proteins involved in multiple oncogenic processes, HSP90 inhibitors are promising therapeutic agents for cancer treatment. In cancer cells, HSP90 client proteins play a major role in oncogenic signal transduction (i.e., mutant epidermal growth factor receptor), angiogenesis (i.e., vascular endothelial growth factor), anti-apoptosis (i.e., AKT), and metastasis (i.e., matrix metalloproteinase 2 and CD91), processes central to maintaining the cancer phenotype. Thus, HSP90 has emerged as a viable target for antitumor drug development, and several HSP90 inhibitors have transitioned to clin. trials. HSP90 inhibitors include geldanamycin and its derivs. (i.e., tanespimycin, alvespimycin, IPI-504), synthetic and small mol. inhibitors (i.e., AUY922, AT13387, STA9090, MPC3100), other inhibitors of HSP90 and its isoforms (i.e., shepherdin and 5'-N-ethylcarboxamideadenosine). With more than 200 "client" proteins, many of them meta-stable and oncogenic, HSP90 inhibition can affect an array of tumors. Here we review the mol. structure of HSP90, structural features of HSP90 inhibition, pharmacodynamic effects and tumor responses in clin. trials of HSP90 inhibitors. We also discuss lessons learned from completed clin. trials of HSP90 inhibitors, and future directions for these promising therapeutic agents.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslGjsLvM&md5=485735cfb38cb7113648b54e2ec99426
    62. 62
      Parkash, J. A. K.; Asotra, K. Calcium Wave Signaling in Cancer Cells. Life Sci. 2010, 87, 587– 595,  DOI: 10.1016/j.lfs.2010.09.013
      62
      Calcium wave signaling in cancer cells
      Parkash, Jai; Asotra, Kamlesh
      Life Sciences (2010), 87 (19-22), 587-595CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)
      A review. Ca2+ functions as an important signaling messenger right from beginning of life to the final moments of the end of life. Ca2+ is needed at several steps of the cell cycle such as early G1, at the G1/S, and G2/M transitions. The Ca2+ signals in the form of time-dependent changes in intracellular Ca2+ concns., [Ca2+]i, are presented as brief spikes organized into regenerative Ca2+ waves. Ca2+-mediated signaling pathways have also been shown to play important roles in carcinogenesis such as transformation of normal cells to cancerous cells, tumor formation and growth, invasion, angiogenesis and metastasis. Since the global Ca2+ oscillations arise from Ca2+ waves initiated locally, it results in stochastic oscillations because although each cell has many IP3Rs and Ca2+ ions, the law of large nos. does not apply to the initiating event which is restricted to very few IP3Rs due to steep Ca2+ concn. gradients. The specific Ca2+ signaling information is likely to be encoded in a calcium code as the amplitude, duration, frequency, waveform or timing of Ca2+ oscillations and decoded again at a later stage. Since Ca2+ channels or pumps involved in regulating Ca2+ signaling pathways show altered expression in cancer, one can target these Ca2+ channels and pumps as therapeutic options to decrease proliferation of cancer cells and to promote their apoptosis. These studies can provide novel insights into alterations in Ca2+ wave patterns in carcinogenesis and lead to the development of newer technologies based on Ca2+ waves for the diagnosis and therapy of cancer.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlyrsL7N&md5=af1b4b6b150398756fd56267e884e8d3
    63. 63
      Ohkubo, T.; Yamazaki, J. T-Type Voltage-Activated Calcium Channel Cav3.1, but Not Cav3.2, Is Involved in the Inhibition of Proliferation and Apoptosis in MCF-7 Human Breast Cancer Cells. Int. J. Oncol. 2012, 41, 267– 275,  DOI: 10.3892/ijo.2012.1422
      63
      T-type voltage-activated calcium channel Cav3.1, but not Cav3.2, is involved in the inhibition of proliferation and apoptosis in MCF-7 human breast cancer cells
      Ohkubo, Tsuyako; Yamazaki, Jun
      International Journal of Oncology (2012), 41 (1), 267-275CODEN: IJONES; ISSN:1019-6439. (International Journal of Oncology)
      T-type voltage-gated Ca2+ channels have unique electrophysiol. properties, suitable for generating Ca2+ oscillations and waves and thus controlling the proliferation of various tumor cells. In the present study, we investigated the role of Cav3.1, a candidate tumor suppressor gene, in neoplastic processes, and compared the differences between Cav3.1 with Cav3.2 channels. While the overexpression of a full-length Cav3.1 clone suppressed cell proliferation, the knockdown of the Cav3.1 gene by siRNA, or treatment with ProTx-I, a relatively selective inhibitor for Cav3.1, promoted the cell proliferation of MCF-7 cells (a human breast adenocarcinoma cell line). Although Cav3.1 and Cav3.2 channels possess comparable biophys. properties and are often co-expressed in various tissues, gene knockdown or the overexpression of Cav3.2 channels exhibited no effect on cell proliferation. Using immunocytochem. co-staining, the Cav3.1 channels were specifically visualized in the plasma membranes of apoptotic cells, identified by Annexin V and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assays and nuclear condensation. On the contrary, Cav3.2 channels were expressed at the membrane of large portions of cells, with no likely relation to Cav3.1 expression or apoptosis. An apoptosis assay revealed that the overexpression of the Cav3.1 clone caused an increase in the no. of apoptotic cells. Furthermore, Cav3.1 knockdown blocked cyclophosphamide-induced apoptosis. These results suggest that Cav3.1 channels may contribute to the repression of tumor proliferation and the promotion of apoptosis mediated via Cav3.1-specific Ca2+ influx.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xptl2lu70%253D&md5=41e795de3daa07a10623522b410a61fa
    64. 64
      Wang, C.; Lai, M. D.; Phan, N. N.; Sun, Z.; Lin, Y. C. Meta-Analysis of Public Microarray Datasets Reveals Voltage-Gated Calcium Gene Signatures in Clinical Cancer Patients. PLoS ONE 10 2015, 10, e0125766  DOI: 10.1371/journal.pone.0125766
      There is no corresponding record for this reference.
    65. 65
      Comes, N.; Serrano-Albarrás, A.; Capera, J.; Serrano-Novillo, C.; Condom, E.; Ramón y Cajal, S.; Ferreres, J.; Felipe, A. Involvement of Potassium Channels in the Progression of Cancer to a More Malignant Phenotype. Biochim. Biophys. Acta, Biomembr. 2015, 1848, 2477– 2492,  DOI: 10.1016/j.bbamem.2014.12.008
      65
      Involvement of potassium channels in the progression of cancer to a more malignant phenotype
      Comes, Nuria; Serrano-Albarras, Antonio; Capera, Jesusa; Serrano-Novillo, Clara; Condom, Enric; Ramon y Cajal, Santiago; Ferreres, Joan Carles; Felipe, Antonio
      Biochimica et Biophysica Acta, Biomembranes (2015), 1848 (10_Part_B), 2477-2492CODEN: BBBMBS; ISSN:0005-2736. (Elsevier B.V.)
      A review. Potassium channels are a diverse group of pore-forming transmembrane proteins that selectively facilitate potassium flow through an electrochem. gradient. They participate in the control of the membrane potential and cell excitability in addn. to different cell functions such as cell vol. regulation, proliferation, cell migration, angiogenesis as well as apoptosis. Because these physiol. processes are essential for the correct cell function, K + channels have been assocd. with a growing no. of diseases including cancer. In fact, different K + channel families such as the voltage-gated K + channels, the ether ´a-go-go K + channels, the two pore domain K + channels and the Ca2+-activated K + channels have been assocd. to tumor biol. Potassium channels have a role in neoplastic cell-cycle progression and their expression has been found abnormal in many types of tumors and cancer cells. In addn., the expression and activity of specific K + channels have shown a significant correlation with the tumor malignancy grade. The aim of this overview is to summarize published data on K + channels that exhibit oncogenic properties and have been linked to a more malignant cancer phenotype. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVansw%253D%253D&md5=ff2a87329344104e1fd1e21e074abe13
    66. 66
      Brevet, M.; Ahidouch, A.; Sevestre, H.; Merviel, P.; el Hiani, Y.; Micheline Robbe, M.; Ouadid-Ahidouch, H. Expression of K+ Channels in Normal and Cancerous Human Breast. Histol. Histopathol. 2008, 23, 965– 972,  DOI: 10.14670/HH-23.965
      66
      Expression of K+ channels in normal and cancerous human breast
      Brevet Marie; Ahidouch Ahmed; Sevestre Henri; Merviel Philippe; El Hiani Yassine; Robbe Micheline; Ouadid-Ahidouch Halima
      Histology and histopathology (2008), 23 (8), 965-72 ISSN:.
      Potassium (K+) channels contribute to the regulation of cell proliferation and apoptosis and are also involved in tumor generation and malignant growth. Using immunohistochemical analysis, we investigated the expression of four K+ channels GIRK1 (G-Protein Inwardly Rectifying Potassium Channel 1), Ca2+-activated K channel (K Ca 1.1), voltage activated K+ channels (KV 1.1 and KV 1.3) and of the anti-apoptotic protein Bcl2 in normal and cancerous breast tissues and compared their expression with clinicopathological data. GIRK1 was overexpressed in carcinomatous tissues. In contrast, K V 1.1 and K V 1.3 were less expressed in cancerous tissue. The expression of Bcl-2 was similar in both tissues. As to the clinicopathological data, a correlation between K Ca 1.1 channel and estrogen receptor (ER) expression was observed. GIRK1 was overexpressed in breast carcinoma suggesting its involvement in proliferation and oncogenesis and its possible use as a putative pharmaceutical target. The correlation between K Ca 1.1 channel and ER suggests the involvement of this channel in proliferation. The loss of expression of the two channels K V 1.1 and K V 1.3 may correspond to their role in apoptosis.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1czjsFSjug%253D%253D&md5=4cdc13d7c67685d9574a5e9da303ec1a
    67. 67
      Hassan, M. S. U.; Ansari, J.; Spooner, D.; Hussain, S. A. Chemotherapy for Breast Cancer (Review). Oncol. Rep. 2010, 24, 1121– 1131,  DOI: 10.3892/or_00000963
      67
      Chemotherapy for breast cancer (review)
      Hassan, M. S. U.; Ansari, J.; Spooner, D.; Hussain, S. A.
      Oncology Reports (2010), 24 (5), 1121-1131CODEN: OCRPEW; ISSN:1021-335X. (Oncology Reports)
      A review. The use of cytotoxic chemotherapy in both advanced and early stage breast cancer has made significant progress in the last 10 years with several landmark studies identifying clear survival benefits for newer therapies. In spite of these developments the optimal approach for any specific patient can not be detd. from a literature review or decision-making algorithm alone. Treatment choices are predominantly based on practice detd. by individual or collective experience and the historical development of treatment within a locality. The improvement in the understanding of the mol. biol. basis of breast cancer provides possible targets for novel therapies. Personalised therapies for breast cancer based on the mol. characteristics of the tumor could improve the risk:benefit ratio of current therapies. Increased improvements in the use of a panel of biomarkers will thus not only move us towards tailored therapies but will also spare a group of patients that do not benefit from adjuvant chemotherapy. At the same time a better understanding of tumor biol. will also streamline the development of new regimens for those who are unlikely to benefit from existing drugs. This review will focus on the evidence for the use of chemotherapy and highlight advances in chemotherapy treatments with the addn. of new and novel drugs marching into our clinics as std. treatments based on evidence from clin. trials and from a better understanding of tumor biol. that has transformed the outlook in breast cancer in both the adjuvant and metastatic setting.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVegsbrM&md5=70ca40ffc1ef655e3b64c58b63a2e602
    68. 68
      Muranen, T.; Selfors, L. M.; Worster, D. T.; Iwanicki, M. P.; Song, L.; Morales, F. C.; Gao, S.; Mills, G. B.; Brugge, J. S. Inhibition of PI3K/MTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells. Cancer Cell 2012, 21, 227– 239,  DOI: 10.1016/j.ccr.2011.12.024
      68
      Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells
      Muranen, Taru; Selfors, Laura M.; Worster, Devin T.; Iwanicki, Marcin P.; Song, Loling; Morales, Fabiana C.; Gao, Sizhen; Mills, Gordon B.; Brugge, Joan S.
      Cancer Cell (2012), 21 (2), 227-239CODEN: CCAECI; ISSN:1535-6108. (Elsevier Inc.)
      The PI3K/mTOR-pathway is the most commonly dysregulated pathway in epithelial cancers and represents an important target for cancer therapeutics. Here, we show that dual inhibition of PI3K/mTOR in ovarian cancer-spheroids leads to death of inner matrix-deprived cells, whereas matrix-attached cells are resistant. This matrix-assocd. resistance is mediated by drug-induced upregulation of cellular survival programs that involve both FOXO-regulated transcription and cap-independent translation. Inhibition of any one of several upregulated proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to PI3K/mTOR inhibition. These results demonstrate that acute adaptive responses to PI3K/mTOR inhibition in matrix-attached cells resemble well-conserved stress responses to nutrient and growth factor deprivation. Bypass of this resistance mechanism through rational design of drug combinations could significantly enhance PI3K-targeted drug efficacy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xit12jt70%253D&md5=78ff56774f7e2588a1c8ffbce49ad8a2
    69. 69
      Campiglio, M.; Somenzi, G.; Olgiati, C.; Beretta, G.; Balsari, A.; Zaffaroni, N.; Valagussa, P.; Ménard, S. Role of Proliferation in HER2 Status Predicted Response to Doxorubicin. Int. J. Cancer 2003, 105, 568– 573,  DOI: 10.1002/ijc.11113
      69
      Role of proliferation in HER2 status predicted response to doxorubicin
      Campiglio, Manuela; Somenzi, Giulia; Olgiati, Clelia; Beretta, Giovanni; Balsari, Andrea; Zaffaroni, Nadia; Valagussa, Pinuccia; Menard, Sylvie
      International Journal of Cancer (2003), 105 (4), 568-573CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)
      The role of HER2 in predicting response to doxorubicin (DXR) therapy in breast cancer was evaluated in vivo in a series of breast carcinomas from 220 patients with tumors larger than 2.5 cm and treated with 3 cycles of DXR (75 mg/m2) as neoadjuvant chemotherapy. Patients with HER2-pos. tumors were more frequently responsive to DXR treatment compared with HER2-neg. patients (p = 0.05; Mantel-Haenszel X2 = 0.009). Progesterone receptor (PgR) negativity, but not mutated p53, was also assocd. with response to DXR (p = 0.05; Mantel-Haenszel X2 = 0.004). Further anal. of those correlations using breast carcinoma cell lines characterized for different biol. parameters revealed a trend between HER2 positivity/PgR negativity and greater DXR sensitivity, but the strongest direct correlation was found between the proliferation rate and sensitivity to DXR (r = 0.82, p = 0.00009). Neither p53 nor the DXR target mol. topoisomerase-II-α was significantly assocd. with in vitro sensitivity to DXR. Thus, whereas data showed that the major biol. parameter assocd. with in vitro response to DXR in breast cancer cells appears to be the tumor proliferation rate, HER2 expression together with PgR negativity may serve as the counterpart of the proliferation marker in predicting the in vivo response to DXR.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXktlOqsbY%253D&md5=2dcdfcda5e2e08428584f20521b2ab24
    70. 70
      Yu, D.; Huynh, T.; Truong, A.; Haber, M.; Norris, M. Chapter Five - ABC Transporters and Neuroblastoma. In Advances in Cancer Research; Schuetz, J.; Ishikawa, T., Eds.; Academic Press, 2015, Vol. 125, p 139– 170.
      There is no corresponding record for this reference.
    71. 71
      Calcagno, A.; Fostel, J.; To, K.; Salcido, C.; Martin, S.; Chewning, K.; Wu, C.; Varticovski, L.; Bates, S.; Caplen, N.; Ambudkar, S. Single-Step Doxorubicin-Selected Cancer Cells Overexpress the ABCG2 Drug Transporter through Epigenetic Changes. Br. J. Cancer 2008, 98, 1515– 1524,  DOI: 10.1038/sj.bjc.6604334
      71
      Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes
      Calcagno, A. M.; Fostel, J. M.; To, K. K. W.; Salcido, C. D.; Martin, S. E.; Chewning, K. J.; Wu, C.-P.; Varticovski, L.; Bates, S. E.; Caplen, N. J.; Ambudkar, S. V.
      British Journal of Cancer (2008), 98 (9), 1515-1524CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)
      Understanding the mechanisms of multidrug resistance (MDR) could improve clin. drug efficacy. Multidrug resistance is assocd. with ATP binding cassette (ABC) transporters, but the factors that regulate their expression at clin. relevant drug concns. are poorly understood. We report that a single-step selection with low doses of anti-cancer agents, similar to concns. reported in vivo, induces MDR that is mediated exclusively by ABCG2. We selected breast, ovarian and colon cancer cells (MCF-7, IGROV-1 and S-1) after exposure to 14 or 21 n doxorubicin for only 10 days. We found that these cells overexpress ABCG2 at the mRNA and protein levels. RNA interference anal. confirmed that ABCG2 confers drug resistance. Furthermore, ABCG2 upregulation was facilitated by histone hyperacetylation due to weaker histone deacetylase 1-promoter assocn., indicating that these epigenetic changes elicit changes in ABCG2 gene expression. These studies indicate that the MDR phenotype arises following low-dose, single-step exposure to doxorubicin, and further suggest that ABCG2 may mediate early stages of MDR development. This is the first report to our knowledge of single-step, low-dose selection leading to overexpression of ABCG2 by epigenetic changes in multiple cancer cell lines.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXltl2it7g%253D&md5=c83033d75c6cf30c8e40f13155307b3e

  • Supporting Information

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsami.2c00920.

    • Additional experimental details; composition (%) and Young’s moduli (E) of the hydrogels; primers used in RT-qPCR; cell viability of MCF-7 cells in TGA and TGAC bioinks and in Col1 hydrogels; TDM bioprinting at different concentrations; MCF-7 viability in cell-laden TDM bioprinted hydrogels; temperature sweeps, bioprinting, and MCF-7 viability of TDM and alginate bioinks; MCF-7 viability with calcein AM/PI staining in TDM and alginate hydrogels; Young’s moduli of T2, T3, G2.5, and A0.5 hydrogels; amplitude sweeps and flow curves; cell proliferation in TGA and TGAC bioinks, Col1 hydrogels, and in 2D; CACNA1G and KCNA1Ct values (PDF)


    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

PDF [ 3MB]

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

STEP 1:
Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect