Review
Green tea and its anti-angiogenesis effects
Introduction
Angiogenesis is the generation of new blood vessels from a pre-existing vasculature [1]. Angiogenesis is divided into two components: physiological and non-physiological or pathological angiogenesis. Physiological angiogenesis occurs during various processes such as wound healing, tissue remodeling, luteinisation of the follicle in the ovary, placental development and pregnancy establishment. Pathological angiogenesis is a hallmark of many ischaemic and inflammatory diseases (e.g. endometriosis, psoriasis, rheumatoid arthritis (RA), neovascular age-related macular degeneration of the eye, diabetic retinopathy) and cancer growth and metastasis [2]. Under physiological conditions, angiogenesis is highly regulated by the balance between a huge number of pro- and antiangiogenic factors [3]. There is currently great interest in the use of nutraceuticals, i.e. plant chemicals used as ingredients of foods and drinks.
Green tea (from the Camellia sinensis plant) is one of the most popular beverages worldwide and its consumption has an effect on many diseases. Green tea consuming populations have been examined in several (pre)clinical studies [4], [5], [6], [7].
It has been revealed that the green tea catechins not only possess anti-inflammatory and anti-oxidative-stress activities but they have also shown anti-carcinogenic, anti-microbial, anti-obesity and anti-diabetic properties [8]. The main catechins found in green tea are (−)-epigallocatechin-3-gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC) and epicatechin (EC) [9], gallocatechin gallate (GCG), catechin gallate (CG) and cathecin (CT) [10]. EGCG is the most abundant and active catechin in green tea, accounting for 50–80% of the catechin content [11]. Green tea polyphenols inhibit cell proliferation and present a strong antiradical activity [12].
Some evidences indicated that EGCG could protect cells from tumor development through the enhancement of gap junctional communication between cells.
It was observed that polyphenols and various components present in Green tea exert their effects by various mechanisms. One of the main mechanisms is blocking the promotion of tumor growth by sealing receptors in the affected cells. Another one implies that this substance may aid direct binding to some carcinogens [13]. Some reports indicated that EGCG is able to induce cell growth arrest and apoptosis by regulating the expression of some regulatory proteins, suppressing NF-κB activation and activating killer caspases [14]. In addition, it was observed that EGCG could inhibit matrix metalloproteinase activity. Matrix metalloproteinase could contribute to tumor cell invasion and angiogenesis [15].
Pharmacokinetic studies indicated that a daily dosage of 800 mg/day of EGCG for up to 4 weeks could be safe and well-tolerated [16], [17]. On other hand, high-dose oral green tea extract and EGCG could be associated with hepatotoxic effects in rats. Therefore, Green tea and its components such as catechins could be a safe option for treatment of various diseases such as cancer, diabetic, cardiovascular, and anogenital warts [17].
Among different receptors affected by green tea constituents, microRNAs (miRNAs) have emerged as a new class of molecules that are involved in various molecular and cellular pathways [18]. This study focuses on the cellular/molecular pathway of anti-angiogenic properties of green tea especially EGCG, as well as on various miRNAs involved in these mechanisms.
So far, many growth factors have been characterized and shown to have angiogenic activities. This includes fibroblast growth factor (FGF), platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), angiopoietin/endothelial tyrosine kinase (ANG/TIE), ephrin (EPH), cadherin and semaphoring [19]. The receptor protein-tyrosine kinase and the vascular endothelial growth factor/VEGF receptor (VEGF/VEGFR) families are involved in neovascularization and angiogenesis. The VEGF/VEGFR family is the key regulator of vascular development which is the main focus of this review. The ANG/TIE system controls vascular remodeling [20] while the EPH system regulates the positioning and segregation of arterial and venous endothelial cells during development [21]. Because the members of the VEGF family and their receptors have a crucial role in formation of blood vessels, anti-angiogenic therapies are focused on developing molecules which target these factors [22].
Section snippets
VEGF family
The VEGF family plays a key role in vasculogenesis, angiogenesis and lymphangiogenesis. The human VEGF family comprises of five members including VEGF (or VEGF-A), VEGF-B, VEGF-C, VEGF-D and placental growth factor (PlGF) Multiple isoforms of VEGF, VEGF-B, and PlGF are generated through alternative splicing of their corresponding immature mRNAs.
Three members of the VEGF family have receptor protein-tyrosine kinase activity including VEGFR1 (also known as Flt-1), VEGFR2 (also known as Flk-1 in
VEGFR1 (Flt-1)
VEGFR1 (Flt-1, fms-like tyrosyl kinase-1, where fms refers to feline McDonough sarcoma virus) has an ability to bind to VEGF, PlGF and VEGF-B (Fig. 2) [24], [25], [26]. The developmental stage and location of endothelial cells expressing VEGFR1 determines various functions of this receptor [27].
Note that VEGF has higher affinity for VEGFR1 than VEGFR2 (approximately ten-fold higher affinity) [24], [27], [28]. Unlike VEGFR2, VEGFR1 has weak tyrosine kinase phosphorylation activity following
Cell cycle arrest
In a study, It has been shown that Green tea extract (GTE) specifically EGCG in culture media did not affect cell viability but significantly reduced cell proliferation in a dose-dependent manner and caused a dose-dependent cell cycle arrest in the G1 phase. GTE also decreased the expression of Flt-1 and KDR/Flk-1 in HUVEC. The authors concluded that GTE may have preventive effects on tumor angiogenesis and metastasis through reduction of expression of VEGF receptors [78].
Shankar and colleagues
Green tea and microRNAs
MiRNAs have been emerged as a class of small non-coding RNAs [94], [95], [96], [97], [98], [99], [100]. These molecules have central roles in many biological processes such as metastasis, angiogenesis and growth tumor [101], [102]. The aberration of the expression profiles of various miRNAs in several diseases such as cancer is reported [103], [104], [105], [106], [107]. Natural products are as one of the most important components for treatment of various diseases [101]. Various studies
Conclusions and future perspectives
Recent studies have shown that angiogenesis is one of the most important factors in the growth and development of tumors and endothermic lesions. Angiogenesis is affected by conditions such as induction of hypoxia and inflammation and the presence of receptor tyrosine kinases. Recently, in addition to the people of China, green tea has been proven popular in many countries worldwide. The main reason is the health benefits of this type of drink. Green tea catechins are helpful because of
Conflicts of interest statement
The authors declare that they have no conflict interests.
References (116)
- et al.
Phytosomal curcumin: a review of pharmacokinetic, experimental and clinical studies
Biomed. Pharmacother.
(2017) - et al.
Tea polyphenols for health promotion
Life Sci.
(2007) Enhancement of gap junctional intercellular communication in tumor promoter-treated cells by components of green tea
Cancer Lett.
(1993)- et al.
Gene regulation mediated by microRNAs in response to green tea polyphenol EGCG in mouse lung cancer
BMC Genomics
(2014) - et al.
Basic and therapeutic aspects of angiogenesis
Cell
(2011) Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling
Exp. Cell Res.
(2006)- et al.
Eph receptor and ephrin ligand mediated interactions during angiogenesis and tumor progression
Exp. Cell Res.
(2006) - et al.
Vascular endothelial growth factors growthfactors and receptors: anti-angiogenic therapy in the treatment of cancer
Mol. Aspects Med.
(2011) - et al.
Structure and function of placental growth factor
Trends Cardiovasc. Med.
(2002) - et al.
Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor
J. Biol. Chem.
(1994)
Placenta growth factors.Potentiation of vascular endothelial growth factor bioactivity in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR
J. Biol. Chem.
Identification of vascular endothelial growth factor receptor-1 tyrosine phosphorylation sites and binding of SH2 domain-containing molecules
J. Biol. Chem.
Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2)
J. Biol. Chem.
Vascular endothelial growth factor effect on endothelial cell proliferation, migration, and platelet-activating factor synthesis is Flk-1-dependent
J. Biol. Chem.
Tea catechins as inhibitors of receptor tyrosine kinases: Mechanistic insights and human relevance
Pharmacol. Res.
Pathological roles of MAPK signaling pathways in human diseases
Biochim. Biophys. Acta.
The phosphorylated 1169-Tyrosine containing region of Flt-1 Kinase (VEGFR-1) is a major binding site for PLCgamma
Biochem. Biophys. Res. Commun.
Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis
Exp. Cell Res.
Vascular endothelial growth factor receptor KDR tyrosine kinase activity is increased by autophosphorylation of two activation loop tyrosine residues
J. Biol. Chem.
The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration
J. Biol. Chem.
Vascular endothelial growth factor (VEGF) signaling in tumor progression
Crit. Rev. Oncol. Hematol.
Endothelial Tie2/Tek ligands angiopoietin-1 (ANGPT1) and angiopoietin-2 (ANGPT2): regional localization of the human genes to 8q22.3-q23 and 8p23
Genomics
Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning
Cell
Angiopoietin-2 is implicated in the regulation of tumor angiogenesis
Am. J. Pathol.
Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1
Dev. Cell.
Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells
J. Biol. Chem.
Treatment with EGCG in NSCLC leads to decreasing interstitial fluid pressure and hypoxia to improve chemotherapy efficacy through rebalance of Ang-1 and Ang-2
Chin. J. Nat. Med.
The ephrins and Eph receptors in angiogenesis
Cytokine Growth Factor Rev.
Ephrin-A1 is expressed at sites of vascular development in the mouse
Mech. Dev.
Green tea extract inhibits angiogenesis of human umbilical vein endothelial cells through reduction of expression of VEGF receptors
Life Sci.
Role of the retinoblastoma (pRb)-E2F/DP pathway in cancer chemopreventive effects of green tea polyphenol epigallocatechin-3-gallate
Arch. Biochem. Biophys.
VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia
Blood
Tea catechins inhibit angiogenesis in vitro, measured by human endothelial cell growth, migration and tube formation, through inhibition of VEGF receptor binding
Cancer Lett.
Inhibition of the vascular-endothelial growth factor-induced intracellularsignaling and mitogenesis of human endothelial cells by epigallocatechin-3 gallate
Eur. J. Pharmacol.
The biology of VEGF and its receptors
Nat. Med.
Vascular endothelial growth factor: basic science and clinical progress
Endocr. Rev.
Angiogenesis in life, disease and medicine
Nature
Green tea for weight loss and weight maintenance in overweight or obese adults
Cochrane Database Syst. Rev.
Phylogenetic analysis of selected menthol-producing species belonging to the lamiaceae family
Nucleosides Nucleotides Nucl. Acids
Can curcumin and its analogs be a new treatment option in cancer therapy?
Cancer Gene Ther.
Flavonoids and other polyphenols in consumerbrews of tea and other caffeinated beverages
J. Agric. Food Chem.
The inhibitory effects of tea polyphenols (flavan-3-ol derivatives)on Cu2+ mediated oxidative modification of low density lipoprotein
Biol. Pharm. Bull.
Inhibition of carcinogenesis by tea
Annu. Rev. Pharmacol. Toxicol.
Epigallocatechin-3-gallate (EGCG) affects the antioxidant and immune defense of the rainbow trout, Oncorhynchus mykiss
Fish Physiol. Biochem.
Essential role of caspases in epigallocatechin-3-gallate-mediated inhibition of nuclear factor kappa B and induction of apoptosis
Oncogene
Tumor gelatinase and invasion inhibited by the green tea flavonol epigallocatechin-3-gallate
Cancer
Does tea affect cardiovascular disease? A meta-analysis
Am. J. Epidemiol.
Green tea tablets – a review
Pharmaceut. Res.
Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells
Proc. Natl. Acad. Sci. U S A
The fms-like tyrosine kinase, a receptor for vascular endothelial growth factors
Science
Cited by (162)
-
Purification, structural characteristics and anti-atherosclerosis activity of a novel green tea polysaccharide
2024, International Journal of Biological Macromolecules -
Angiogenesis and prostate cancer: MicroRNAs comes into view
2023, Pathology Research and Practice -
Acute green tea intake attenuates circulating microRNA expression induced by a high-fat, high-saturated meal in obese women: A randomized crossover study
2023, Journal of Nutritional Biochemistry -
The therapeutic potential of matcha tea: A critical review on human and animal studies
2023, Current Research in Food Science