Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo
Yan-Xi Sun
Department of Periodontics, Prevention, Geriatrics, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan
Search for more papers by this authorJingcheng Wang
Department of Periodontics, Prevention, Geriatrics, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan
Search for more papers by this authorCharles E. Shelburne
Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan
Search for more papers by this authorDennis E. Lopatin
Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan
Search for more papers by this authorArul M. Chinnaiyan
Department of Pathology and Urology, University of Michigan School of Medicine, 1301 Catherine Road, Ann Arbor, Michigan
Search for more papers by this authorMark A. Rubin
Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts
Search for more papers by this authorKenneth J. Pienta
Division of Hematology and Medical Oncology, Department of Internal Medicine, University of Michigan School of Medicine, 1500 E. Medical Center Drive, Ann Arbor, Michigan
Search for more papers by this authorCorresponding Author
Russell S. Taichman
Department of Periodontics, Prevention, Geriatrics, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan
Department of Periodontics, Prevention, Geriatrics, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan 48109-1078.Search for more papers by this authorYan-Xi Sun
Department of Periodontics, Prevention, Geriatrics, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan
Search for more papers by this authorJingcheng Wang
Department of Periodontics, Prevention, Geriatrics, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan
Search for more papers by this authorCharles E. Shelburne
Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan
Search for more papers by this authorDennis E. Lopatin
Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan
Search for more papers by this authorArul M. Chinnaiyan
Department of Pathology and Urology, University of Michigan School of Medicine, 1301 Catherine Road, Ann Arbor, Michigan
Search for more papers by this authorMark A. Rubin
Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts
Search for more papers by this authorKenneth J. Pienta
Division of Hematology and Medical Oncology, Department of Internal Medicine, University of Michigan School of Medicine, 1500 E. Medical Center Drive, Ann Arbor, Michigan
Search for more papers by this authorCorresponding Author
Russell S. Taichman
Department of Periodontics, Prevention, Geriatrics, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan
Department of Periodontics, Prevention, Geriatrics, University of Michigan School of Dentistry, 1011 North University Ave., Ann Arbor, Michigan 48109-1078.Search for more papers by this authorAbstract
Human prostate cancers (PCa) express great variability in their ability to metastasize to bone. The identification of molecules associated with aggressive phenotypes will help to define PCa subsets and will ultimately lead to better treatment strategies. The chemokine stromal-derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 are now known to modulate the migration and survival of an increasing array of normal and malignant cell types including breast, pancreatic cancers, glioblastomas, and others. The present investigation extends our previous investigations by determining the expression of CXCR4 and CXCL12 in humans using high-density tissue microarrays constructed from clinical samples obtained from a cohort of over 600 patients. These data demonstrate that CXCR4 protein expression is significantly elevated in localized and metastastic cancers. At the RNA level, human PCa tumors also express CXCR4 and message, but overall, they were not significantly different suggesting post-transcriptional regulation of the receptor plays a major role in regulating protein expression. Similar observations were made for CXCL12 message, but in this case more CXCL12 message was expressed by metastastic lesions as compared to normal tissues. PCa cell lines also express CXCL12 mRNA, and regulate mRNA expression in response to CXCL12 and secrete biologically active protein. Furthermore, neutralizing antibody to CXCL12 decreased the proliferation of bone homing LNCaP C4-2B and PC3 metastastic tumor cells. These investigations provide important new information pertaining to the molecular basis of how tumors may ‘home’ to bone, and the mechanisms that may account for their growth in selected end organs. © 2003 Wiley-Liss, Inc.
REFERENCES
- Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC. 1997. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med 185: 111–120.
- Aiuti A, Tavian M, Cipponi A, Ficara F, Zappone E, Hoxie J, Peault B, Bordignon C. 1999a. Expression of CXCR4, the receptor for stromal cell-derived factor-1 on fetal and adult human lympho-hematopoietic progenitors. Eur J Immunol 29: 1823–1831.
10.1002/(SICI)1521-4141(199906)29:06<1823::AID-IMMU1823>3.0.CO;2-B CASPubMedWeb of Science®Google Scholar
- Aiuti A, Tavian M, Cipponi A, Ficara F, Zappone E, Hoxie J, Peault B, Bordignon C. 1999b. Expression of CXCR4, the receptor for stromal cell-derived factor-1 on fetal and adult human lympho-hematopoietic progenitors. Eur J Immunol 29: 1823–1831.
10.1002/(SICI)1521-4141(199906)29:06<1823::AID-IMMU1823>3.0.CO;2-B CASPubMedWeb of Science®Google Scholar
- Baggiolini M. 1998. Chemokines and leukocyte traffic. Nature 392: 565–568.
- Begum NA, Shibuta K, Mori M, Barnard GF. 1999. Reduced expression of the CXCR4 receptor mRNA in hepatocellular carcinoma and lack of inducibility of its ligand alpha-chemokine hIRH/SDF1alpha/PBSF in vitro. Int J Oncol 14: 927–934.
- Caruz A, Samsom M, Alonso JM, Alcami J, Baleux F, Virelizier JL, Parmentier M, Arenzana-Seisdedos F. 1998. Genomic organization and promoter characterization of human CXCR4 gene. FEBS Lett 426: 271–278.
- Cheng ZJ, Zhao J, Sun Y, Hu W, Wu YL, Cen B, Wu GX, Pei G. 2000. Beta-arrestin differentially regulates the chemokine receptor CXCR4-mediated signaling and receptor internalization, and this implicates multiple interaction sites between beta-arrestin and CXCR4. J Biol Chem 275: 2479–2485.
- Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, Varambally S, Kurachi K, Pienta KJ, Rubin MA, Chinnaiyan AM. 2001. Delineation of prognostic biomarkers in prostate cancer. Nature 412: 822–826.
- Feil C, Augustin HG. 1998. Endothelial cells differentially express functional CXC-chemokine receptor-4 (CXCR-4/fusion) under the control of autocrine activity and exogenous cytokines. Biochem Biophys Res Commun 247: 38–45.
- Fidler IJ. 1999. Critical determinants of cancer metastasis: Rationale for therapy. Cancer Chemother Pharmacol 43: S3–S10.
- Geldof AA. 1997a. Models for cancer skeletal metastasis: A reappraisal of Batson's plexus. Anticancer Res 17: 1535–1539.
- Geldof AA. 1997b. Models for cancer skeletal metastasis: A reappraisal of Batson's plexus. Anticancer Res 17: 1535–1539.
- Geminder H, Sagi-Assif O, Goldberg L, Meshel T, Rechavi G, Witz IP, Ben-Baruch A. 2001. A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma. J Immunol 167: 4747–4757.
- Gerard C, Rollins BJ. 2001. Chemokines and disease. Nat Immunol 2: 108–115.
- Gerritsen ME, Peale FV, Jr., Wu T. 2002. Gene expression profiling in silico: Relative expression of candidate angiogenesis associated genes in renal cell carcinomas. Exp Nephrol 10: 114–119.
- Grafte-Faure S, Leveque C, Ketata E, Jean P, Vasse M, Soria C, Vannier JP. 2000. Recruitment of primitive peripheral blood cells: Synergism of interleukin 12 with interleukin 6 and stromal cell-derived factor-1. Cytokine 12: 1–7.
- Guise TA. 2002. How Metastases Home to Bone: The Attraction of Chemokines July 2002 Commentary on: Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res. 2002 Mar 15;62(6):1832–1837. Internet Communication.
- Gupta SK, Pillarisetti K. 1999. Cutting edge: CXCR4-Lo: Molecular cloning and functional expression of a novel human CXCR4 splice variant. J Immunol 163: 2368–2372.
- Hamada T, Mohle R, Hesselgesser J, Hoxie J, Nachman RL, Moore MA, Rafii S. 1998. Transendothelial migration of megakaryocytes in response to stromal cell-derived factor 1 (SDF-1) enhances platelet formation. J Exp Med 188: 539–548.
- Hodohara K, Fujii N, Yamamoto N, Kaushansky K. 2000. Stromal cell-derived factor-1 (SDF-1) acts together with thrombopoietin to enhance the development of megakaryocytic progenitor cells (CFU-MK). Blood 95: 769–775.
- Jacobs SC. 1983. Spread of prostatic cancer to bone. Urology 21: 337–344.
- Kim CH, Broxmeyer HE. 1999. SLC/exodus2/6Ckine/TCA4 induces chemotaxis of hematopoietic progenitor cells: Differential activity of ligands of CCR7, CXCR3, or CXCR4 in chemotaxis vs. suppression of progenitor proliferation. J Leukoc Biol 66: 455–461.
- Korenchuk S, Lehr JE, McLean L, Lee YG, Whitney S, Vessella R, Lin DL, Pienta KJ. 2001. VCaP, a cell-based model system of human prostate cancer. In Vivo 15: 163–168.
- Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsuji S, Nakajima S, Kawaguchi M, Kobayashi H, Doi R, Hori T, Fujii N, Imamura M. 2000. Expression of stromal cell-derived factor 1 and CXCR4 ligand–receptor system in pancreatic cancer: A possible role for tumor progression. Clin Cancer Res 6: 3530–3535.
- Koutsilieris M. 1993. Osteoblastic metastasis in advanced prostate cancer. Anticancer Res 13: 443–449.
- Lazarini F, Casanova P, Tham TN, De Clercq E, Arenzana-Seisdedos F, Baleux F, Dubois-Dalcq M. 2000. Differential signalling of the chemokine receptor CXCR4 by stromal cell-derived factor 1 and the HIV glycoprotein in rat neurons and astrocytes. Eur J Neurosci 12: 117–125.
- Libura JD. 2002. CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood 100: 2597–2606.
- McGrath KE, Koniski AD, Maltby KM, McGann JK, Palis J. 1999. Embryonic expression and function of the chemokine SDF-1 and its receptor, CXCR4. Dev Biol (Orlando) 213: 442–456.
- Mitra P, Shibuta K, Mathai J, Shimoda K, Banner BF, Mori M, Barnard GF. 1999. CXCR4 mRNA expression in colon, esophageal, and gastric cancers and hepatitis C infected liver. Int J Oncol 14: 917–925.
- Moore MA. 2001. The role of chemoattraction in cancer metastases. Bioessays 23: 674–676.
- Muller CA, Homey B, Sato H, Ge N, Catron D, Buchanan M, McClanahan T, Murphy E, Yuan W, Wagners S, Barrera J, Mohar A, Verastegui E, Zlotnik A. 2001. Involvement of chemokine receptors in breast cancer metastasis. Nature 410: 50–56.
- Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa Y, Kitamura N, Yoshida H, Kikutani T. 1996. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382: 635–638.
- Parker SL, Tong T, Bolden S, Wingo PA. 1996. Cancer statistics. CA Cancer J Clin 46: 5–27.
- Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk A, Nagler H, Ben-Hur A, Many L, Shultz O, Lider R, Alon D, Zipori T. 1999. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283: 845–848.
- Perrone EE, Theoharis C, Mucci NR, Hayasaka S, Taylor JM, Cooney KA, Rubin MA. 2000. Tissue microarray assessment of prostate cancer tumor proliferation in African-American and white men. J Natl Cancer Inst 92: 937–939.
- Pienta KJ, Esper PS. 1993. Risk factors for prostate cancer. Ann Intern Med 118: 793–803.
- Putzi MJ, De Marzo AM. 2000. Morphologic transitions between proliferative inflammatory atrophy and high-grade prostatic intraepithelial neoplasia. Urology 56: 828–832.
- Rempel SA, Dudas S, Ge S, Gutierrez JA. 2000. Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 6: 102–111.
- Robey PG, Termine JD. 1985. Human bone cells in vitro. Calcif Tissue Int 37: 453–460.
- Robledo MM, Bartolome RA, Longo N, Rodriguez-Frade JM, Mellado M, Longo I, van MG, Sanchez-Mateos P, Teixido J. 2001. Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells. J Biol Chem 276: 45098–45105.
- Rossi D, Zlotnik A. 2000. The biology of chemokines and their receptors. Annu Rev Immunol 18: 217–242.
- Rottman JB. 1999. Key role of chemokines and chemokine receptors in inflammation, immunity, neoplasia, and infectious disease. Vet Pathol 36: 357–367.
- Rubin MA, Putzi M, Mucci N, Smith DC, Wojno K, Korenchuk S, Pienta KJ. 2000. Rapid (“warm”) autopsy study for procurement of metastatic prostate cancer. Clin Cancer Res 6: 1038–1045.
- Sehgal A, Keener C, Boynton AL, Warrick J, Murphy GP. 1998. CXCR-4, a chemokine receptor, is overexpressed in and required for proliferation of glioblastoma tumor cells. J Surg Oncol 69: 99–104.
- Shibuta KM. 2002. Regional expression of CXCL12/CXCR4 in liver and hepatocellular carcinoma and cell-cycle variation during in vitro differentiation. Jpn J Cancer Res 93: 789–797.
- Shibuta K, Begum NA, Mori M, Shimoda K, Akiyoshi T, Barnard GF. 1997. Reduced expression of the CXC chemokine hIRH/SDF-1alpha mRNA in hepatoma and digestive tract cancer. Int J Cancer 73: 656–662.
10.1002/(SICI)1097-0215(19971127)73:5<656::AID-IJC8>3.0.CO;2-W CASPubMedWeb of Science®Google Scholar
- Taichman RS, Emerson SG. 1994. Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J Exp Med 179: 1677–1682.
- Taichman RS, Emerson SG. 1998. The role of osteoblasts in the hematopoietic microenvironment. Stem Cell 16: 7–15.
- Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman N, McCauley LK. 2002. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res 62: 1832–1837.
- Wang JF, Liu ZY, Groopman JE. 1998. The alpha-chemokine receptor CXCR4 is expressed on the megakaryocytic lineage from progenitor to platelets and modulates migration and adhesion. Blood 92: 756–764.
- Wegner SA, Ehrenberg PK, Chang G, Dayhoff DE, Sleeker al, Michael NL. 1998. Genomic organization and functional characterization of the chemokine receptor CXCR4, a major entry co-receptor for human immunodeficiency virus type 1. J Biol Chem 273: 4754–4760.
- Weingartner K, Ben-Sasson SA, Stewart R, Richie JP, Riedmiller H, Folkman J. 1998. Endothelial cell proliferation activity in benign prostatic hyperplasia and prostate cancer: An in vitro model for assessment. J Urol 159: 465–470.
- Zeelenberg IS, Ruuls-Van Stalle L, Roos E. 2001. Retention of CXCR4 in the endoplasmic reticulum blocks dissemination of a T cell hybridoma. J Clin Invest 108: 269–277.
- Zhou Y, Larsen PH, Hao C, Yong VW. 2002. CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. J Biol Chem M206: 200–222.