Skip to main content
Top
Published in: World Journal of Surgical Oncology 1/2012

Open Access 01-12-2012 | Research

High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma

Authors: Linhui Wang, Wei Chen, Li Gao, Qing Yang, Bing Liu, Zhenjie Wu, Yang Wang, Yinghao Sun

Published in: World Journal of Surgical Oncology | Issue 1/2012

Login to get access

Abstract

Background

Chemokines and their receptors are known to play important roles in the tumorigenesis of many malignancies. The aim of this study was to evaluate the prognostic impact of the expression of the chemokine SDF-1 and its receptors CXCR4 and CXCR7 in patients with renal cell carcinoma.

Methods

The expression of CXCR4, CXCR7 and SDF-1 in specimens from 97 renal cell carcinoma patients was evaluated by immunohistochemistry on a tissue microarray. These results were correlated with the clinicopathological parameters and survival of the patients.

Results

CXCR4 and CXCR7 were expressed in all patients, whereas SDF-1 was expressed in 61 patients (62.9%). No association was observed between the expression of CXCR4, CXCR7 or SDF-1 and the clinical or pathological data except between SDF-1 expression and Fuhrman’s grade (P = 0.015). Patients with high expression of CXCR4, CXCR7 and SDF-1 had shorter overall survival and recurrence-free survival than those with low expression. In a multivariate analysis, the high expression of CXCR4, CXCR7 and SDF-1 correlated with poor overall survival and recurrence-free survival independent of gender, age, AJCC stage, lymph node status, metastasis, histologic variant and Fuhrman’s grade.

Conclusions

High levels of CXCR4, CXCR7 and SDF-1 were associated with poor overall survival and recurrence-free survival in renal cell carcinoma patients. CXCR4, CXCR7 and SDF-1 may serve as useful prognostic markers and therapeutic targets for renal cell carcinoma.
Appendix
Available only for authorised users
Literature
1.
go back to reference Jones J, Libermann TA: Genomics of renal cell cancer: the biology behind and the therapy ahead. Clin Cancer Res. 2007, 13: 685s-692s. 10.1158/1078-0432.CCR-06-1867.CrossRefPubMed Jones J, Libermann TA: Genomics of renal cell cancer: the biology behind and the therapy ahead. Clin Cancer Res. 2007, 13: 685s-692s. 10.1158/1078-0432.CCR-06-1867.CrossRefPubMed
2.
go back to reference Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, Gitlitz B, Belldegrun AS, Figlin RA: Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer. 2003, 97: 2995-3002. 10.1002/cncr.11422.CrossRefPubMed Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, Gitlitz B, Belldegrun AS, Figlin RA: Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer. 2003, 97: 2995-3002. 10.1002/cncr.11422.CrossRefPubMed
3.
go back to reference Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A: Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001, 410: 50-56. 10.1038/35065016.CrossRefPubMed Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A: Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001, 410: 50-56. 10.1038/35065016.CrossRefPubMed
4.
go back to reference Lazennec G, Richmond A: Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol Med. 2010, 16: 133-144. 10.1016/j.molmed.2010.01.003.PubMedCentralCrossRefPubMed Lazennec G, Richmond A: Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol Med. 2010, 16: 133-144. 10.1016/j.molmed.2010.01.003.PubMedCentralCrossRefPubMed
5.
go back to reference Zlotnik A, Yoshie O: Chemokines: a new classification system and their role in immunity. Immunity. 2000, 12: 121-127. 10.1016/S1074-7613(00)80165-X.CrossRefPubMed Zlotnik A, Yoshie O: Chemokines: a new classification system and their role in immunity. Immunity. 2000, 12: 121-127. 10.1016/S1074-7613(00)80165-X.CrossRefPubMed
6.
go back to reference Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, Power CA: International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev. 2000, 52: 145-176.PubMed Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, Power CA: International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev. 2000, 52: 145-176.PubMed
7.
go back to reference Schimanski CC, Galle PR, Moehler M: Chemokine receptor CXCR4-prognostic factor for gastrointestinal tumors. World J Gastroenterol. 2008, 14: 4721-4724. 10.3748/wjg.14.4721.PubMedCentralCrossRefPubMed Schimanski CC, Galle PR, Moehler M: Chemokine receptor CXCR4-prognostic factor for gastrointestinal tumors. World J Gastroenterol. 2008, 14: 4721-4724. 10.3748/wjg.14.4721.PubMedCentralCrossRefPubMed
8.
go back to reference Matsusue R, Kubo H, Hisamori S, Okoshi K, Takagi H, Hida K, Nakano K, Itami A, Kawada K, Nagayama S, Sakai Y: Hepatic stellate cells promote liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis. Ann Surg Oncol. 2009, 16: 2645-2653. 10.1245/s10434-009-0599-x.CrossRefPubMed Matsusue R, Kubo H, Hisamori S, Okoshi K, Takagi H, Hida K, Nakano K, Itami A, Kawada K, Nagayama S, Sakai Y: Hepatic stellate cells promote liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis. Ann Surg Oncol. 2009, 16: 2645-2653. 10.1245/s10434-009-0599-x.CrossRefPubMed
9.
go back to reference Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ: A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 2006, 203: 2201-2213. 10.1084/jem.20052144.PubMedCentralCrossRefPubMed Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ: A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 2006, 203: 2201-2213. 10.1084/jem.20052144.PubMedCentralCrossRefPubMed
10.
go back to reference Miao Z, Luker KE, Summers BC, Berahovich R, Bhojani MS, Rehemtulla A, Kleer CG, Essner JJ, Nasevicius A, Luker GD, Howard MC, Schall TJ: CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A. 2007, 104: 15735-15740. 10.1073/pnas.0610444104.PubMedCentralCrossRefPubMed Miao Z, Luker KE, Summers BC, Berahovich R, Bhojani MS, Rehemtulla A, Kleer CG, Essner JJ, Nasevicius A, Luker GD, Howard MC, Schall TJ: CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A. 2007, 104: 15735-15740. 10.1073/pnas.0610444104.PubMedCentralCrossRefPubMed
11.
go back to reference Hattermann K, Held-Feindt J, Lucius R, Müerköster SS, Penfold ME, Schall TJ, Mentlein R: The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res. 2010, 70: 3299-3308. 10.1158/0008-5472.CAN-09-3642.CrossRefPubMed Hattermann K, Held-Feindt J, Lucius R, Müerköster SS, Penfold ME, Schall TJ, Mentlein R: The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res. 2010, 70: 3299-3308. 10.1158/0008-5472.CAN-09-3642.CrossRefPubMed
12.
go back to reference Wang J, Shiozawa Y, Wang J, Wang Y, Jung Y, Pienta KJ, Mehra R, Loberg R, Taichman RS: The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem. 2008, 283: 4283-4294.CrossRefPubMed Wang J, Shiozawa Y, Wang J, Wang Y, Jung Y, Pienta KJ, Mehra R, Loberg R, Taichman RS: The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem. 2008, 283: 4283-4294.CrossRefPubMed
13.
go back to reference Zagzag D, Krishnamachary B, Yee H, Okuyama H, Chiriboga L, Ali MA, Melamed J, Semenza GL: Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res. 2005, 65: 6178-6188. 10.1158/0008-5472.CAN-04-4406.CrossRefPubMed Zagzag D, Krishnamachary B, Yee H, Okuyama H, Chiriboga L, Ali MA, Melamed J, Semenza GL: Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res. 2005, 65: 6178-6188. 10.1158/0008-5472.CAN-04-4406.CrossRefPubMed
14.
go back to reference Li Q, Bavikatty N, Michael CW: The role of immunohistochemistry in distinguishing squamous cell carcinoma from mesothelioma and adenocarcinoma in pleural effusion. Semin Diagn Pathol. 2006, 23: 15-19. 10.1053/j.semdp.2006.06.007.CrossRefPubMed Li Q, Bavikatty N, Michael CW: The role of immunohistochemistry in distinguishing squamous cell carcinoma from mesothelioma and adenocarcinoma in pleural effusion. Semin Diagn Pathol. 2006, 23: 15-19. 10.1053/j.semdp.2006.06.007.CrossRefPubMed
15.
go back to reference Woo SU, Bae JW, Kim CH, Lee JB, Koo BW: A significant correlation between nuclear CXCR4 expression and axillary lymph node metastasis in hormonal receptor negative breast cancer. Ann Surg Oncol. 2008, 15: 281-285. 10.1245/s10434-007-9595-1.CrossRefPubMed Woo SU, Bae JW, Kim CH, Lee JB, Koo BW: A significant correlation between nuclear CXCR4 expression and axillary lymph node metastasis in hormonal receptor negative breast cancer. Ann Surg Oncol. 2008, 15: 281-285. 10.1245/s10434-007-9595-1.CrossRefPubMed
16.
go back to reference Na IK, Scheibenbogen C, Adam C, Stroux A, Ghadjar P, Thiel E, Keilholz U, Coupland SE: Nuclear expression of CXCR4 in tumor cells of non-small cell lung cancer is correlated with lymph node metastasis. Hum Pathol. 2008, 39: 1751-1755. 10.1016/j.humpath.2008.04.017.CrossRefPubMed Na IK, Scheibenbogen C, Adam C, Stroux A, Ghadjar P, Thiel E, Keilholz U, Coupland SE: Nuclear expression of CXCR4 in tumor cells of non-small cell lung cancer is correlated with lymph node metastasis. Hum Pathol. 2008, 39: 1751-1755. 10.1016/j.humpath.2008.04.017.CrossRefPubMed
17.
go back to reference Wang L, Wang Z, Yang B, Yang Q, Wang L, Sun Y: CXCR4 nuclear localization follows binding of its ligand SDF-1 and occurs in metastatic but not primary renal cell carcinoma. Oncol Rep. 2009, 22: 1333-1339.PubMed Wang L, Wang Z, Yang B, Yang Q, Wang L, Sun Y: CXCR4 nuclear localization follows binding of its ligand SDF-1 and occurs in metastatic but not primary renal cell carcinoma. Oncol Rep. 2009, 22: 1333-1339.PubMed
18.
go back to reference D’Alterio C, Consales C, Polimeno M, Franco R, Cindolo L, Portella L, Cioffi M, Calemma R, Marra L, Claudio L, Perdonà S, Pignata S, Facchini G, Cartenì G, Longo N, Pucci L, Ottaiano A, Costantini S, Castello G, Scala S: Concomitant CXCR4 and CXCR7 expression predicts poor prognosis in renal cancer. Curr Cancer Drug Targets. 2010, 10: 772-781. 10.2174/156800910793605839.CrossRefPubMed D’Alterio C, Consales C, Polimeno M, Franco R, Cindolo L, Portella L, Cioffi M, Calemma R, Marra L, Claudio L, Perdonà S, Pignata S, Facchini G, Cartenì G, Longo N, Pucci L, Ottaiano A, Costantini S, Castello G, Scala S: Concomitant CXCR4 and CXCR7 expression predicts poor prognosis in renal cancer. Curr Cancer Drug Targets. 2010, 10: 772-781. 10.2174/156800910793605839.CrossRefPubMed
19.
go back to reference Hou KL, Hao MG, Bo JJ, Wang JH: CXCR7 in tumorigenesis and progression. Chin J Cancer. 2010, 29: 456-459. 10.5732/cjc.009.10404.CrossRefPubMed Hou KL, Hao MG, Bo JJ, Wang JH: CXCR7 in tumorigenesis and progression. Chin J Cancer. 2010, 29: 456-459. 10.5732/cjc.009.10404.CrossRefPubMed
20.
go back to reference Thelen M, Thelen S: CXCR7, CXCR4 and CXCL12: an eccentric trio?. J Neuroimmunol. 2008, 198: 9-13. 10.1016/j.jneuroim.2008.04.020.CrossRefPubMed Thelen M, Thelen S: CXCR7, CXCR4 and CXCL12: an eccentric trio?. J Neuroimmunol. 2008, 198: 9-13. 10.1016/j.jneuroim.2008.04.020.CrossRefPubMed
21.
go back to reference Levoye A, Balabanian K, Baleux F, Bachelerie F, Lagane B: CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood. 2009, 113: 6085-6093. 10.1182/blood-2008-12-196618.CrossRefPubMed Levoye A, Balabanian K, Baleux F, Bachelerie F, Lagane B: CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood. 2009, 113: 6085-6093. 10.1182/blood-2008-12-196618.CrossRefPubMed
22.
go back to reference Liang JJ, Zhu S, Bruggeman R, Zaino RJ, Evans DB, Fleming JB, Gomez HF, Zander DS, Wang H: High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev. 2010, 19: 2598-2604. 10.1158/1055-9965.EPI-10-0405.CrossRefPubMed Liang JJ, Zhu S, Bruggeman R, Zaino RJ, Evans DB, Fleming JB, Gomez HF, Zander DS, Wang H: High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev. 2010, 19: 2598-2604. 10.1158/1055-9965.EPI-10-0405.CrossRefPubMed
23.
go back to reference Gebauer F, Tachezy M, Effenberger K, von Loga K, Zander H, Marx A, Kaifi JT, Sauter G, Izbicki JR, Bockhorn M: Prognostic impact of CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol. 2011, 104: 140-145. 10.1002/jso.21957.CrossRefPubMed Gebauer F, Tachezy M, Effenberger K, von Loga K, Zander H, Marx A, Kaifi JT, Sauter G, Izbicki JR, Bockhorn M: Prognostic impact of CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol. 2011, 104: 140-145. 10.1002/jso.21957.CrossRefPubMed
24.
go back to reference Rubin JB, Kung AL, Klein RS, Chan JA, Sun Y, Schmidt K, Kieran MW, Luster AD, Segal RA: A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci U S A. 2003, 100: 13513-13518. 10.1073/pnas.2235846100.PubMedCentralCrossRefPubMed Rubin JB, Kung AL, Klein RS, Chan JA, Sun Y, Schmidt K, Kieran MW, Luster AD, Segal RA: A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci U S A. 2003, 100: 13513-13518. 10.1073/pnas.2235846100.PubMedCentralCrossRefPubMed
25.
go back to reference Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D, Luker GD: CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res. 2004, 64: 8604-8612. 10.1158/0008-5472.CAN-04-1844.CrossRefPubMed Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D, Luker GD: CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res. 2004, 64: 8604-8612. 10.1158/0008-5472.CAN-04-1844.CrossRefPubMed
26.
go back to reference Burger JA, Stewart DJ: CXCR4 chemokine receptor antagonists: perspectives in SCLC. Expert Opin Investig Drugs. 2009, 18: 481-490. 10.1517/13543780902804249.CrossRefPubMed Burger JA, Stewart DJ: CXCR4 chemokine receptor antagonists: perspectives in SCLC. Expert Opin Investig Drugs. 2009, 18: 481-490. 10.1517/13543780902804249.CrossRefPubMed
27.
go back to reference Hartmann TN, Grabovsky V, Pasvolsky R, Shulman Z, Buss EC, Spiegel A, Nagler A, Lapidot T, Thelen M, Alon R: A crosstalk between intracellular CXCR7 and CXCR4 involved in rapid CXCL12-triggered integrin activation but not in chemokine-triggered motility of human T lymphocytes and CD34+ cells. J Leukoc Biol. 2008, 84: 1130-1140. 10.1189/jlb.0208088.CrossRefPubMed Hartmann TN, Grabovsky V, Pasvolsky R, Shulman Z, Buss EC, Spiegel A, Nagler A, Lapidot T, Thelen M, Alon R: A crosstalk between intracellular CXCR7 and CXCR4 involved in rapid CXCL12-triggered integrin activation but not in chemokine-triggered motility of human T lymphocytes and CD34+ cells. J Leukoc Biol. 2008, 84: 1130-1140. 10.1189/jlb.0208088.CrossRefPubMed
Metadata
Title
High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma
Authors
Linhui Wang
Wei Chen
Li Gao
Qing Yang
Bing Liu
Zhenjie Wu
Yang Wang
Yinghao Sun
Publication date
01-12-2012
Publisher
BioMed Central
Published in
World Journal of Surgical Oncology / Issue 1/2012
Electronic ISSN: 1477-7819
DOI
https://doi.org/10.1186/1477-7819-10-212

Other articles of this Issue 1/2012

World Journal of Surgical Oncology 1/2012 Go to the issue