Objective: To elucidate the role of CXCR4 in the metastasis of bladder transitional cell carcinoma (BTCC) by examining CXCR4 expression in BTCC tissue and its correlation with clinicopathological features. Methods: The expression of CXCR4 was assessed in bladder tissues from 70 BTCC patients and 18 normal controls, respectively, using immunohistochemistry. The correlation of CXCR4 expression with lymph node metastasis was also examined by determining the lymphatic vessel density (LVD). Results: Overexpression of CXCR4 was detected in 58/70 (82.9%) BTCC tissues, whereas only in 3/18 (16.7%) normal bladder tissues. The expression was significantly higher in BTCC than that in normal controls (p < 0.01). CXCR4 expression level was closely associated with tumor size, pathological grades, clinical stages, and pelvic lymph node metastasis (p < 0.05). Multivariate analysis indicated that CXCR4 expression and lymph node metastasis were independent predictors for disease-free survival (both p < 0.05). The disease-free survival rate among the patients with high CXCR4 expression level was remarkably lower than that among the patients with no or low level expression (p < 0.01). Conclusion: Highly expressed in BTCC tissues, CXCR4 may play a critical role in the metastasis of BTCC, and the expression level in biopsy specimens might be a good indicator of lymph node metastasis.

Keywords:
Bladder transitional cell carcinoma, CXCR4, Lymph node metastasis, Prognosis
1.
Lerner SP: Bladder cancer clinical trials. Urol Oncol 2005;23:275-279.
2.
Von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000;18:3068-3077.
3.
Balkwill F: Chemokine biology in cancer. Semin Immunol 2003;15:49-55.
4.
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.
5.
Balkwill F: The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol 2004;14:171-179.
6.
Eisenhardt A, Frey U, Tack M, Rosskopf D, Lümmen G, Rübben H, Siffert W: Expression analysis and potential functional role of the CXCR4 chemokine receptor in bladder cancer. Eur Urol 2005;47:111-117.
7.
Weidner N, Semple JP, Welch WR, Folkman J: Tumor angiogenesis and metastasis - correlation in invasive breast carcinoma. N Engl J Med 1991;324:1-8.
8.
Homey B, Müller A, Zlotnik A: Chemokines: agents for the immunotherapy of cancer? Nat Rev Immunol 2002;2:175-184.
9.
Rossi D, Zlotnik A: The biology of chemokines and their receptors. Annu Rev Immunol 2000;18:271-342.
10.
Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR: Function of the chemokine receptor CXCR4 in hematopoiesis and in cerebellar development. Nature 1998;393:595-599.
11.
Feng Y, Broder CC, Kennedy PE, Berger EA: HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G-protein-coupled receptor. Science 1996;272:872-877.
12.
Vicari AP, Caux C: Chemokines in cancer. Cytokine Growth factor Rev 2002;13:143-145.
13.
Strieter RM: Chemokines: not just leukocyte chemoattractants in the promotion of cancer. Nat Immunol 2001;2:285-286.
14.
Schrader AJ, Lechner O, Templin M, Dittmar KE, Machtens S, Mengel M, Probst-Kepper M, Franzke A, Wollensak T, Gatzlaff P, Atzpodien J, Buer J, Lauber J: CXCR4/CXCL12 expression and signalling in kidney cancer. Br J Cancer 2002;86:1250-1256.
15.
Bachelder RE, Wendt MA, Mercurio AM: Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4. Cancer Res 2002;62:7203-7206.
16.
Geminder H, Sagi-Assif O, Goldberg L, Meshel T, Rechavi G, Witz IP, Ben-Baruch A: A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases and neuroblastoma. J Immunol 2001;167:4747-4757.
17.
Phillips RJ, Burdick MD, Lutz M, Belperio JA, Keane MP, Strieter RM: The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am J Respir Crit Care Med 2003;167:1676-1686.
18.
Retz MM, Sidhu SS, Blaveri E, Kerr SC, Dolganov GM, Lehmann J, Carroll P, Simko J, Waldman FM, Basbaum C: CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells. Int J Cancer 2005;114:182-189.
19.
Wang H, Yang D, Wang K, Wang J: Expression and potential role of chemokine receptor CXCR4 in human bladder carcinoma cell lines with different metastatic ability. Mol Med Report 2011;4:525-528.
20.
Baltaci S, Resorlu B, Yagci C, Turkolmez K, Gogus C, Beduk Y: Computerized tomography for detecting perivesical infiltration and lymph node metastasis in invasive bladder carcinoma. Urol Int 2008;81:399-402.
21.
Zhou M, He L, Zu X, Zhang H, Zeng H, Qi L: Lymphatic vessel density as a predictor of lymph node metastasis and its relationship with prognosis in urothelial carcinoma of the bladder. BJU Int 2011;107:1930-1935.
22.
Kitadai Y, Kodama M, Cho S, Kuroda T, Ochiumi T, Kimura S, Tanaka S, Matsumura S, Yasui W, Chayama K: Quantitative analysis of lymphangiogenic markers for predicting metastasis of human gastric carcinoma to lymph nodes. Int J Cancer 2005;115:388-392.
23.
Roma AA, Magi-Galluzzi C, Kral MA, Jin TT, Klein EA, Zhou M: Peritumoral lymphatic invasion is associated with regional lymph node metastases in prostate adenocarcinoma. Mod Pathol 2006;19:392-398.
© 2013 S. Karger AG, Basel
2013
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