CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells

Abstract

Transitional cell carcinoma of the urinary bladder remains life threatening due to the high occurrence of metastases. Emerging evidence suggests that chemokines and their receptors play a critical role in tumor metastases. In our study, we performed a systematic analysis of the mRNA and protein expression levels of all 18 chemokine receptors in normal urothelium and bladder cancer. CXCR4 was the only chemokine receptor whose mRNA expression level was upregulated in bladder cancer cell lines as well as in invasive and locally advanced bladder cancer tissue samples (pT2-pT4). In contrast, superficial bladder tumors (pTa and pT1) displayed low CXCR4 expression levels and normal urothelial cells were negative for CXCR4. Immunohistochemistry of a bladder cancer tissue microarray (TMA) confirmed that a subgroup of invasive bladder cancers revealed a high CXCR4 protein expression, while superficial bladder tumors showed low immunoreactivity. To investigate the functional significance of CXCR4 expression, we performed migration and invasion assays. Exposure of CXCR4-positive bladder cancer cells to CXCL12 in a Boyden chamber type assay provoked a significant increase in migration as well as invasion across a Matrigel barrier. Enhanced migration and invasion were inhibited by a CXCR4-specific blocking antibody. In contrast, normal urothelial cells did not respond to CXCL12 and lacked chemotactic migration. In conclusion, bladder cancer cells express CXCR4 progressively with advanced tumorigenesis and this receptor interacts with CXCL12 to mediate tumor chemotaxis and invasion through connective tissue. These properties identify CXCR4 as a potential target for the attenuation of bladder cancer metastases. © 2004 Wiley-Liss, Inc.Key words: chemokine; bladder cancer; metastasis; migration; invasion Transitional cell carcinoma of the bladder is the most frequent tumor of the urinary tract. Despite advances in early detection and therapy, bladder cancer remains life threatening due to the high occurrence of metastases. Radical cystectomy is the preferred treatment for muscle-invasive bladder cancer in the United States, Japan and some countries of Europe. However, at least 50% of patients with locally advanced disease are expected to develop systemic progression within 3 years. 1 Patients suffering from metastatic bladder cancer are commonly treated with systemic chemotherapy. Analyzing survival rates from standard chemotherapy schedules such as M-VAC (methotrexate, vinblastine, adriamycin and cisplatin), results are more or less discouraging. In the Loehrer trial, only 5 of 133 (3.7%) of the patients randomized to M-VAC were alive at the 6-year follow-up time. These results indicate that patients with systemic metastases continue to be incurable by chemotherapy. 2,3 Despite the fact that it is the metastases rather than the primary tumors that cause most cancer deaths, there has been little progress in identifying drugs to specifically block metastases.Metastasis is not a simple phenomenon, but a highly organized process com...

Steroid Receptor Coactivator-3 Promotes Bladder Cancer Through Upregulation of CXCR4

“…Exposure of CXCR4-positive bladder cancer cells to its ligand (CXCL12) provoked a significant increase in proliferation as well as invasion across a Matrigel barrier in a Boyden chamber type assay (Eisenhardt et al, 2005;Retz et al, 2005). Consistently, enhanced migration and invasion were inhibited by a CXCR4-specific blocking antibody (Eisenhardt et al, 2005;Retz et al, 2005). Moreover, a recent study demonstrated that higher CXCR4 expression was associated with Stat3 signaling activation in bladder cancer [30].…”

CXCR4 and VEGF expression in the primary site and the metastatic site of human osteosarcoma: analysis within a group of patients, all of whom developed lung metastasis

“…Following their investigation, CXCR4 involvement in metastasis has been suggested in a variety of tumors and its expression in the primary site has been clinically correlated with poor survival or tumor progression in ovarian carcinoma, 2 neuroblastoma, 8 head and neck squamous cell carcinoma, 10 colorectal carcinoma 11 and urinary bladder cancer. 12 However, no investigators have compared CXCR4 expression in the primary site with that in the concordant metastatic site, using a rather large series of clinical samples. Moreover, no studies have evaluated CXCR4 expression in human sarcoma.…”

“…Among chemokines and their receptors, the stromal cell-derived factor-1 (SDF-1/CXCL12)/CXCR4 system has been demonstrated to be involved in the lymph node metastasis or distant metastasis of several types of cancer. [1][2][3][4][5][6][7][8][9][10][11][12] Osteosarcoma is the most frequent primary bone tumor in young adults and adolescents. Despite recent advances in multimodality treatments consisting of adjuvant chemotherapy and surgical-wide resection, pulmonary metastasis occurs in approximately 40-50% of the patients.…”

Expression analysis and clinical significance of CXCL16/CXCR6 in patients with bladder cancer

“…Retz et al (11) showed that bladder cancer cells express CXCR4 progressively with advanced tumorigenesis and that this receptor interacts with CXCL12 to mediate tumor chemotaxis and invasion through connective tissue. These properties identify CXCR4 as a potential target for the attenuation of bladder cancer metastases.…”