Human Melanoma Metastases Express Functional CXCR4

Abstract

Purpose: The chemokine receptor CXCR4 was identified as an independent predictor of poor prognosis in primary melanoma. The aim of the study was to investigate the role of CXCR4 in human melanoma metastases. Experimental Design: CXCR4 expression was evaluated in melanoma metastases and in metastatic cell lines through immunohistochemistry, immunoblotting, immunofluorescence, and reverse transcription-PCR. The function of CXCR4 was tested in the presence of the ligand, CXCL12, through induction of extracellular signal-regulated kinase-1and -2 (Erk-1and -2) phosphorylation, proliferation, apoptosis, and migration capabilities. Results: CXCR4 expression was detected in 33 out of 63 (52.4%) metastases from cutaneous melanomas. Metastatic melanoma cell lines expressed cell surface CXCR4; PES 43, Alo 40, and COPA cell lines showed the highest levels of CXCR4 (>90% of positive cells); PES 41, Alo 39, PES 47, POAG, and CIMA cell lines showed low to moderate degrees of expression (5-65% of positive cells). Other chemokine receptors, CCR7 and CCR10, were detected on the melanoma cell lines; CXCL12 activated Erk-1 and Erk-2, the whose induction was specifically inhibited by AMD3100 treatment. CXCL12 increased the growth in PES 41, PES 43, and PES 47 cells under suboptimal (1% serum) and serum-free culture conditions; AMD3100 (1 Amol/L) inhibited the spontaneous and CXCL12-induced proliferation. No rescue from apoptosis was shown but PES 41, PES 43, and PES 47 cells migrate toward CXCL12. Conclusions: These findings indicate that CXCR4 is expressed and active in human melanoma metastases, suggesting that active inhibitors such as AMD3100 may be experienced in human melanoma.The incidence and mortality rate of melanoma have increased in the last 30 years. The National Cancer Institute Surveillance, Epidemiology, and End Results database documents increases of 619% in annual diagnoses of cutaneous melanoma and of 165% in annual mortality from 1950 to 2000 (1). Metastatic spread may arise from very small tumor masses and in about two-thirds of all cases of malignant melanoma, spreading develop primarily as locoregional metastases. In about onethird of the cases, primary development of distant metastases is observed (2). The metastatic potential of primary melanoma is considerably higher than that of other primary solid tumors when comparing the size of primary lesion. The usual outcome for patients with distant metastases remains bleak, with median survival of 6 to 10 months and <5% of patients surviving for >5 years (1). Except for high-dose IFN as adjuvant therapy in stage III disease, little success has emerged over the last 20 years for metastatic melanoma (3). The underlying molecular events that explain malignant melanoma genesis and progression have been only partially characterized, and only a small number of genes have been identified as playing key roles in melanoma. Among these, some cell cycle regulators, apoptotic, signal transduction, cell adhesion, and matrix digestion genes have been shown to be deregu...

CXCR4 nuclear localization follows binding of its ligand SDF-1 and occurs in metastatic but not primary renal cell carcinoma

“…CXCR4 is one of the major chemokine receptors on several cancer cells (1,(29)(30)(31)(32)(33). Increasing lines of evidence support the proposal that the SDF-1/CXCR4 axis plays a role in the proliferation, adhesion, chemotaxis and invasion of several tumors (34)(35)(36).…”

Manipulating the chemokine‐chemokine receptor network to treat cancer

“…Researchers found that the majority of metastases from melanoma in their study expressed CXCR4. 27 In glioblastoma cells, CXCR4 expression is up-regulated compared with that in normal brain tissue, and tumor cells secrete CXCL12. 9 Strong expression of CXR4 has been associated with adverse outcome in osteosarcoma, 28 epithelial ovarian cancer, 29 NSCLC, 24 colon, 22,30 and esophageal carcinoma, 23 nasopharyngeal carcinoma, 31 and melanoma 32 ( Table 2).…”

Molecular Pathways: Targeting the CXCR4–CXCL12 Axis—Untapped Potential in the Tumor Microenvironment

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