Clinical significance of CXCR3 and CXCR4 expression in primary melanoma

Abstract

Tumor cell migration involved in metastases is a tightly regulated, nonrandom process. Chemokines have been identified as critical molecules guiding cell migration. We performed a prospective study to analyze a possible association between the expression of chemokine receptors CXCR3 and CXCR4 by primary melanoma and clinical outcome. Forty primary melanomas were available for analysis; 57% of the tumors expressed CXCR3 and 35% expressed CXCR4 by melanoma cells. At initial diagnosis, 5 patients had subclinical lymph node involvement and after a median follow-up time of 32 months, 2 additional patients developed regional lymph node metastases and 5 patients developed distant metastases. The expression of CXCR4, but not CXCR3, by melanoma cells in primary lesions was significantly associated with the presence of ulceration, increased tumor thickness, a greater risk of developing regional and distant metastases and a higher mortality rate. Our study underscores the value of CXCR4 expression as a useful marker for predicting outcome in patients with localized melanoma. In addition, our findings support that, among chemokine receptors, CXCR4 might be an appropriate therapeutic target for adjuvant therapy in patients at risk for metastatic disease. ' 2005 Wiley-Liss, Inc.Key words: melanoma; chemokine receptors; clinical significanceThe incidence of cutaneous melanoma has steeply increased in the last decade.1 The most important prognostic factors of the primary tumor include depth of invasion 2 and presence of ulceration.3,4 Roughly 20% of patients will develop metastases that are the main cause of death. The mechanisms involved in metastasis are not completely understood. The capability of a tumor clone to metastasize depends on its ability to disrupt the basal membrane, migrate, proliferate and survive to allow progressive growth at distant sites. The development of metastases implies a stepwise and organ-specific process. Tumor cell migration to target organs is achieved by a chemotactic response to certain molecules. Chemokines comprise a group of key molecules involved in migration of different cell lineages. They constitute a family of small proteins that are classified based on the specific cysteine motifs in their amino acid sequence. [5][6][7] Through their interaction with G-proteincoupled receptors, chemokines mediate many physiologic and pathologic processes involving cell migration. [5][6][7] Tumor cells might employ similar mechanisms to migrate to specific organs as do leukocytes and other cell types through the expression of certain chemokine receptors.8 Current evidence supports a strong role for chemokines in the complex process of metastasis.9 Moreover, chemokines have been identified as angiogenic factors that promote tumor cell growth and progression. The chemokines most thoroughly studied in melanoma are CXCL1, CXCL2 and CXCL8. The increased expression of CXCL1 and CXCL2 (previously known as melanoma growth stimulatory activity alpha and beta, respectively) in melanoma lesions correlates with tu...

Serum Immunoregulatory Proteins as Predictors of Overall Survival of Metastatic Melanoma Patients Treated with Ipilimumab

“…Paired analysis of mRNAs and proteins in tissue and serum might provide evidence to resolve this discrepancy. As CXCL11 has distinct immunoregulatory functions, in contrast to immunostimulatory functions mediated by CXCL9 and CXCL10 (24,25), we prefer the following nonmutually exclusive explanations of how CXCL11, even in the presence of CXCL9 and CXCL10, may limit T-cell effector function as a part of negative feedback loop: (i) disrupting chemokine gradients for directional migration of T cells (26), (ii) preventing CXCR3-CXCL9/10 interaction by promoting receptor internalization (24), (iii) suppressing T-cell responses through induction and/or recruitment of regulatory T cells (25,27), and (iv) promoting growth and metastasis of tumors expressing CXCR3 (28)(29)(30)(31).…”

Activation of Vav/Rho GTPase Signaling by CXCL12 Controls Membrane-Type Matrix Metalloproteinase–Dependent Melanoma Cell Invasion

“…Furthermore, we showed that CXCL12-triggered up-regulation of MT1-MMP expression and function on these cells contributed to increase in invasion and that Rac and Rho controlled this up-regulation. Importantly, CXCR4 expression on malignant melanoma predicts poor prognosis (11,14). The present study addressed several important points for a better characterization of signaling events and MMP activities that are involved in CXCL12-promoted melanoma cell invasion.…”

“…Importantly, inhibition of CXCL12/CXCR4 interactions impairs metastasis of human breast cancer cells into regional lymph nodes and lung in mice, and expression of CXCR4 on murine B16 melanoma cells correlated with enhanced pulmonary and lymph node metastatic potential (3,8). Further in vivo studies of tumor cell metastasis in mice together with clinical data indicate that CXCR4 expression conveys tumor cell invasiveness and patient poor prognosis in a variety of solid cancer types (9)(10)(11)(12)(13)(14). CXCL12/ CXCR4 interaction is likely important not only for tumor cell invasion but also for tumor growth (10,15).…”

Chemokines in tumor angiogenesis and metastasis

“…For example, CXCL9 and CXCL10 induce the migration and invasion of melanoma cell lines and multiple myeloma cells [185][186][187]. CXCR3, the receptor for CXCL9 and CXCL10 was shown to be expressed by cancer cells of solid tumors, such as breast tumor cells, renal carcinoma cells and melanoma cells [185,[188][189][190]. A direct role for CXCR3 in inducing tumor cell migration to metastatic sites was suggested by observations showing that the expression of this chemokine receptor by melanoma cells is causally involved in metastasis to lymph nodes [187].…”