The prognostic significance and impact of the CXCR4/CXCR7/CXCL12 axis in primary cutaneous melanoma

Background Expression of the chemokine receptor CXCR4 is known to regulate melanoma metastasis to distant sites with high expression of CXCL12 ligand, but the prognostic impact of CXCR4 expression and potential for autocrine mediated activation of pro-survival mitogen-activated-protein-kinase signalling remains enigmatic. Furthermore expression of the decoy receptor CXCR7, within the local cutaneous melanoma microenvironment remains undefined. Objectives The current study aimed to define the contribution and prognostic impact of CXCR4/CXCR7/CXCL12 signalling in primary cutaneous melanomas and immediate tumour microenvironment. Methods Immunohistochemical/immunofluorescent expression of CXCR4, CXCR7 or CXC12 was analysed in human metastatic melanoma cell lines, primary cutaneous cell types and in a retrospective cohort of primary melanomas/benign nevi. CXCL12 secretion by melanoma/cutaneous cells was evaluated by enzyme-linked Immuno-absorbent assay and autocrine CXCR4/CXCL12 signalling investigated by addition of a CXCL12 neutralising antibody. Results CXCR4 expression was significantly higher in primary melanomas which subsequently metastasised after 7 years (P=0.037). Stratification for AJCC stage II disease revealed significantly decreased disease free survival in patients with >50% CXCR4 expression (P=0.036) while comparative analysis of CXCL12 expression in the adjacent epidermis of all AJCC stage melanomas revealed increased CXCL12 correlated with prolonged time to metastasis (P=0.014). CXCR7 expression was expressed within the primary melanoma microenvironment but was absent on primary tumours. Addition of anti-CXCL12 to BRAF mutant melanoma cells resulted in down regulation of phospho-CXCR4 and phospho-ERK, indicating autocrine CXCR4/CXCL12 signalling. Conclusions CXCR4 expression defines a potential prognostic biomarker for AJCC stage II melanoma. Moreover, targeting the CXCR4/CXCR7/CXCL12 axis maybe represent a novel therapeutic strategy to prevent early melanoma progression. This article is protected by copyright. All rights reserved.