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The prognostic significance and impact of the CXCR 4– CXCR 7– CXCL 12 axis in primary cutaneous melanoma
Author(s) -
McConnell A.T.,
Ellis R.,
Pathy B.,
Plummer R.,
Lovat P.E.,
O'Boyle G.
Publication year - 2016
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.14720
Subject(s) - autocrine signalling , melanoma , cancer research , cxcr4 , chemokine receptor , metastasis , medicine , cancer , tumor microenvironment , immunohistochemistry , biology , chemokine , pathology , receptor
Summary Background Expression of the chemokine receptor CXCR 4 is known to regulate melanoma metastasis to distant sites with high expression of the CXCL 12 ligand. However, the prognostic impact of CXCR 4 expression and potential for autocrine‐mediated activation of prosurvival mitogen‐activated protein kinase signalling remains enigmatic. Furthermore, expression of the decoy receptor CXCR 7 within the local cutaneous melanoma microenvironment remains undefined. Objectives To define the contribution and prognostic impact of CXCR 4– CXCR 7– CXCL 12 signalling in primary cutaneous melanomas and the immediate tumour microenvironment. Methods Immunohistochemical/immunofluorescent expression of CXCR 4, CXCR 7 or CXC 12 was analysed in human metastatic melanoma cell lines, primary cutaneous cell types and a retrospective cohort of primary melanomas/benign naevi. CXCL 12 secretion by melanoma/cutaneous cells was evaluated by enzyme‐linked immunosorbent assay, and autocrine CXCR 4– CXCL 12 signalling was investigated by addition of a CXCL 12‐neutralizing antibody. Results CXCR 4 expression was significantly higher in primary melanomas that subsequently metastasized after 7 years ( P = 0·037). Stratification for American Joint Committee on Cancer ( AJCC ) stage II disease revealed significantly decreased disease‐free survival in patients with > 50% CXCR 4 expression ( P = 0·036), while comparative analysis of CXCL 12 expression in the adjacent epidermis of all AJCC stage melanomas revealed increased CXCL 12 correlated with prolonged time to metastasis ( P = 0·014). CXCR 7 was expressed within the primary melanoma microenvironment but was absent on primary tumours. Addition of anti‐ CXCL 12 to BRAF ‐mutant melanoma cells resulted in downregulation of phospho‐ CXCR 4 and phospho‐extracellular signal‐related kinase, indicating autocrine CXCR 4– CXCL 12 signalling. Conclusions CXCR 4 expression defines a potential prognostic biomarker for AJCC stage II melanoma. Moreover, targeting the CXCR 4– CXCR 7– CXCL 12 axis may represent a novel therapeutic strategy to prevent early melanoma progression.