Protein expression of the chemokine receptor CXCR4 and its ligand CXCL12 in primary cutaneous melanoma—biomarkers of potential utility?

Brendon Mitchell, Dominick Leone, Kyle Feller, Sandeep Menon, Philip Bondzie, Shi Yang, Hee-Young Park, Meera Mahalingam

Dysregulation of the CXCR4/CXCL12 axis, relevant in melanoma progression, activates cell cycle progression and migration via stimulation of the MAPK pathway. We sought to ascertain the cooperativity of the CXCR4/CXCL12 axis with established prognosticators and BRAF status in melanoma. Samples (n = 107) of primary cutaneous melanoma were assessed for protein expression of CXCR4 and CXCL12, and molecular analyses were performed to ascertain BRAF status. Univariate analyses of CXCR4 protein showed that the proportion of CXCR4 positives was greater in melanomas with absence of mitoses (P < .0001), absence of ulceration (P = .0008), and absence of regression (P = .02). Patients presenting at shallower stages (American Joint Committee on Cancer [AJCC] 1-2) exhibited a larger proportion of CXCR4 positives (76.9%, P < .0001 and 69.0%, P = .008), whereas those at deeper stages (AJCC 3-4) exhibited a larger proportion of negatives (75.0%, P = .004 and 66.7%, P = .22). In a multivariate analysis, lower odds of CXCR4 protein expression were associated with AJCC stage 3 (odds ratio [OR]=0.16, P = .01), AJCC stage 4 (OR=0.17, P = .04), and mitoses (OR=0.21, P = .01). Univariate analyses of CXCL12 protein showed that the proportion of CXCL12 negatives was significantly smaller in melanomas with depth of at least 1 mm, absence of ulceration, and absence of vascular invasion (P < .0001 for all). CXCR4 and CXCL12 appear to be biomarkers associated with established prognosticators of good and poor clinical outcome, respectively, in primary cutaneous melanoma. A BRAF mutation does not appear to be associated with CXCR4/CXCL12 axis upregulation in primary cutaneous melanoma.