Brain
metastasis confers an extremely unfavorable prognosis upon
melanoma patients. The mechanisms underlying the homing of metastatic
melanoma to the brain and survival of metastatic
melanoma cells in the brain are unknown.
Tumor cells, including
melanoma, use
chemokine receptor-
ligand axes to home to specific organ sites. To identify
chemokine receptors that might be involved in brain-targeted
melanoma metastasis, we first established a
chemokine receptor profile of cultured
melanoma cells (3 cell lines of cutaneous
melanoma and 5 cell lines of
melanoma brain
metastasis). The expression of the membrane-bound
chemokine CX3CL1 by these lines was also determined. We show that out of 19 receptors tested, cultured
melanoma cells express CCR3, CCR4, CXCR3, CXCR7, CX3CR1 and membrane CX3CL1. Utilizing cells from newly created variants of human
melanoma xenografts, we found that the expression of CCR4 was significantly higher in one brain metastatic variant compared to its expression in the corresponding local variant. Local and metastatic variants stimulated with the CCR4
ligand, CCL22, showed a differential AKT phosphorylation pattern. These findings may suggest the involvement of CCR4 in the process of brain
metastasis in human
melanoma, and that CCR4 may be a novel molecular
biomarker for the identification of
melanoma cells likely to metastasize to the brain.