Chemokine-chemokine receptor axes in melanoma brain metastasis.
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.
Izraely
Sivan
S
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Klein
Anat
A
Sagi-Assif
Orit
O
Meshel
Tsipi
T
Tsarfaty
Galia
G
Hoon
Dave S B
DS
Witz
Isaac P
IP
D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000503:physiopathology* / Q000556:secondary*; D045744:Cell Line, Tumor; D054414:Chemokine CCL17 / Q000276:immunology; D054422:Chemokine CCL22 / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D019707:Receptors, Chemokine / Q000502:physiology*; D012878:Skin Neoplasms / Q000276:immunology / Q000503:physiopathology*
D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019707:Receptors, Chemokine