CCR4 is a determinant of melanoma brain metastasis
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Anat Klein1, Orit Sagi-Assif1, Tsipi Meshel1, Alona Telerman1, Sivan Izraely1, Shlomit Ben-Menachem1, Jagadeesh Bayry2, Diego M. Marzese3, Shuichi Ohe3, Dave S.B. Hoon3, Neta Erez4, Isaac P. Witz1
1Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel
2Inserm Unité 1138, Center de Recherche des Cordeliers, Université Pierre et Marie Curie, Université, Paris Descartes, Paris, France
3Department of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, USA
4Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Isaac P. Witz, email: email@example.com
Keywords: CCR4, CCL17, melanoma, brain, metastasis
Received: January 18, 2017 Accepted: March 02, 2017 Published: March 10, 2017
We previously identified the chemokine receptor CCR4 as part of the molecular signature of melanoma brain metastasis. The aim of this study was to determine the functional significance of CCR4 in melanoma brain metastasis. We show that CCR4 is more highly expressed by brain metastasizing melanoma cells than by local cutaneous cells from the same melanoma. Moreover, we found that the expression of CCR4 is significantly higher in paired clinical specimens of melanoma metastases than in samples of primary tumors from the same patients. Notably, the expression of the CCR4 ligands, Ccl22 and Ccl17 is upregulated at the earliest stages of brain metastasis, and precedes the infiltration of melanoma cells to the brain. In-vitro, CCL17 induced migration and transendothelial migration of melanoma cells. Functionally, human melanoma cells over-expressing CCR4 were more tumorigenic and produced a higher load of spontaneous brain micrometastasis than control cells. Blocking CCR4 with a small molecule CCR4 antagonist in-vivo, reduced the tumorigenicity and micrometastasis formation of melanoma cells. Taken together, these findings implicate CCR4 as a driver of melanoma brain metastasis.
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