CD146 mediates VEGF‐induced melanoma cell extravasation through FAK activation

• Published in: International journal of cancer 2015-07, Vol.137 (1), p.50-60
• Main Authors: Jouve, Nathalie, Bachelier, Richard, Despoix, Nicolas, Blin, Muriel G., Matinzadeh, Maryam Khalili, Poitevin, Stéphane, Aurrand‐Lions, Michel, Fallague, Karim, Bardin, Nathalie, Blot‐Chabaud, Marcel, Vely, Frédéric, Dignat‐George, Françoise, Leroyer, Aurélie S.
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - metabolism; Cadherins - metabolism; Cancer; CD146; CD146 Antigen - genetics; CD146 Antigen - metabolism; Cell adhesion & migration; endothelium; Endothelium, Vascular - metabolism; FAK; Focal Adhesion Kinase 1 - metabolism; Gene Expression Regulation, Neoplastic; Life Sciences; Lung - blood supply; Lung - cytology; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Medical research; Melanoma; Melanoma, Experimental - genetics; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Metastasis; Mice; Mice, Knockout; Neoplasm Transplantation; Neovascularization, Pathologic - metabolism; Rodents; Tumor Cells, Cultured; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29370

CD146 is an adhesion molecule expressed by both melanoma and endothelial cells and thus is well positioned to control melanoma extravasation. Nevertheless, during melanoma metastasis, the involvement of CD146 expressed within tumor microenvironment has never been analyzed. To investigate whether host CD146 mediates the extravasation of melanoma cells across the endothelium, we generated CD146 KO mice. We demonstrated that host CD146 did not affect melanoma growth or tumor angiogenesis but promoted hematogenous melanoma metastasis to the lung. Accordingly, the survival of CD146‐deficient mice was markedly prolonged during melanoma metastasis. Interestingly, vascular endothelial growth factor‐induced vascular permeability was significantly decreased in CD146 KO mice. We also provided evidence that VEGF‐induced transendothelial migration of melanoma cells was significantly reduced across CD146 KO lung microvascular endothelial cells (LMEC). CD146 deficiency decreased the expression of VEGFR‐2/Ve‐cadherin and altered focal adhesion kinase (FAK) activation in response to VEGF. In addition, inhibition of FAK phosphorylation reduced transmigration of B16 melanoma cells across WT LMEC at the same level that across CD146 KO LMEC. Altogether, we propose a novel mechanism involving the VEGF/CD146/FAK/Ve‐cadherin network in melanoma extravasation across the vessel barrier that identifies CD146‐targeted therapy as a potential strategy for the treatment of melanoma metastasis. What's new? To win the fight against metastatic melanoma—one of the most drug‐resistant cancers—novel therapeutic targets must be identified. A promising candidate is melanoma cell adhesion molecule (MCAM), or CD146, which is present at both endothelial junctions and tumor‐endothelial contact sites, making it well‐positioned to modulate melanoma extravasation. In the present study, CD146‐deficient mice are shown to experience prolonged survival during melanoma metastasis. Evaluation of signaling molecules downstream of CD146 suggests that the VEGF/CD146/FAK/Ve‐cadherin network plays a key role in mediating the hematogenous spread of melanoma to the lungs.