title: CD146 mediates VEGF-induced melanoma cell extravasation through FAK activation.
abstract: 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.
authors.affiliation: Aix-Marseille Université, Vascular Research Center of Marseille, Inserm, UMR-S 1076, 13385, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jouve
authors.forename: Richard
authors.initials: R
authors.lastname: Bachelier
authors.forename: Nicolas
authors.initials: N
authors.lastname: Despoix
authors.forename: Muriel G
authors.initials: MG
authors.lastname: Blin
authors.forename: Maryam Khalili
authors.initials: MK
authors.lastname: Matinzadeh
authors.forename: Stéphane
authors.initials: S
authors.lastname: Poitevin
authors.forename: Michel
authors.initials: M
authors.lastname: Aurrand-Lions
authors.forename: Karim
authors.initials: K
authors.lastname: Fallague
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bardin
authors.forename: Marcel
authors.initials: M
authors.lastname: Blot-Chabaud
authors.forename: Frédéric
authors.initials: F
authors.lastname: Vely
authors.forename: Françoise
authors.initials: F
authors.lastname: Dignat-George
authors.forename: Aurélie S
authors.initials: AS
authors.lastname: Leroyer
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D051929:CD146 Antigen / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D008168:Lung / Q000098:blood supply / Q000166:cytology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D051929:CD146 Antigen; D015820:Cadherins; D051417:Focal Adhesion Kinase 1; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C497903:Mcam protein, mouse; C467480:vascular endothelial growth factor A, mouse; C496051:Ptk2 protein, mouse
keywords: CD146; FAK; endothelium; metastasis