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Vascular Leak in Melanoma is Triggered by VEGF and Other Secreted Factors

Because leaky blood vessels promote melanoma progression and blockade of VEGF‐A by Avastin (bevacizumab; FDA‐approved anti‐VEGF‐A) is only partially effective, we have developed new models for studying the endothelial cell (EC) response to YUSIT, a human melanoma cell line. Human dermal microvascular EC (HDMEC) forming leak‐resistant monolayers on transwells reduced transendothelial electrical resistance (TEER) by 50% at 24 h when co‐cultured with YUSIT, suggesting YUSIT secrete leak‐inducing factors. Indeed, YUSIT conditioned medium contains VEGF‐A (6 ng/ml) and incubation with HDMEC decreased TEER 40–50% by 4 h. Although this response was inhibitable by Avastin, TEER was partially decreased even by conditioned medium depleted of VEGF. Adding back a small amount of VEGF (0.2 ng/ml) to VEGF‐depleted conditioned medium decreased TEER more effectively than a 100‐fold greater VEGF concentration in fresh medium, suggesting YUSIT secrete additional leak factors. YUSIT injected s.c. formed leaky tumors in human skin grafted onto immunodeficient SCID mice and conditioned medium elicited vascular leak as well as high concentration VEGF; depleting conditioned medium of VEGF removed most of the in vivo leak activity. We conclude melanoma VEGF and other secreted factors trigger vascular leak and that these new models can be used for understanding how human EC contribute to melanoma progression. Supported by NCI.