Abstract
Abstract Phenotypic and genotypic analyses of cutaneous melanoma have identified endothelin B receptor (ETBR) as tumor progression marker, thus representing a potential therapeutic target. We previously reported that the binding of ET-1 to ETBR stimulates angiogenesis and lymphangiogenesis directly and by stimulating vascular endothelial growth factor (VEGF)-A and VEGF-C production. In this study we investigated as to whether in melanoma cells ET-1 axis may interact with VEGF-A and VEGF-C signaling pathways to heighten cellular responsiveness. We found that in primary and metastatic melanoma cell lines, ET-1 increased VEGF-A, VEGF-C and its selective receptor VEGFR-3, at mRNA and protein level. Following ET-1 stimulation, VEGF-A and VEGF-C were upregulated, VEGFR-3 was rapidly phosphorylated and downstream signaling intermediates, such as p42/44 MAPK and Akt, were activated through ETBR. Inhibition of c-Src activity by PP2, reduced ET-1-induced VEGFR-3 phosphorylation, demonstrating that ET-1 transactivates VEGFR-3 through an intracellular mechanism mediated by c-Src. Stimulation with ET-1 in combination with VEGF-A or VEGF-C increased p42/44 MAPK and AKT phosphorylation, and resulted in a greater degree of melanoma cell migration compared to a single factor. Furthermore, this combination significantly enhanced the ET-1-induced vasculogenic differentiation of melanoma cells in capillary-like structures, vasculogenic mimicry, indicating that crosstalk between ET-1/ETBR axis with VEGFR-3/VEGF-C system may enhance cancer cell motility and invasiveness and contributes to the promotion of cancer metastasis. Finally, in melanoma xenografts, ETBR antagonist suppressed tumor growth and neovascularization-related effectors, indicating that targeting ETBR related signalling cascade may represent a novel treatment of melanoma by impairing the crosstalk between ET-1 axis and VEGF in melanoma. Supported by AIRC Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 493. doi:1538-7445.AM2012-493
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