VEGF receptor-3 interacts with PI3K directly to regulate lymphangiogenesis

Abstract Dissemination of malignant cells into the regional lymph nodes is a common occurrence in many cancers. The vascular endothelial growth factor (VEGF) family is a major regulator spread of cancer to lymph nodes via induction of lymphangiogenesis. We have used primary lymphatic endothelial cells and clinical material to investigate VEGF-C/VEGF receptor (VEGFR)-3 signalling pathways. We found that treatment with VEGF-C induced activation of PI3K/Akt and MEK/Erk in lymphatic endothelial cells. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCγ1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in lymphatic endothelial cells was demonstrated both in vitro and in clinical specimens, where it was associated with the presence of lymph node metastases in small cell carcinoma of the lung. Blocking PI3K abolished VEGF-C-stimulated lymphatic endothelial cell tube formation and migration. Our findings demonstrate that specific VEGFR-3 signalling pathways are activated in lymphatic endothelial cells by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for tumor lymphatic metastasis. 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 5299. doi:1538-7445.AM2012-5299