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Vascular Endothelial Growth Factor C Expression and Lymph Node Metastasis Are Regulated by the Type I Insulin-like Growth Factor Receptor¹

Departments of Surgery [Y. T., D. Z., L. F., P. B.] and Medicine [P. B.], McGill University Health Center, the Royal Victoria Hospital, Montreal, Quebec, H3A 1A1 Canada

Vascular endothelial growth factor (VEGF)-C is a lymphangiogenic factor implicated in lymphatic metastasis. In this study, we investigated the role of the type I insulin-like growth factor receptor (IGF-IR) in the regulation of VEGF-C expression. We used Lewis lung carcinoma subline M-27 cells transfected with human IGF-IR cDNA. These cells, but not the wild-type cells, expressed VEGF-C mRNA, produced a M_r 58,000 VEGF-C precursor protein, and secreted a M_r 29,000 processed form in response to IGF-I. In vivo, they acquired a lymph node metastasizing potential. VEGF-C induction was abolished in cells expressing an IGF-IR with tyrosine-phenylalanine substitutions in the kinase domain, but not in the COOH-terminal domain. The induction was phosphatidylinositol 3'-kinase dependent and, to a lesser extent, mitogen-activated protein kinase signaling dependent, as determined by the use of the respective inhibitors LY294002 (84.6% reduction) and PD98059 (38% reduction). The results identify the IGF-IR as a positive regulator of VEGF-C expression and implicate it in the control of lymphatic metastasis.

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