Vascular endothelial growth factor C expression and lymph node metastasis are regulated by the type I insulin-like growth factor receptor

• Published in: Cancer research (Chicago, Ill.) Ill.), 2003-03, Vol.63 (6), p.1166-1171
• Main Authors: YUCHENG TANG, DONGLEI ZHANG, FALLAVOLLITA, Lucia, BRODT, Pnina
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Carcinoma, Lewis Lung - enzymology; Carcinoma, Lewis Lung - metabolism; Carcinoma, Lewis Lung - secondary; Chromones - pharmacology; Dissemination; Endothelial Growth Factors - antagonists & inhibitors; Endothelial Growth Factors - biosynthesis; Endothelial Growth Factors - genetics; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Insulin-Like Growth Factor I - antagonists & inhibitors; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - physiology; Lymphatic Metastasis; Medical sciences; Mice; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Morpholines - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol 3-Kinases - physiology; Phosphorylation - drug effects; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1 - metabolism; Receptor, IGF Type 1 - physiology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Signal Transduction - drug effects; Signal Transduction - physiology; Tumor cell; Tumors; Vascular Endothelial Growth Factor C
• ISSN: 0008-5472; 1538-7445

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.