Vascular endothelial growth factor C expression and lymph node metastasis are regulated by the type I insulin-like growth factor receptor.
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.
Tang
Yucheng
Y
Department of Surgery, McGill University Health Center, the Royal Victoria Hospital, Montreal, Quebec, H3A 1A1 Canada.
Zhang
Donglei
D
Fallavollita
Lucia
L
Brodt
Pnina
P
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000201:enzymology / Q000378:metabolism* / Q000556:secondary*; D002867:Chromones / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D008207:Lymphatic Metastasis; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D042582:Vascular Endothelial Growth Factor C
D002867:Chromones; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D042582:Vascular Endothelial Growth Factor C; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one