title: Induction of angiogenesis by expression of soluble type II transforming growth factor-beta receptor in mouse hepatoma.
abstract: The biological effect of transforming growth factor-beta (TGF-beta) is cell type-specific and complex. The precise role of TGF-beta is not clear in vivo. To elucidate the regulation mechanism of endogenous TGF-beta on hepatoma progression, we modified the MH129F mouse hepatoma cell with a retroviral vector encoding the extracellular region of type II TGF-beta receptor (TRII). Soluble TRII (TRIIs) blocked TGF-beta binding to TRII on the membrane of hepatoma cells. Growth of MH129F cells was inhibited by TGF-beta1 treatment; however, soluble TRII-overexpressing cells (MH129F/TRIIs) did not show any change in proliferation after TGF-beta1 treatment. MH129F/TRIIs cells also increased vascular endothelial growth factor (VEGF) expression, endothelial cell migration, and tube formation. Implantation of MH129F/TRIIs cells into C3H/He mice showed the significantly enhanced tumor formation. According to Western blot and protein kinase C assay, the expression of VEGF, KDR/flk-1 receptor, and endothelial nitric-oxide synthase was enhanced, and the phosphorylation activity of protein kinase C was increased up to 3.7-fold in MH129F/TRIIs tumors. Finally, a PECAM-1-stained intratumoral vessel was shown to be 4.2-fold higher in the MH129F/TRIIs tumor. These results indicate that VEGF expression is up-regulated by a blockade of endogenous TGF-beta signaling in TGF-beta-sensitive hepatoma cells and then stimulates angiogenesis and tumorigenicity. Therefore, we suggest that endogenous TGF-beta is a major regulator of the VEGF/flk-1-mediated angiogenesis pathway in hepatoma progression.
authors.affiliation: Central Genome Center, National Institute of Health, Seoul 122-701, Korea.
authors.forename: K Y
authors.initials: KY
authors.lastname: Kim
authors.forename: S Y
authors.initials: SY
authors.lastname: Jeong
authors.forename: J
authors.initials: J
authors.lastname: Won
authors.forename: P D
authors.initials: PD
authors.lastname: Ryu
authors.forename: M J
authors.initials: MJ
authors.lastname: Nam
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D008222:Lymphokines / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D009389:Neovascularization, Pathologic; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D000077294:Receptor, Transforming Growth Factor-beta Type II; D017978:Receptors, Growth Factor / Q000096:biosynthesis; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis*; D040262:Receptors, Vascular Endothelial Growth Factor; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D000077294:Receptor, Transforming Growth Factor-beta Type II