title: Oncogenic transformation induces tumor angiogenesis: a role for PAR1 activation.
abstract: The formation of new blood vessels is a critical determinant of tumor progression. We find that Par1 gene expression plays a central role in blood vessel recruitment in animal models. By in vivo injection of either Matrigel plugs containing Par1-expressing cells or of rat prostatic carcinoma cells transfected with tetracycline-inducible Par1 expression vectors, we show that Par1 significantly enhances both angiogenesis and tumor growth. Several vascular endothelial growth factor (VEGF) splice forms are induced in cells expressing Par1. Activation of PAR1 markedly augments the expression of VEGF mRNAs and of functional VEGFs as determined by in vitro assays for endothelial tube alignment and bovine aortic endothelial cell proliferation. Because neutralizing anti-VEGF antibodies potently inhibited Par1-induced endothelial cell proliferation, we conclude that Par1-induced angiogenesis requires VEGF. Specific inhibitors of protein kinase C (PKC), Src, and phosphatidylinositol 3-kinase (PI3K) inhibit Par1-induced VEGF expression, suggesting the participation of these kinases in the process. We also show that oncogenic transformation by genes known to be part of PAR1 signaling machinery is sufficient to increase VEGF expression in NIH 3T3 cells. These data support the novel notion that initiation of cell signaling either by activating PAR1 or by the activated forms of oncogenes is sufficient to induce VEGF and hence angiogenesis.
authors.affiliation: Department of Oncology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Yin
authors.forename: Zaidoun
authors.initials: Z
authors.lastname: Salah
authors.forename: Myriam
authors.initials: M
authors.lastname: Maoz
authors.forename: Sharona Cohen
authors.initials: SC
authors.lastname: Even Ram
authors.forename: Shalom
authors.initials: S
authors.lastname: Ochayon
authors.forename: Gera
authors.initials: G
authors.lastname: Neufeld
authors.forename: Shulamit
authors.initials: S
authors.lastname: Katzav
authors.forename: Rachel
authors.initials: R
authors.lastname: Bar-Shavit
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015152:Blotting, Northern; D002471:Cell Transformation, Neoplastic; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D011905:Genes, ras / Q000235:genetics; D016391:Genes, src / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D009857:Oncogenes / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D011493:Protein Kinase C