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Oncogenic transformation induces tumor angiogenesis: a role for PAR1 activation
Author(s) -
Yin YongJun,
Salah Zaidoun,
Maoz Myriam,
Ram Sharona Cohen Even,
Ochayon Shalom,
Neufeld Gera,
Katzav Shulamit,
BarShavit Rachel
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0316com
Subject(s) - angiogenesis , matrigel , microbiology and biotechnology , biology , transfection , cancer research , vascular endothelial growth factor , signal transduction , endothelial stem cell , chemistry , cell culture , in vitro , biochemistry , genetics , vegf receptors
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. Yin, Y.‐J., Salah, Z., Maoz, M., Cohen Even Ram, S., Ochayon, S., Neufeld, G., Katzav, S., Bar‐Shavit, R. Oncogenic transformation induces tumor angiogenesis: a role for PAR1 activation. FASEB J . 17, 163–174 (2003)