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Tumor Biology |
Division of Cancer Biology Research, Sunnybrook Health Science Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M4N 3M5 Canada [J. R., Y. M., C. S., A. T., A. V-P., J. F., R. S. K.], and Department of Molecular, Cellular and Developmental Biology and Howard Hughes Medical Institute Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 30303 [S. J. M., N. G. A.]
A possible link between oncogenes and tumor angiogenesis has been
implicated by the finding that expression of various oncogenes,
particularly mutant ras, can lead to a marked induction of
a potent paracrine stimulator of angiogenesis, vascular endothelial
growth factor (VEGF). We sought to determine how oncogenic
ras induction of VEGF is mediated at the molecular level
and whether the mechanisms involved differ fundamentally between
transformed epithelial cells and fibroblasts. Our results suggest that
in a subline (called RAS-3) of immortalized nontumorigenic rat
intestinal epithelial cells (IEC-18) that acquired a tumorigenic
phenotype upon transfection of mutant ras, up-regulation of
VEGF occurs in the absence of an autocrine growth factor circuit. The
expression of VEGF mRNA and protein by RAS-3 cells was strongly
suppressed in the presence of LY294002, an inhibitor of
phosphatidylinositol 3'-kinase, but remained largely unaffected in the
same cells treated with an inhibitor (PD98059) of mitogen-activated
protein/extracellular signal-regulated kinase kinase 1
(MKK/MEK-1). This is consistent with the observation that
overexpression of a constitutively activated mutant of MEK-1
(
N3/S222D) in the parental IEC-18 cells did not result in
up-regulation of VEGF production. The impact of mutant ras
on VEGF expression was also significantly amplified at high cell
density, conditions under which RAS-3 cells became less sensitive to
LY294002-induced VEGF down-regulation.
In marked contrast to cells of epithelial origin, ras-transformed murine fibroblasts (3T3RAS) up-regulated VEGF in a manner that was strongly inhibitable by MEK-1 blockade (i.e. treatment with PD98059), whereas these cells were relatively unaffected by treatment with the phosphatidylinositol 3'-kinase inhibitor LY294002. In addition, VEGF was up-regulated by 2–3-fold in NIH3T3 cells overexpressing mutant MEK-1. Collectively, the data suggest that the stimulatory effect of mutant ras on VEGF expression is executed in a nonautocrine and cell type-dependent manner and that it can be significantly exacerbated by physiological/environmental influences such as high cell density.
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C. Blancher, J. W. Moore, N. Robertson, and A. L. Harris Effects of ras and von Hippel-Lindau (VHL) Gene Mutations on Hypoxia-inducible Factor (HIF)-1{alpha}, HIF-2{alpha}, and Vascular Endothelial Growth Factor Expression and Their Regulation by the Phosphatidylinositol 3'-Kinase/Akt Signaling Pathway Cancer Res., October 1, 2001; 61(19): 7349 - 7355. [Abstract] [Full Text] [PDF]
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