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Impact of Oncogenes in Tumor Angiogenesis: Mutant K-ras up-Regulation of Vascular Endothelial Growth Factor/Vascular Permeability Factor is Necessary, but not Sufficient for Tumorigenicity of Human Colorectal Carcinoma Cells

Impact of Oncogenes in Tumor Angiogenesis: Mutant K-ras up-Regulation of Vascular Endothelial Growth Factor/Vascular Permeability Factor is Necessary,

Impact of Oncogenes in Tumor Angiogenesis: Mutant K-ras up-Regulation of Vascular Endothelial Growth Factor/Vascular Permeability Factor is Necessary, but not Sufficient for Tumorigenicity of Human Colorectal Carcinoma Cells   (Citations: 108)
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Targeted disruption of the single mutant K-ras allele in two human colorectal carcinoma cell lines (DLD-1 and HCT-116) leads to loss of tumorigenic competence in nude mice with retention of ability to grow indefinitely in monolayer culture. Because expression of the mutant K-ras oncogene in these cell lines is associated with marked up-regulation of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), we sought to determine whether this potent angiogenesis inducer plays a role in K-ras-dependent tumorigenic competence. Transfection of a VEGF121 antisense expression vector into DLD-1 and HCT-116 cells resulted in suppression of VEGF/VPF production by a factor of 3- to 4-fold. The VEGF/VPF-deficient sublines, unlike the parental population or vector controls, were profoundly suppressed in their ability to form tumors in nude mice for as long as 6 months after cell injection. In contrast, in vitro growth of these sublines was unaffected, thus demonstrating the critical importance of VEGF/VPF as an angiogenic factor for HCT-116 and DLD-1 cells. Transfection of a full-length VEGF121 cDNA into two nontumorigenic mutant K-ras knockout sublines resulted in a weak but detectable restoration of tumorigenic ability in vivo in a subset of the transfectants, with no consistent change in growth properties in vitro. The findings indicate that mutant ras-oncogene-dependent VEGF/VPF expression is necessary, but not sufficient, for progressive tumor growth in vivo and highlight the relative contribution of oncogenes, such as mutant K-ras, to the process of tumor angiogenesis.
Journal: Proceedings of The National Academy of Sciences - PNAS , vol. 95, no. 7, pp. 3609-3614, 1998
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