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

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