Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function

There is considerable controversy concerning the importance of tumor-derive d angiogenic factors to the neovascularization of solid tumors. Tumor, endo thelial, and stromal expression of vascular endothelial growth factor (VEGF ) have been hypothesized to be critical for tumor angiogenesis. To determin e the relative contribution of tumor versus nontransformed tissue expressio n of VEGF to tumor growth, we used gene targeting and cre-loxP recombinatio n to generate embryonic stem cell Lines in which VEGF can be conditionally deleted, These lines were used to derive mouse embryonic fibroblast lines w ith null mutations in both alleles of VEGF. Upon immortalization and H-ras transformation, we used these VEGF null fibroblasts to make fibrosarcomas i n immunocompromised mice. We report that tumorigenic VEGF expression is cri tical for ms-mediated tumorigenesis, and the loss of tumorigenic expression causes dramatic decreases in vascular density and vascular permeability an d increases in tumor cell apoptosis.