Grunstein J, Roberts W G, Mathieu-Costello O, Hanahan D, Johnson R S
Department of Biology and Medicine, University of California, San Diego 92093, USA.
Cancer Res. 1999 Apr 1;59(7):1592-8.
There is considerable controversy concerning the importance of tumor-derived angiogenic factors to the neovascularization of solid tumors. Tumor, endothelial, and stromal expression of vascular endothelial growth factor (VEGF) have been hypothesized to be critical for tumor angiogenesis. To determine the relative contribution of tumor versus nontransformed tissue expression of VEGF to tumor growth, we used gene targeting and cre-loxP recombination to generate embryonic stem cell lines in which VEGF can be conditionally deleted. These lines were used to derive mouse embryonic fibroblast lines with null mutations in both alleles of VEGF. Upon immortalization and H-ras transformation, we used these VEGF null fibroblasts to make fibrosarcomas in immunocompromised mice. We report that tumorigenic VEGF expression is critical for ras-mediated tumorigenesis, and the loss of tumorigenic expression causes dramatic decreases in vascular density and vascular permeability and increases in tumor cell apoptosis.
关于肿瘤衍生的血管生成因子对实体瘤新生血管形成的重要性存在相当大的争议。血管内皮生长因子（VEGF）在肿瘤、内皮细胞和基质中的表达被认为对肿瘤血管生成至关重要。为了确定VEGF在肿瘤组织与未转化组织中的表达对肿瘤生长的相对贡献，我们利用基因靶向和cre-loxP重组技术生成了可条件性缺失VEGF的胚胎干细胞系。这些细胞系被用于衍生VEGF两个等位基因均发生无效突变的小鼠胚胎成纤维细胞系。在永生化和H-ras转化后，我们使用这些VEGF缺失的成纤维细胞在免疫缺陷小鼠中制备纤维肉瘤。我们报告，致瘤性VEGF表达对ras介导的肿瘤发生至关重要，致瘤性表达的缺失会导致血管密度和血管通透性显著降低，并增加肿瘤细胞凋亡。
