Millauer B, Shawver L K, Plate K H, Risau W, Ullrich A
Department of Molecular Biology, Max-Planck-Institut für Biochemie, Martinsried, Germany.
Nature. 1994 Feb 10;367(6463):576-9. doi: 10.1038/367576a0.
Angiogenesis, the sprouting of capillaries from pre-existing blood vessels, is a fundamental process in the formation of the vascular system during embryonic development. In adulthood, angiogenesis takes place during corpus luteum formation and in pathological conditions such as wound healing, diabetic retinopathy, and tumor-igenesis. Vascularization is essential for solid tumour growth and is thought to be regulated by tumour cell-produced factors, which have a chemotactic and mitogenic effect on endothelial cells. Vascular endothelial growth factor (VEGF), a homodimeric glycoprotein of relative molecular mass 45,000, is the only mitogen, however, that specifically acts on endothelial cells, and it may be a major regulator of tumour angiogenesis in vivo. Its expression has been shown to be upregulated by hypoxia, and its cell-surface receptor, Flk-1, is exclusively expressed in endothelial cells. Here we investigate the biological relevance of the VEGF/Flk-1 receptor/ligand system for angiogenesis using a retrovirus encoding a dominant-negative mutant of the Flk-1/VEGF receptor to infect endothelial target cells in vivo, and find that tumour growth is prevented in nude mice. Our results emphasize the central role of the Flk-1/VEGF system in angiogenesis in general and in the development of solid tumours in particular.
血管生成，即从已有的血管中生出毛细血管，是胚胎发育过程中血管系统形成的一个基本过程。在成年期，血管生成发生在黄体形成过程中以及诸如伤口愈合、糖尿病视网膜病变和肿瘤发生等病理状况下。血管形成对于实体肿瘤的生长至关重要，并且被认为受肿瘤细胞产生的因子调控，这些因子对内皮细胞具有趋化作用和促有丝分裂作用。血管内皮生长因子（VEGF）是一种相对分子质量为45,000的同二聚体糖蛋白，然而它是唯一特异性作用于内皮细胞的促有丝分裂原，并且它可能是体内肿瘤血管生成的主要调节因子。其表达已被证明受缺氧上调，并且其细胞表面受体Flk-1仅在内皮细胞中表达。在这里，我们使用编码Flk-1/VEGF受体显性负性突变体的逆转录病毒在体内感染内皮靶细胞，研究VEGF/Flk-1受体/配体系统对血管生成的生物学相关性，并发现裸鼠的肿瘤生长受到抑制。我们的结果强调了Flk-1/VEGF系统在一般血管生成中，特别是在实体肿瘤发展中的核心作用。
