GLIOBLASTOMA GROWTH INHIBITED IN-VIVO BY A DOMINANT-NEGATIVE FLK-1 MUTANT

ANGIOGENESIS, the sprouting of capillaries from pre-existing blood ves sels, 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 tumorigenesis. Vascularizatio n is essential for solid tumour growth and is thought to be regulated by tumour cell-produced factors, which have a chemotactic and mitogeni c effect on endothelial cells1-4. Vascular endothelial growth factor ( VEGF), a homodimeric glycoprotein of relative molecular mass 45,000, i s the only mitogen, however, that specifically acts on endothelial cel ls, and it may be a major regulator of tumour angiogeness in vivo5,6. Its expression has been shown to be upregulated by hypoxia, and its ce ll-surface receptor, Flk-1, is exclusively expressed in endothelial ce lls7,8. 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 endothe lial 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 tumo urs in particular.