Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant.
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.
Millauer
B
B
Department of Molecular Biology, Max-Planck-Institut für Biochemie, Martinsried, Germany.
Shawver
L K
LK
Plate
K H
KH
Risau
W
W
Ullrich
A
A
D000818:Animals; D001483:Base Sequence; D001808:Blood Vessels / Q000254:growth & development; D002455:Cell Division; D002460:Cell Line; D016228:Endothelial Growth Factors / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D005799:Genes, Dominant; D005909:Glioblastoma / Q000098:blood supply* / Q000473:pathology; D008222:Lymphokines / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009154:Mutation; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D009053:Sarcoma Viruses, Murine / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D009838:Oligodeoxyribonucleotides; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor