Loss of vascular endothelial growth factor expression reduces vascularization, but not growth, of tumors lacking the Von Hippel-Lindau tumor suppressor gene.
Individuals bearing germ line mutations in the Von Hippel-Lindau (VHL) tumor suppressor gene are predisposed to the development of highly angiogenic tumors. This is correlated with an increased expression of the angiogenic factor vascular endothelial growth factor (VEGF) in these tumors, which is in part caused by elevated expression of the HIF-1 hypoxia inducible transcription factors. We created malignant astrocytes with genetic deletions of the VHL gene and implanted them in subcutaneous and intracranial sites; these sites are respectively vessel poor and vessel-rich tissues. When grown in a vessel poor site, VEGF expression in VHL null cells was important for both vascularization and tumor growth. However, when the same cells are grown in the vessel-rich intracranial environment, loss of VEGF expression reduces vascularization, but does not affect tumor growth. This indicates that antiangiogenic therapies for tumors that express high levels of angiogenic factors such as VEGF may vary in their efficacy, with potentially lowered effectiveness in sites, such as the brain, that are inherently vessel rich.
Blouw
B
B
Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, La Jolla, California 92093-0377, USA.
Haase
V H
VH
Song
H
H
Bergers
G
G
Johnson
R S
RS
D000818:Animals; D001254:Astrocytoma / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein