Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth.
Deficiencies in oxygenation are widespread in solid tumors. The transcription factor hypoxia-inducible factor (HIF)-1alpha is an important mediator of the hypoxic response of tumor cells and controls the up-regulation of a number of factors important for solid tumor expansion, including the angiogenic factor vascular endothelial growth factor (VEGF). We have isolated two cell lines nullizygous for HIF-1alpha, one from embryos genetically null for HIF-1alpha, and the other from embryos carrying loxP-flanked alleles of the gene, which allows for cre-mediated excision. The loss of HIF-1alpha negatively affects tumor growth in these two sets of H-ras-transformed cell lines, and this negative effect is not due to deficient vascularization. Despite differences in VEGF expression, vascular density is similar in wild-type and HIF-1alpha-null tumors. The evidence from these experiments indicates that hypoxic response via HIF-1alpha is an important positive factor in solid tumor growth and that HIF-1alpha affects tumor expansion in ways unrelated to its regulation of VEGF expression.
Ryan
H E
HE
Department of Biology, University of California, San Diego 92093-0366, USA.
Poloni
M
M
McNulty
W
W
Elson
D
D
Gassmann
M
M
Arbeit
J M
JM
Johnson
R S
RS
D000818:Animals; D002455:Cell Division / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005354:Fibrosarcoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation / Q000502:physiology; D011905:Genes, ras / Q000235:genetics / Q000502:physiology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019426:Integrases / Q000235:genetics; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D014170:Transformation, Genetic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019426:Integrases