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.