Hypoxia-inducible factor-1 alpha is a positive factor in solid tumor growth

Deficiencies in oxygenation are widespread in solid tumors. The transcripti on factor hypoxia-inducible factor (HIF)-1 alpha is an important mediator o f the hypoxic response of tumor cells and controls the up regulation of a n umber of factors important for solid tumor expansion, including the angioge nic factor vascular endothelial growth factor (VEGF). We have isolated two cell lines nullizygous for HIF-1 alpha, one from embryos genetically null f or HIF-1 alpha, and the other from embryos carrying loxP-flanked alleles of the gene, which allows for cre-mediated excision. The loss of HLF-1 alpha negatively affects tumor growth in these two sets of H-ras-transformed cell lines, and this negative effect is not due to deficient vascularization. D espite differences in VEGF expression, vascular density is similar in wild- type and HIF-1 alpha-null tumors. The evidence from these experiments indic ates that hypoxic response via HIF-1 alpha is an important positive factor in solid tumor growth and that HIF-1 alpha affects tumor expansion in ways unrelated to its regulation of VEGF expression.