Hypoxia-inducible factor-1α promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts

Hypoxia-inducible factor-1 alpha. (HIF-1 alpha) is a transcription factor that directly transactivates genes important for the growth and metabolism of solid tumors. HIF-1 alpha is overexpressed in cancer, and its level of expression is correlated with patient mortality. Increased synthesis or stability of HIT-let can be induced by hypoxia-dependent or hypoxia-independent factors. Thus, HIF-1 alpha is expressed in both nonhypoxic and hypoxic cancer cells. The role of HIF-1 alpha in nonhypoxia-mediated cancer cell proliferation remains speculative. We have disrupted HLF-1 alpha by targeted homologous recombination in HCT116 and RKO human colon cancer cells. Loss of HIF-1 alpha significantly reduced nonhypoxia-mediated cell proliferation in vitro and in vivo. Paradoxically, loss of HIF-1 alpha expression did not grossly affect the hypoxic compartments within tumor xenografts in vivo, although HIF-1 alpha promoted cell proliferation and survival under hypoxia in vitro. To further test the role of HIF-1 alpha within tumor compartments, we generated cells with combined disruptions of both HLF-1 alpha and vascular endothelial growth factor (VEGF). In all xenografts, disruption of VEGF led to marked expansion of the hypoxic compartments and growth delay. Nonetheless, the presence or absence of HIF-1 alpha did not grossly affect these expanded hypoxic compartments. These data provide compelling evidence that, in a subset of colon cancers, (a) HIF-1 alpha. is a positive factor for nonhypoxia-mediated cell proliferation in vitro and in vivo and (b) HIF-1 alpha is a positive factor for cell proliferation and survival under hypoxic conditions in vitro, but does not grossly contribute to the tumor hypoxic compartments in vivo.