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

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