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Hypoxia-Inducible Factor-1 Promotes Nonhypoxia-Mediated Proliferation in Colon Cancer Cells and Xenografts

Divisions of ¹ Gastroenterology and ² Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical Center; ³ University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan; ⁴ Department of Medicine, New York University Medical Center, New York, New York; and ⁵ Sidney Kimmel Comprehensive Cancer Center and ⁶ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Long H. Dang, University of Michigan Medical Center, 1150 West Medical Center Drive, MSRB I, 6514, Ann Arbor, MI 48109. Phone: 734-647-2964; Fax: 734-763-2535; E-mail: lhdang{at}umich.edu.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that directly transactivates genes important for the growth and metabolism of solid tumors. HIF-1 is overexpressed in cancer, and its level of expression is correlated with patient mortality. Increased synthesis or stability of HIF-1 can be induced by hypoxia-dependent or hypoxia-independent factors. Thus, HIF-1 is expressed in both nonhypoxic and hypoxic cancer cells. The role of HIF-1 in nonhypoxia-mediated cancer cell proliferation remains speculative. We have disrupted HIF-1 by targeted homologous recombination in HCT116 and RKO human colon cancer cells. Loss of HIF-1 significantly reduced nonhypoxia-mediated cell proliferation in vitro and in vivo. Paradoxically, loss of HIF-1 expression did not grossly affect the hypoxic compartments within tumor xenografts in vivo, although HIF-1 promoted cell proliferation and survival under hypoxia in vitro. To further test the role of HIF-1 within tumor compartments, we generated cells with combined disruptions of both HIF-1 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 did not grossly affect these expanded hypoxic compartments. These data provide compelling evidence that, in a subset of colon cancers, (a) HIF-1 is a positive factor for nonhypoxia-mediated cell proliferation in vitro and in vivo and (b) HIF-1 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. (Cancer Res 2006; 66(3): 1684-93)

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