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Reduced Expression of Hypoxia-Inducible Factor-1 in Perinecrotic Regions of Solid Tumors

¹ British Columbia Cancer Research Center; ² British Columbia Cancer Agency, Vancouver, British Columbia, Canada; and ³ University of California Irvine, Irvine, California

Requests for reprints: Peggy L. Olive, Medical Biophysics Department, British Columbia Cancer Research Centre, 601 West 10th Avenue, Vancouver, BC, Canada V5Z 1L3. Phone: 604-877-6271; Fax: 604-877-6002; E-mail: polive{at}bccrc.ca.

Hypoxia that develops in solid tumors stabilizes the hypoxia-inducible factor-1 (HIF-1) subunit of the HIF-1 transcription factor, leading to up-regulation of dozens of hypoxia-regulated genes that increase glycolysis and oxygen delivery. HIF-1 and its downstream target gene CA9 have both been used as surrogate hypoxia markers, and, in general, high expression predicts for a poor response to treatment. Combinations of hypoxia markers offer the opportunity to measure changes in tumor oxygenation that may be relevant to tumor response to treatment. We compared the degree of colocalization of two endogenous markers for hypoxia, HIF-1 and carbonic anhydrase IX (CAIX), with a chemical marker for hypoxia, pimonidazole. Unexpectedly, expression of HIF-1 was reduced in the most hypoxic regions that border necrosis in xenograft tumors composed of SiHa cervical carcinoma, WiDr colon carcinoma, or M006 astrocytoma cells. Similar results were obtained for samples from three cervical cancer biopsies. However, CAIX was present in these perinecrotic cells that were also capable of metabolizing and binding a chemical marker for hypoxia, pimonidazole. In vitro experiments using tumor cells and tumor cubes incubated under anoxic conditions indicated that nutrient deprivation seems to be largely responsible for the lack of HIF-1 expression in perinecrotic regions. The half-life of CAIX was sufficiently long that, once formed, it remained for days in the absence of continued HIF-1 expression. These results have implications for the use of HIF-1 as an indicator of tumor hypoxia and aggressiveness as well as development of hypoxia-directed antitumor therapies based on the expression of HIF-1.

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