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Hypoxia-inducible Factor-1 Is an Intrinsic Marker for Hypoxia in Cervical Cancer Xenografts 1

The hypoxia-inducible factor 1 (HIF-1) is known to induce the expression of several proteins linked to the maintenance of oxygen homeostasis, cellular energy metabolism, and tumor progression. Its subunit (HIF1 ) is stabilized under hypoxic conditions and, therefore, might represent an intrinsic marker for tissue hypoxia. Here we report on the spatial relationship between HIF-1 and the nitroimidazole hypoxia marker EF5 in cervical carcinoma xenografts, and on their spatial relationship to tumor blood vessels. EF5 was administered to mice bearing ME180 and SiHa cervical cancer xenografts. Frozen tumor tissue sections, triplestained for HIF-1 , the endothelial cell marker CD31, and EF5, were imaged using wide-field multiparameter immunofluorescence microscopy. Expression levels of EF5 and HIF-1 were similar in ME180 xenografts, but the percentage of tumor area stained with EF5 was significantly smaller than the percentage of HIF-1 -positive area in SiHa tumors. In both tumor types the EF5-HIF-1 overlap was statistically significant, thus confirming their spatial and temporal colocalization. Spatial distribution analysis of EF5 and HIF-1 is consistent with different pO2 value “thresholds” for EF5 binding and HIF-1 expression. Summarized, our results indicate that HIF-1 is a useful intrinsic marker for hypoxia in cervical carcinoma xenografts.