Hypoxia-inducible factor-1 alpha is an intrinsic marker for hypoxia in cervical cancer xenografts

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 alpha subunit (HIF-1 alpha) is stabilized under hypoxic conditions and, therefore, might represent an i ntrinsic marker for tissue hypoxia. Here we report on the spatial relations hip between HIF-1 alpha and the nitroimidazole hypoxia marker EF5 in cervic al carcinoma xenografts, and on their spatial relationship to tumor blood v essels. EF5 was administered to mice bearing ME180 and SiHa cervical cancer xenografts. Frozen tumor tissue sections, triplestained for HIF-1 alpha, t he endothelial cell marker CD31, and EF5, were imaged using wide-field mult iparameter immunofluorescence microscopy. Expression levels of EF5 and HIF- 1 alpha were similar in ME180 xenografts, but the percentage of tumor area stained with EF5 was significantly smaller than the percentage of HIF-1 alp ha -positive area in SiHa tumors. In both tumor types the EF5-HIF-1 alpha o verlap was statistically significant, thus confirming their spatial and tem poral colocalization. Spatial distribution analysis of EF5 and HIF-1 alpha is consistent with different pO(2) value "thresholds" for EF5 binding and H IF-1a expression. Summarized, our results indicate that HIF-1 alpha is a us eful intrinsic marker for hypoxia in cervical carcinoma xenografts.