Hypoxia-Inducible Factors HIF-1α and HIF-2α Expression in Bladder Cancer and Their Associations with Other Angiogenesis-Related Proteins

Hypoxia-inducible factors (HIF-1alpha and HIF-2alpha) are closely related protein complexes that activate transcription of target genes in response to hypoxia. The immunohistochemical expression of these two proteins was investigated in 144 bladder cancer tissue samples and correlated with standard clinicopathological features, in order to elucidate their prognostic significance. We also evaluated their possible associations with other angiogenesis related markers such as microvessel density (MVD), vascular endothelial growth factor, thymidine phosphorylase, tenascin, fibronectin, p53 and bcl-2 to further clarify their implication in tumor stroma vascularization. Nuclear HIF-1alpha expression in tumor cells was detected in 57.1% of the cases. A trend of correlation of this expression with poorly differentiated tumors was observed. In addition, HIF-1alpha expression was positively correlated with stromal cells thymidine phosphorylase expression. Tumors that were progressed in muscle-infiltrating disease showed a higher HIF-1alpha expression. A higher HIF-1alpha expression was also observed in tumors with an in situ component. In tumor cells, low HIF-2alpha expression was observed in 6.3%, moderate in 31.9% and high in 61.8% of the cases. A trend of correlation of this expression with MVD was observed. In addition, HIF-2alpha expression was positively correlated with thymidine phosphorylase and fibronectin expression. A lower HIF-2alpha expression was detected in tumors that recurred earlier in univariate methods of analysis. HIF-2alpha was expressed in tumor stroma associated cells in 53.5% of specimens and was correlated with advance tumor stage, thymidine phosphorylase and tenascin expression. There was no statistically significant difference in the expression of both HIF-1alpha and HIF-2alpha between primary and recurrent tumors. In multivariate analysis including T stage, T grade, multifocality and T size, both HIF-1alpha and HIF-2alpha expression were not considered dependent in the prediction of recurrence or progression. In conclusion, the results of the present study indicate that HIF-1alpha and HIF-2alpha expression may help to predict recurrence or progression to muscle invasive disease but not as independent prognostic factors. In addition, the expression of HIF-1alpha and HIF-2alpha, appear to play a role in bladder cancer, vascularization possibly and in cooperation with other angiogenic factors.