Association of hypoxia-inducible factors 1α and 2α with activated angiogenic pathways and prognosis in patients with endometrial carcinoma

Abstract

BACKGROUND. Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α are essential regulatory proteins for the adaptation of tumor cells to hypoxia, and they stimulate angiogenesis through activation of the vascular endothelial growth factor (VEGF) gene. METHODS. HIF-1α and HIF-2α proteins were studied immunohistochemically in a group of 81 patients with Stage I endometrial adenocarcinoma of the endometrioid cell type. The results were correlated with intratumoral angiogenesis, the expression of the angiogenic factors VEGF and thymidine phosphorylase (TP), and the VEGF/receptor (VEGF/KDR) complex. Relations also were sought with estrogen receptor (ER) and progesterone receptor (PR), with the apoptosis-related proteins bcl-2 and p53, with several histopathologic parameters, and with patient prognosis. In addition, a sample of 25 normal endometria at various phases of the menstrual cycle was studied for the presence of HIF-1α and HIF-2α. RESULTS. HIF-1α expression was detected in 49% of endometrial carcinomas. The expression was cytoplasmic or mixed nuclear/ cytoplasmic. HIF-1α expression was associated with up-regulation of the VEGF pathway and with increased standard microvessel density (sMVD) and activated VEGF/KDR microvessel density (aMVD). It also was associated with a poor prognosis in both univariate and multivariate analyses. HIF-2α protein showed a pattern of expression similar to the pattern seen in HIF-1α, but expression of HIF-2α protein occurred in only 17% of endometrial carcinomas, and it was associated with increased TP reactivity. There also was a relation of HIF-1α expression with well-differentiated endometrial neoplasms, and there was a marginal association of HIF-1α and HIF-2α with ER expression. With reference to normally cycling tissues, HIF-1α nuclear/cytoplasmic expression was particularly strong in the samples of early proliferative phase endometrium compared with HIF-2α protein expression, which showed a constant reaction throughout the menstrual cycle. CONCLUSIONS. The up-regulation of HIF-1α and, to a lesser extent, of HIF-2α is a common event in Stage I endometrial adenocarcinomas. In these tumors, HIF-1α expression is related to increased angiogenesis, through activation of the VEGF angiogenic pathway, and to an unfavorable prognosis. HIF-2α accumulation is associated with increased expression of the angiogenic factor TP. © 2002 American Cancer Society.