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. Cancer 2002;95:1055–63. © 2002 American Cancer Society. DOI 10.1002/cncr.10774