摘要：

BACKGROUNDHypoxia-inducible factor 1 (HIF-1) and HIF-2 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.METHODSHIF-1 and HIF-2 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-1 and HIF-2.RESULTSHIF-1 expression was detected in 49% of endometrial carcinomas. The expression was cytoplasmic or mixed nuclear/cytoplasmic. HIF-1 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-2 protein showed a pattern of expression similar to the pattern seen in HIF-1, but expression of HIF-2 protein occurred in only 17% of endometrial carcinomas, and it was associated with increased TP reactivity. There also was a relation of HIF-1 expression with well-differentiated endometrial neoplasms, and there was a marginal association of HIF-1 and HIF-2 with ER expression. With reference to normally cycling tissues, HIF-1 nuclear/cytoplasmic expression was particularly strong in the samples of early proliferative phase endometrium compared with HIF-2 protein expression, which showed a constant reaction throughout the menstrual cycle.CONCLUSIONSThe up-regulation of HIF-1 and, to a lesser extent, of HIF-2 is a common event in Stage I endometrial adenocarcinomas. In these tumors, HIF-1 expression is related to increased angiogenesis, through activation of the VEGF angiogenic pathway, and to an unfavorable prognosis. HIF-2 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

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