Background:
Hypoxia-inducible factor 1alpha (hif-1alpha) and hif-2alpha 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-1alpha and hif-2alpha 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-1alpha and hif-2alpha.
Results:
Hif-1alpha expression was detected in 49% of endometrial carcinomas. the expression was cytoplasmic or mixed nuclear/cytoplasmic. hif-1alpha 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-2alpha protein showed a pattern of expression similar to the pattern seen in hif-1alpha, but expression of hif-2alpha protein occurred in only 17% of endometrial carcinomas, and it was associated with increased tp reactivity. there also was a relation of hif-1alpha expression with well-differentiated endometrial neoplasms, and there was a marginal association of hif-1alpha and hif-2alpha with er expression. with reference to normally cycling tissues, hif-1alpha nuclear/cytoplasmic expression was particularly strong in the samples of early proliferative phase endometrium compared with hif-2alpha protein expression, which showed a constant reaction throughout the menstrual cycle.
Conclusions:
The up-regulation of hif-1alpha and, to a lesser extent, of hif-2alpha is a common event in stage i endometrial adenocarcinomas. in these tumors, hif-1alpha expression is related to increased angiogenesis, through activation of the vegf angiogenic pathway, and to an unfavorable prognosis. hif-2alpha accumulation is associated with increased expression of the angiogenic factor tp.