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

Cancer. 2002 Sep 1;95(5):1055-63. doi: 10.1002/cncr.10774.


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.

MeSH terms

  • Adenocarcinoma / physiopathology*
  • Adult
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / pharmacology*
  • Endometrial Neoplasms / physiopathology*
  • Endothelial Growth Factors / biosynthesis
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunohistochemistry
  • Lymphokines / biosynthesis
  • Neovascularization, Pathologic*
  • Nuclear Proteins / biosynthesis*
  • Nuclear Proteins / pharmacology*
  • Prognosis
  • Thymidine Phosphorylase / biosynthesis
  • Trans-Activators / biosynthesis*
  • Trans-Activators / pharmacology*
  • Transcription Factors*
  • Up-Regulation
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • Endothelial Growth Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lymphokines
  • Nuclear Proteins
  • Trans-Activators
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • endothelial PAS domain-containing protein 1
  • Thymidine Phosphorylase