Hypoxia contributes to development of recurrent endometrial carcinoma

Tumor hypoxia can trigger the induction of angiogenesis. High microvessel density (MVD) as well as hypoxia-inducible factor-1 alpha (HIF-1 alpha) have been related to recurrent disease and tumor aggressiveness, respectively. In this study, MVD and hypoxic status were investigated in primary and recurrent endometrial carcinomas. A total of 65 primary tumors of patients with recurrent endometrial carcinoma (n = 40), and without recurrent endometrial carcinoma (n = 25) were studied. Immunohistochemical analysis was performed on paraffin-embedded tumor tissue. MVD was determined by quantitative analysis of CD31/FVIII positive vessels. Tumor hypoxia was estimated by evaluating the expression of the hypoxia-regulated gene HIF-1 alpha and its target gene carbonic anhydrase IX (CA-IX). An additional 23 recurrent tumors were available for determination of MVD and HIF-1 alpha expression. Effects of hypoxia on tumor protein p53 (TP53) expression were evaluated in the endometrial cancer cell lines (ECC-1), Ishikawa (derived from adenocarcinomas), and AN3CA (derived from a lymph node metastasis). MVD, CA-IX, and HIF-1 alpha expression were not significantly different in primary tumors of patients with recurrence compared to the control tumors. The MVD was significantly lower, and HIF-1 alpha expression was significantly higher in recurrent tumors when compared with their primary tumors (paired t test, P < 0.05). HIF-1 alpha expression correlated well with TP53 expression levels in primary tumors, but not in recurrences. TP53 protein levels were highest in AN3CA cells. Hypoxic conditions induced TP53 protein in ECC-1 and Ishikawa, but not AN3CA cells. We conclude that MVD, CA-IX, and HIF-1 alpha expression are not independent prognostic markers for recurrent endometrial carcinoma. The low MVD, increased HIF-1 alpha protein levels, dissociation of hypoxia, and TP53 protein induction in the metastatic tumor cells (AN3CA) support a role for hypoxia in the development of recurrent endometrial carcinoma.