title: Hypoxia contributes to development of recurrent endometrial carcinoma.
abstract: Tumor hypoxia can trigger the induction of angiogenesis. High microvessel density (MVD) as well as hypoxia-inducible factor-1alpha (HIF-1alpha) 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-1alphaand its target gene carbonic anhydrase IX (CA-IX). An additional 23 recurrent tumors were available for determination of MVD and HIF-1alpha 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-1alpha expression were not significantly different in primary tumors of patients with recurrence compared to the control tumors. The MVD was significantly lower, and HIF-1alpha expression was significantly higher in recurrent tumors when compared with their primary tumors (paired t test, P < 0.05). HIF-1alpha 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-1alpha expression are not independent prognostic markers for recurrent endometrial carcinoma. The low MVD, increased HIF-1alpha 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.
authors.affiliation: Department of Obstetrics and Gynecology, Tweesteden Hospital, Tilburg, The Netherlands. h.pijnenborg@planet.nl
authors.forename: J M A
authors.initials: JM
authors.lastname: Pijnenborg
authors.forename: M
authors.initials: M
authors.lastname: Wijnakker
authors.forename: J
authors.initials: J
authors.lastname: Hagelstein
authors.forename: B
authors.initials: B
authors.lastname: Delvoux
authors.forename: P G
authors.initials: PG
authors.lastname: Groothuis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis; D018269:Carcinoma, Endometrioid / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000378:metabolism; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases