Pijnenborg J M A, Wijnakker M, Hagelstein J, Delvoux B, Groothuis P G
Department of Obstetrics and Gynecology, Tweesteden Hospital, Tilburg, The Netherlands.
Int J Gynecol Cancer. 2007 Jul-Aug;17(4):897-904. doi: 10.1111/j.1525-1438.2007.00893.x. Epub 2007 Mar 13.
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.
肿瘤缺氧可触发血管生成的诱导。高微血管密度（MVD）以及缺氧诱导因子-1α（HIF-1α）分别与疾病复发和肿瘤侵袭性相关。在本研究中，对原发性和复发性子宫内膜癌的MVD和缺氧状态进行了研究。共研究了65例复发性子宫内膜癌患者（n = 40）和非复发性子宫内膜癌患者（n = 25）的原发性肿瘤。对石蜡包埋的肿瘤组织进行免疫组织化学分析。通过对CD31/FVIII阳性血管的定量分析来确定MVD。通过评估缺氧调节基因HIF-1α及其靶基因碳酸酐酶IX（CA-IX）的表达来估计肿瘤缺氧情况。另外23例复发性肿瘤可用于MVD和HIF-1α表达的测定。在子宫内膜癌细胞系（ECC-1）、 Ishikawa（源自腺癌）和AN3CA（源自淋巴结转移）中评估了缺氧对肿瘤蛋白p53（TP53）表达的影响。与对照肿瘤相比，复发患者原发性肿瘤中的MVD、CA-IX和HIF-1α表达无显著差异。与原发性肿瘤相比，复发性肿瘤中的MVD显著降低，HIF-1α表达显著升高（配对t检验，P < 0.05）。HIF-1α表达在原发性肿瘤中与TP53表达水平密切相关，但在复发性肿瘤中则不然。TP53蛋白水平在AN3CA细胞中最高。缺氧条件在ECC-1和Ishikawa细胞中诱导了TP53蛋白，但在AN3CA细胞中未诱导。我们得出结论，MVD、CA-IX和HIF-1α表达不是复发性子宫内膜癌的独立预后标志物。转移性肿瘤细胞（AN3CA）中低MVD、HIF-1α蛋白水平升高、缺氧解离以及TP53蛋白诱导支持缺氧在复发性子宫内膜癌发生发展中的作用。
