Department of Cellular and Molecular Medicine, University of Ottawa, and Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada.
Endocrinology. 2010 Mar;151(3):929-38. doi: 10.1210/en.2009-0602. Epub 2010 Jan 7.
Epithelial ovarian cancer is thought to be derived from the ovarian surface epithelium (OSE) but often goes undetected in the early stages, and as a result, the factors that contribute to its initiation and progression remain poorly understood. Epidemiological studies have suggested that the female steroid hormones are involved in ovarian carcinogenesis and that women who use hormone replacement therapy are at increased risk of developing the disease. A novel transgenic mouse model of ovarian cancer (tgCAG-LS-TAg) was developed to examine the role of the female reproductive steroid hormones [17beta-estradiol (E(2)) and progesterone (P(4))] on the initiation, progression, and pathology of ovarian cancer. The mouse model uses the Cre-LoxP system to induce expression of the simian virus 40 large and small T antigens (SV40 TAg). After targeted induction of the oncogene in the OSE, mice develop poorly differentiated ovarian tumors, tumor dissemination to tissues within the abdominal cavity, and a subset develops hemorrhagic ascites. Treatment with P(4) had no impact on the disease, but E(2) altered the pathophysiology, resulting in an earlier onset of tumors, decreased overall survival time, and a distinctive papillary histology. Normal ovaries collected from mice treated with E(2), but lacking expression of SV40 TAg, displayed an increase in the areas of columnar and hyperplastic OSE cells compared to placebo-treated controls. A better understanding of the mechanisms by which E(2) alters the morphology of normal OSE cells and reduces survival in this mouse model may translate into improved prevention and treatment options for women using hormone replacement therapy.
上皮性卵巢癌被认为来源于卵巢表面上皮（OSE），但在早期往往无法检测到，因此，导致其发生和发展的因素仍知之甚少。流行病学研究表明，女性类固醇激素参与卵巢癌的发生，使用激素替代疗法的女性患该病的风险增加。一种新型卵巢癌转基因小鼠模型（tgCAG-LS-TAg）被开发出来，以研究女性生殖类固醇激素[17β-雌二醇（E（2））和孕酮（P（4））]对卵巢癌的发生、发展和病理学的作用。该小鼠模型使用 Cre-LoxP 系统诱导表达猿猴病毒 40 大、小 T 抗原（SV40 TAg）。在 OSE 中靶向诱导致癌基因后，小鼠会发展出低分化卵巢肿瘤、肿瘤扩散到腹腔内组织，并出现一部分小鼠出现血性腹水。P（4）治疗对疾病没有影响，但 E（2）改变了病理生理学，导致肿瘤更早发生、总生存时间缩短，并出现独特的乳头状组织学。从接受 E（2）治疗但缺乏 SV40 TAg 表达的小鼠中收集的正常卵巢与安慰剂治疗对照组相比，柱状和增生性 OSE 细胞的面积增加。更好地了解 E（2）改变正常 OSE 细胞形态并降低这种小鼠模型中生存率的机制，可能会转化为改善接受激素替代疗法的女性的预防和治疗选择。
