Gonadotropins & Cox-2 in Ovarian Cancer Prevention

促性腺激素

• 批准号: 6588263
• 负责人: XiangXi Mike Xu
• 金额: $ 40.6万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6588263
• 关键词: basement membrane; cancer prevention; chemoprevention; collagen; collagenase; fatty acid biosynthesis; gene mutation; gene targeting; genetically modified animals; gonadotropins; indomethacin; laboratory mouse; laminin; neoplastic transformation; nonsteroidal antiinflammatory agent; ovary neoplasms; oxidoreductase inhibitor; prostaglandin endoperoxide synthase; prostaglandins; tissue /cell culture

DESCRIPTION (provided by applicant): The gonadotropin stimulation hypothesis is a leading idea in the etiology of ovarian cancer explaining the association of cancer risk with the number of ovulatory cycles. However, gonadotropins have only unremarkable effects on the growth of ovarian surface epithelial cells in culture. Thus, a convincing mechanism for the ovarian carcinogenic activity of gonadotropins is lacking. Recently, we found that pre-neoplastic ovarian surface epithelia that are located immediately adjacent to morphologically neoplastic lesions often lack basement membranes and have proposed that the loss of basement membrane is an early step in ovarian tumorigenicity. Thus, we hypothesize a mechanism for the carcinogenic effect of gonadotropins, that the hormones stimulate the loss of basement membranes similar to pre-ovulatory events. As a result, the frequent placement of the ovarian surface epithelium in such a basement membrane-less, pre-neoplastic stage by repeated gonadotropin stimulation increases the frequency for tumor prone cells to transform Gonadotropins induce Cox-2 in both granulosa and surface epithelial cells to mediate ovulation, and the loss of basement membrane and other ovulatory events can be blocked by inhibition of the Cox enzymes. The W or Wv mice are predisposed to tubular adenoma formation from the ovarian surface epithelium. The cause of ovarian neoplasm is thought to be the elevated serum gonadotropins in these spontaneously mutant mice. Another genetically engineered mutant mouse, the Disabled-2 (Dab2) heterozygous knockout model, is also predisposed to the development of ovarian surface epithelial dysplasia and papillomatosis, the pre-malignant lesions of ovarian cancer. We speculate that the combination of Wv/Wv and Dab2 () genotypes will augment the predisposition to ovarian neoplasm. We will test if the inhibition of Cox enzymes reduces the gonadotropin stimulated basement membrane loss, and inhibits or reduces the predisposition of the Wv/Wv, Dab2 () mice to develop ovarian tumors. To investigate the mechanisms, we will also examine the effects of gonadotropin stimulation on the expression of Cox-2, collagen IV, laminin, and MMPs in ovarian surface epithelial cells in culture. These studies will help to understand the etiology of ovarian cancer related to gonadotropins, and provide a mechanism(s) for the chemopreventive activity of Cox-2 inhibitors.

描述（由申请人提供）：促性腺激素刺激假说是卵巢癌病因学的主要观点，解释了癌症风险与排卵周期数的相关性。 然而，促性腺激素对培养的卵巢表面上皮细胞的生长只有不显著的影响。 因此，促性腺激素的卵巢致癌活性缺乏一个令人信服的机制。 最近，我们发现肿瘤前的卵巢表面上皮细胞位于形态学上肿瘤性病变附近，通常缺乏基底膜，并提出基底膜的丧失是卵巢致瘤性的早期步骤。 因此，我们假设促性腺激素的致癌作用机制，即激素刺激类似于排卵前事件的基底膜损失。 结果，通过反复促性腺激素刺激，卵巢表面上皮细胞频繁地置于这种无基底膜的肿瘤前阶段，增加了肿瘤倾向细胞转化促性腺激素的频率，在颗粒细胞和表面上皮细胞中诱导考克斯-2介导排卵，并且基底膜的丧失和其他排卵事件可以通过抑制考克斯酶来阻断。W或Wv小鼠倾向于从卵巢表面上皮形成管状腺瘤。 卵巢肿瘤的原因被认为是这些自发突变小鼠血清促性腺激素升高。 另一种基因工程突变小鼠，残疾人-2（Dab 2）杂合敲除模型，也倾向于发展卵巢表面上皮异型增生和乳头状瘤病，卵巢癌的癌前病变。 我们推测，Wv/Wv和Dab 2（）基因型的组合将增加卵巢肿瘤的易感性。 我们将测试考克斯酶的抑制是否减少促性腺激素刺激的基底膜损失，并抑制或减少Wv/Wv，Dab 2（）小鼠发展卵巢肿瘤的倾向。 为了研究其机制，我们还将检测促性腺激素刺激对培养的卵巢表面上皮细胞中考克斯-2、IV型胶原、层粘连蛋白和MMPs表达的影响。 这些研究将有助于了解促性腺激素相关的卵巢癌病因，并为考克斯-2抑制剂的化学预防活性提供机制。