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的主要思想，解释了癌症风险与排卵周期数量的关联。 然而，促性腺激素对培养物中卵巢表面上皮细胞的生长只有不明显的影响。 因此，缺乏促性腺激素卵巢致癌活性的令人信服的机制。 最近，我们发现位于形态学上肿瘤病变附近的肿瘤前卵巢表面上皮通常缺乏基底膜，并提出地下膜的丧失是卵巢肿瘤性的早期一步。 因此，我们假设促性腺激素致癌作用的机制，即激素刺激了与卵巢前事件相似的基底膜的丧失。 结果，通过反复的促性腺激素刺激，卵巢表面上皮的频繁放置在这种地下膜上，无膜前塑性阶段，增加了肿瘤易于转化的肿瘤细胞的频率，以转化促性腺激素转化granulosa和表面上皮细胞的损失，并在地上损失损失，并诱导Cox-cox-2 Cox酶。 W或WV小鼠易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的突变小鼠中升高的血清促性腺激素。 另一个基因工程的突变小鼠是疾病-2（DAB2）杂合敲除模型，也倾向于卵巢表面上皮性发育不良和乳头状瘤病（卵巢癌的恶性病变）的发展。 我们推测WV/WV和DAB2（）基因型的组合将增强对卵巢肿瘤的倾向。 我们将测试COX酶的抑制是否会减少促性腺激素刺激的基底膜损失，并抑制或减少WV/WV，DAB2（）小鼠的易感性。 为了研究这些机制，我们还将研究促性腺激素刺激对培养中卵巢表面上皮细胞中Cox-2，胶原蛋白IV，层粘连蛋白和MMPs表达的影响。 这些研究将有助于了解与促性腺激素相关的卵巢癌的病因，并为COX-2抑制剂的化学预防活性提供了一种机制。