Gonadotropins & Cox-2 in Ovarian Cancer Prevention

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的关系。然而，促性腺激素对培养的卵巢表面上皮细胞的生长影响不显著。因此，促性腺激素的卵巢癌活性机制尚缺乏令人信服的证据。最近，我们发现肿瘤前卵巢表面上皮位于形态学上的肿瘤病灶附近，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，激素刺激基底膜的损失类似于排卵前的事件。因此，通过反复的促性腺激素刺激，卵巢表面上皮经常处于无基底膜的肿瘤前阶段，增加了肿瘤易感细胞转化为促性腺激素的频率，促性腺激素诱导颗粒和表面上皮细胞中的Cox-2介导排卵，并且可以通过抑制Cox酶来阻止基底膜的丢失和其他排卵事件。W或Wv小鼠卵巢表面上皮易形成管状腺瘤。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，Disabled-2 （Dab2）杂合敲除模型，也容易发生卵巢表面上皮发育不良和乳头状瘤病，这是卵巢癌的恶性前病变。我们推测Wv/Wv和Dab2（）基因型的结合会增加卵巢肿瘤的易感性。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，并抑制或降低Wv/Wv， Dab2（）小鼠发生卵巢肿瘤的易感性。为了研究其机制，我们还将研究促性腺激素刺激对培养卵巢表面上皮细胞中Cox-2、胶原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病因，并为Cox-2抑制剂的化学预防活性提供机制。

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.