Gonadotropins & Cox-2 in Ovarian Cancer Prevention

促性腺激素

• 批准号: 7215144
• 负责人: XiangXi Mike Xu
• 金额: $ 42.13万
• 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/7215144
• 关键词: Age; Basement membrane; Biology; Breeding; Cancer Model; Cells; Chemopreventive Agent; Collagen Type IV; Cultured Cells; Data; Development; Dysplasia; Engineering; Enzymes; Epithelial; Epithelial Cells; Epithelial Neoplasms; Epithelium; Etiology; Event; Frequencies; Genotype; Gonadotropins; Growth; Hormones; Indomethacin; Intraepithelial Neoplasia; Investigation; Knock-out; Knockout Mice; Laminin; Lesion; Malignant Neoplasms; Malignant neoplasm of ovary; Matrix Metalloproteinases; Mediating; Modeling; Mouse Strains; Mus; Mutant Strains Mice; Neoplasms; Neoplastic Cell Transformation; Neoplastic Epithelial Cell; Numbers; Ovarian; Ovulation; Phenotype; Placement; Predisposition; Premalignant; Prostaglandins; Protein Overexpression; Regulation; Role; Serum; Staging; Surface; Testing; Thinking; Transgenic Mice; Tubular Adenoma; Tumor Biology; Tumorigenicity; cancer risk; celecoxib; inhibitor/antagonist; membrane synthesis; mouse model; neoplastic; ovarian cancer prevention; ovarian neoplasm; promoter; tumor

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(申请人提供)：促性腺激素刺激假说是卵巢癌病因学的主导思想，解释了癌症风险与排卵周期数之间的关系。但促性腺激素对体外培养的卵巢表面上皮细胞的生长影响不明显。因此，促性腺激素的卵巢致癌活性缺乏令人信服的机制。最近，我们发现与形态上的肿瘤病变相邻的癌前卵巢表面上皮细胞通常缺乏基底膜，并提出基底膜的缺失是卵巢肿瘤发生的早期步骤。因此，我们假设了促性腺激素致癌作用的机制，即激素刺激基底膜的丢失，类似于排卵前事件。因此，通过反复促性腺激素刺激，卵巢表面上皮细胞频繁地处于无基底膜的癌前阶段，增加了肿瘤倾向细胞转化促性腺激素的频率，诱导颗粒和表面上皮细胞中的COX-2介导排卵，而基底膜的丢失和其他排卵事件可以通过抑制COX酶来阻止。W或WV小鼠容易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的小鼠血清促性腺激素升高所致。另一种基因工程突变小鼠，残疾-2(DAB2)杂合子敲除模型，也容易发生卵巢表面上皮不典型增生和乳头状瘤病，卵巢癌的癌前病变。我们推测，WV/WV和DAB2()等位基因的结合将增加卵巢肿瘤的易感性。我们将测试COX酶的抑制是否减少促性腺激素刺激的基底膜丢失，并抑制或降低WV/WV，DAB2()小鼠发生卵巢肿瘤的易感性。为了探讨其机制，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COX-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卵巢癌与促性腺激素相关的病因，并为COX-2抑制剂的化学预防作用提供机制(S)。