Mechanism of Cox-2 Inhibition in Ovarian Cancer Prevention

抑制 Cox-2 预防卵巢癌的机制

• 批准号: 6958678
• 负责人: XiangXi Mike Xu
• 金额: $ 8.88万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-22 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6958678
• 关键词: basement membrane; biological signal transduction; cancer prevention; chemoprevention; clinical research; collagenase; genetically modified animals; granulosa cell; histopathology; human subject; in situ hybridization; laboratory mouse; laminin; neoplasm /cancer epidemiology; neoplastic transformation; ovary neoplasms; prostaglandin endoperoxide synthase; prostaglandin inhibitors; proteolysis; tissue /cell culture

Epidemiological and experimental data support the use of non-steroidal anti-inflammatory drugs (NSAIDs), including specific inhibitors of Cox-2, as chemopreventive agents in a number of epithelial cancers. In general, it has been suggested that the inhibitors limit Cox-2-catalyzed production of prostaglandins, which may affect cell proliferation, apoptosis, anti-inflammatory responses, and angiogenesis. Based on our recent observations in ovarian cancers and from studies in animal models, we propose here a new mechanism for the chemopreventive activity of Cox-2 inhibitors in ovarian cancers, related to the integrity of the epithelial basement membrane. In the normal premenopausal ovary, the gonadotropins induce Cox-2 expression following the pre-ovulatory phase of follicular maturation. Cox-2 induction signals the initiation of the ovulatory phase, an inflammatory-like biological process. Moreover, prostaglandins, the products of Cox-2 activation, are believed to activate/induce collagenase and proteolysis and decrease the synthesis of the basement membrane components in both granulosa and ovarian surface epithelial cells. A recent study of pre-neoplastic lesions of human ovarian tumors suggests that the collagen IV- and laminin-containing basement membrane of the ovarian surface epithelium is lost prior to morphological transformation of the epithelial cells, suggesting that without an intact basement membrane, the surface epithelium represents a precursor lesion and subsequent genetic and epigenetic changes will lead to overt neoplastic transformation and tumorigenicity. By inhibiting Cox-2, the loss of basement membrane of the ovarian surface epithelium may be lessened and neoplastic transformation of the ovarian surface epithelial cells may be prevented. We propose to investigate the occurrence of basement membrane loss and Cox-2 overexpression in pre-neoplastic lesions of human ovaries from prophylactic oophorectomies of women from high-risk breast and ovarian cancer families. To investigate the mechanisms, we will also examine the effects and cellular signaling pathways of gonadotropin stimulation on the expression of Cox-2, collagen IV, laminin, and MMPs in ovarian surface epithelial cells in culture. The effect of Cox-2 overexpression will be assessed using ovarian surface epithelial-specific transgenic mice. We will also initiate a clinical trial to examine the effect of daily oral intake of Cox-2 inhibitors on the basement membrane integrity and occurrence of pre-neoplastic lesions in ovaries from prophylactic oophorectomies of women from high-risk breast and ovarian cancer families. The reduced loss of basement membrane and reduced number of pre-neoplastic lesions will be used as surrogate endpoints for the preventive activity of Cox-2 inhibitors in ovarian cancer. These studies will help to understand the etiology of ovarian cancer related to gonadotropin stimulation and provide a mechanism(s) for the chemopreventive activity of Cox-2 inhibitors. The ultimate goal will explore the use of Cox-2 inhibitors for chemoprevention of ovarian cancer.

流行病学和实验数据支持使用非甾体抗炎药 (NSAID)，包括 Cox-2 的特异性抑制剂，作为许多上皮癌的化学预防剂。一般来说，有人认为抑制剂限制 Cox-2 催化的前列腺素的产生，前列腺素可能影响细胞增殖、凋亡、抗炎反应和血管生成。根据我们最近对卵巢癌的观察和动物模型研究，我们在此提出了一种与上皮基底膜完整性有关的 Cox-2 抑制剂对卵巢癌化学预防活性的新机制。在正常绝经前卵巢中，促性腺激素在卵泡成熟的排卵前阶段后诱导 Cox-2 表达。 Cox-2 诱导标志着排卵期的开始，这是一种类似炎症的生物过程。此外，前列腺素（Cox-2 激活的产物）被认为可以激活/诱导胶原酶和蛋白水解 并减少颗粒细胞和卵巢表面上皮细胞中基底膜成分的合成。最近对人类卵巢肿瘤的肿瘤前病变的一项研究表明，卵巢表面上皮的含有 IV 型胶原和层粘连蛋白的基底膜在上皮细胞形态转变之前就丢失了，这表明如果没有完整的基底膜，表面上皮就代表了前体细胞。 病变以及随后的遗传和表观遗传变化将导致明显的肿瘤转化和致瘤性。通过抑制Cox-2，可以减少卵巢表面上皮基底膜的损失，并可以防止卵巢表面上皮细胞的肿瘤性转化。我们提议调查高危乳腺癌和卵巢癌女性预防性卵巢切除术中人类卵巢癌前病变中基底膜丢失和 Cox-2 过度表达的发生情况 家庭。为了研究其机制，我们还将检查促性腺激素刺激对培养的卵巢表面上皮细胞中 Cox-2、IV 型胶原、层粘连蛋白和 MMP 表达的影响和细胞信号通路。 Cox-2 过表达的影响将使用卵巢表面上皮特异性转基因小鼠进行评估。我们还将启动一项临床试验，以检查每日口服 Cox-2 抑制剂对基底膜完整性的影响，以及对来自高危乳腺癌和卵巢癌家族的女性进行预防性卵巢切除术的卵巢癌前病变的影响。基底膜损失的减少和肿瘤前病变数量的减少将用作 Cox-2 抑制剂在卵巢癌中预防活性的替代终点。这些研究将有助于了解与促性腺激素刺激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机制。最终目标将探索使用 Cox-2 抑制剂对卵巢癌进行化学预防。