Modeling ovarian carcinoma by defined genetic alterations

2004年，上皮性卵巢癌(HOC)预计将成为美国女性癌症相关死亡的第四大癌症类型。由于其无症状的发展和缺乏准确的动物模型，EOC的发病机制仍然是所有主要癌症中最不了解的之一。 P53、p16/Rb和HGF/c-Met介导的信号通路改变频繁发生，据报道与临床预后不良有关。然而，它们在平等机会形成中的具体作用仍不确定。最近，我们发现卵巢表面上皮(OSE)选择性失活抑癌基因P53会导致肿瘤的发生，而视网膜母细胞瘤(RB)基因的失活会显著加速这一过程。在这个模型中，肿瘤与人类浆液性腺癌的侵袭性变异非常相似。我们的初步结果表明，除了在细胞增殖、凋亡和基因组不稳定方面发挥作用外，缺陷的P53和Rb通路之间的合作 使OSE易于表达晚期癌症特征，如运动性增强和侵袭性。这些特征一直处于休眠状态，直到积累的基质细胞产生的肝细胞生长因子(HGF)激活c-met信号。为了验证这一假设，我们建议(1)确定p53和p16/Rb在上皮性卵巢癌发生过程中对运动和侵袭的作用；(2)评估HGF和c-met在上皮性卵巢癌侵袭和腹膜内扩散中的作用。这些研究将通过揭示P53和Rb通路缺陷可能额外促进肿瘤进展过程的新的生物学机制以及通过建立 HGF/c-met信号通路在OSE癌变过程中作为一种允许的侵袭事件的作用。

In the year 2004, epithelial ovarian cancer (HOC) is expected to be the 4th leading cancer type among cancer-related deaths in women in the United States. Due to its symptomless development and the lack of accurate animal models, EOC pathogenesis remains among the least understood of all major cancers. Alterations in signaling pathways mediated by p53, p16/Rb and HGF/c-met occur frequently and are reported to be associated with the poor clinical prognosis. However, their specific roles in EOC formation remain uncertain. Recently we have demonstrated that the ovarian surface epithelium (OSE) - selective inactivation of tumor suppressor p53 results in carcinogenesis, and that inactivation of the retinoblastoma (Rb) gene dramatically accelerates this process. In this model, neoplasms closely resemble the aggressive variant of human serous adenocarcinoma. Our preliminary results indicate that, in addition to its role in cell proliferation, apoptosis and genomic instability, the cooperation between defective p53 and Rb pathways predisposes OSE to expression of such advanced cancer traits as increased motility and invasion. These traits remain dormant until Hepatocyte Growth Factor (HGF), produced by accumulating stromal cells, activates c-met signaling. To test this hypothesis, we propose (1) to determine contributions of p53 and p16/Rb towards motility and invasion during epithelial ovarian carcinogenesis, and (2) to evaluate roles of HGF and c-met in EOC invasion and intraperitoneal spreading. These studies should advance our understanding of the EOC pathogenesis by demonstrating new biological mechanisms by which defective p53 and Rb pathways may additionally facilitate the course of neoplastic progression and by establishing the role of HGF/c-met signaling as a permissive event leading to invasion during the OSE carcinogenesis.