Modeling ovarian carcinoma by defined genetic alterations

在2004年，上皮性卵巢癌（HOC）预计将成为美国妇女癌症相关死亡的第四大癌症类型。由于EOC的发展不成熟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了解最少的。 由p53、p16/Rb和HGF/c-met介导的信号通路的改变经常发生，并且据报道与不良的临床预后相关。然而，他们在平等机会委员会的组成中的具体作用仍然不确定。最近，我们已经证明，卵巢表面上皮细胞（OSE）的选择性失活的肿瘤抑制基因p53的结果在致癌作用，而视网膜母细胞瘤（Rb）基因的失活显着加速这一进程。在该模型中，肿瘤与人浆液性腺癌的侵袭性变体非常相似。我们的初步研究结果表明，除了在细胞增殖、凋亡和基因组不稳定性中的作用外，缺陷型p53和Rb通路之间的协同作用， 使OSE倾向于表达这种晚期癌症特征，如增加的运动性和侵袭性。这些性状保持休眠，直到肝细胞生长因子（HGF），积累基质细胞产生，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对上皮性卵巢癌发生过程中的运动和侵袭的贡献，（2）评估HGF和c-met在EOC侵袭和腹膜内扩散中的作用。这些研究通过证明缺陷的p53和Rb通路可能另外促进肿瘤进展的过程的新的生物学机制，以及通过建立 HGF/c-met信号传导在OSE致癌过程中作为导致侵袭的容许事件的作用。

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.