Modeling ovarian carcinoma by defined genetic alterations

通过定义的遗传改变来模拟卵巢癌

• 批准号: 6983701
• 负责人: Alexander Y Nikitin
• 金额: $ 28.08万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6983701
• 关键词: carcinoma; disease /disorder model; female; genetic models; hepatocyte growth factor; laboratory mouse; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic growth; ovary neoplasms; p53 gene /protein; protooncogene; retinoblastoma protein; tumor suppressor genes

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.

在2004年，预计上皮卵巢癌（HOC）将是美国女性与癌症相关的死亡中第四次领先的癌症类型。由于其无症状的发育和缺乏准确的动物模型，EOC发病机理仍然是所有主要癌症中最少的理解。 p53，p16/rb和hgf/c-met介导的信号通路的改变经常发生，据报道与临床预后不良有关。但是，它们在EOC形成中的特定作用仍然不确定。最近，我们证明了卵巢表面上皮（OSE） - 选择性失活肿瘤抑制p53导致致癌作用，而衰老胶质细胞瘤（RB）基因的失活极大地加速了这一过程。在该模型中，肿瘤与人类浆液性腺癌的侵略性变体非常相似。我们的初步结果表明，除了其在细胞增殖，凋亡和基因组不稳定性中的作用外，p53和RB途径有缺陷之间的合作 易于表达高级癌症性状，例如增加运动和侵袭。这些特征一直处于休眠状态，直到积累基质细胞产生的肝细胞生长因子（HGF）激活C-MET信号传导。为了检验这一假设，我们建议（1）确定p53和p16/rb对上皮卵巢癌发生过程中的运动性和侵袭的贡献，以及（2）评估HGF和C-MET在EOC入侵和腹膜内扩散中的作用。这些研究应通过证明有缺陷的p53和RB途径可能促进新塑性进展的新生物学机制来提高我们对EOC发病机理的理解。 HGF/C-MET信号传导作为允许的事件的作用，导致癌作用期间侵袭。