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: 7666760
• 负责人: Alexander Y Nikitin
• 金额: $ 26.63万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666760
• 关键词: Adult; Advanced Malignant Neoplasm; Animal Model; Apoptosis; Biological; Cell Culture Techniques; Cell Proliferation; Cells; Cessation of life; Clinical; Detection; Development; Doctor of Medicine; Doctor of Philosophy; Epithelial; Epithelial ovarian cancer; Epithelium; Event; Figs - dietary; Gene Expression; Gene Silencing; Genomic Instability; Goals; Hepatocyte Growth Factor; Human; Image; Immunocompetent; LacZ Genes; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Neoplasms; Ovarian; Ovarian Carcinoma; Ovarian Serous Adenocarcinoma; Pathogenesis; Pathway interactions; Primary Cell Cultures; Process; Protein p53; Reporter; Reporting; Research Personnel; Retinoblastoma; Retinoblastoma Genes; Role; Serous Cystadenocarcinoma; Signal Pathway; Signal Transduction; Spatial Distribution; Staging; Stromal Cells; Surface; TP53 gene; Techniques; Technology; Testing; Time; United States; Variant; Woman; cancer type; carcinogenesis; cell motility; gene function; intraperitoneal; meetings; mouse model; mutant; outcome forecast; overexpression; promoter; trait; tumor progression; vector

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.

2004年，上皮性卵巢癌（HOC）预计将成为美国女性癌症相关死亡中第四大癌症类型。由于其无症状发展且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为人所知的癌症之一。 p53、p16/Rb 和 HGF/c-met 介导的信号通路的改变经常发生，据报道与不良的临床预后相关。然而，它们在 EOC 形成中的具体作用仍不确定。最近我们已经证明，卵巢表面上皮（OSE）——抑癌基因p53的选择性失活会导致癌变，而视网膜母细胞瘤（Rb）基因的失活则显着加速这一过程。在该模型中，肿瘤与人类浆液性腺癌的侵袭性变体非常相似。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中的作用外，缺陷性 p53 和 Rb 途径之间的合作 使 OSE 易于表达诸如运动性和侵袭性增加等晚期癌症特征。这些特征保持休眠状态，直到由累积的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 在上皮性卵巢癌发生过程中对运动和侵袭的贡献，以及（2）评估 HGF 和 c-met 在 EOC 侵袭和腹膜内扩散中的作用。这些研究应该通过证明新的生物学机制（通过该机制，有缺陷的 p53 和 Rb 途径可能另外促进肿瘤进展）并通过建立 HGF/c-met 信号传导在 OSE 致癌过程中作为导致侵袭的许可事件的作用。