Molecular Pathogenesis of Ovarian Endometrioid Adenocarc

卵巢子宫内膜样腺癌的分子发病机制

• 批准号: 7013212
• 负责人: KATHLEEN R. CHO
• 金额: $ 26.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013212
• 关键词: adenocarcinoma; athymic mouse; cadherins; cell cycle; endometriosis; enzyme activity; enzyme induction /repression; human tissue; molecular pathology; neoplasm /cancer genetics; ovary neoplasms; phosphorylation; telomerase

Ovarian carcinoma (OvCa) is a major cause of cancer- associated morbidity and mortality for women, yet much remains to be learned about its pathogenesis. Like other cancers, OvCas are thought to arise through a multi-step process in which repeated cycles of somatic mutation and clonal selection produce variant progeny with increasingly aggressive growth properties. The genes mutated in cancer frequently encode proteins that function in conserved signaling pathways. Molecular genetic analyses suggest that the different histologic subtypes of OvCa (e.g., serous, clear cell, mucinous, and endometrioid) may represent distinct disease entities and that OvCa precursor lesions may be subtype specific. Hence, a clearer understanding of OvCa pathogenesis might be more readily attained by focusing molecular genetic studies on distinct OvCa types for defects in cell signaling pathways. The ovarian endometrioid adenocarcinomas (OEAs) share a number of molecular genetic features with uterine endometrioid adenocarcinomas, including frequent mutations of the CTNNB1 gene which encodes beta-catenin (beta-cat), a critical component of the highly conserved Wnt signaling pathway. Previous studies suggest that although the Wnt/beta-cat/Tcf pathway may be defective in a substantial percentage of OEAs, it is only rarely altered in other histologic subtypes of OvCa. This application describes studies that are focused on defining the molecular mechanisms by which Wnt pathway defects contribute to the development and behavior of a specific type of OvCa, namely endometrioid adenocarcinomas. Toward this end, four specific aims are proposed: 1) To complete a comprehensive mutational analysis of genes encoding proteins known to regulate the Wnt/beta-cat/Tcf signaling pathway in a large group of primary OEAs; 2) To characterize expression of candidate downstream genes transcriptionally activated by the beta-cat/Tcf signaling pathway in OEAs with known pathway defects; 3) To examine a spectrum of endometriosis lesions (putative OEA precursors) for defects in beta-cat/Tcf pathway genes, and to determine whether expression of mutant beta-cat results in malignant transformation of immortalized cells derived from endometriosis, and 4) To determine if selected beta-cat/Tcf- activated genes are necessary and/or sufficient for neoplastic transformation by mutant beta-cat in RK3E cells or human cells with relevance to ovarian cancer (immortalized ovarian surface epithelial cells expressing telomerase, or cell lines derived from endometriosis).

卵巢癌(OvCa)是女性癌症相关发病率和死亡率的主要原因，但其发病机制尚不清楚。与其他癌症一样，OvCas被认为是通过一个多步骤的过程产生的，在这个过程中，重复的体细胞突变和克隆选择产生了具有日益侵略性的生长特性的变异后代。癌症中突变的基因经常编码蛋白质，这些蛋白质在保守的信号通路中发挥作用。分子遗传学分析表明，OvCa的不同组织亚型(如浆液性、透明细胞、粘液性和子宫内膜样)可能代表不同的疾病实体，OvCa前体病变可能是亚型特异性的。因此，通过对细胞信号通路缺陷的不同OvCa类型的分子遗传学研究，可能更容易对OvCa的发病机制有更清晰的了解。卵巢子宫内膜样腺癌与子宫子宫内膜样腺癌有许多共同的分子遗传学特征，包括编码β-连环蛋白(β-CAT)的CTNNB1基因频繁突变，这是高度保守的Wnt信号通路的关键组成部分。以前的研究表明，尽管Wnt/beta-cat/Tcf通路在相当大比例的Ovca中可能存在缺陷，但在Ovca的其他组织学亚型中，它很少发生变化。本申请描述的研究集中在确定Wnt途径缺陷导致一种特定类型的OvCa的发展和行为的分子机制，即子宫内膜样腺癌。为此，提出了四个特定的目标：1)在一大群初级OEA中完成对已知的调节Wnt/β-CAT/Tcf信号通路的编码蛋白的全面突变分析；2)表征由β-CAT/Tcf信号通路转录激活的候选下游基因在已知途径缺陷的OEA中的表达；3)检测子宫内膜异位症病变(可能是OEA的前体)中β-CAT/Tcf途径基因缺陷的范围，并确定突变的β-CAT的表达是否会导致子宫内膜异位症永生化细胞的恶性转化；以及4)确定选定的β-CAT/Tcf激活的基因对于突变的β-CAT在RK3E细胞或与卵巢癌相关的人类细胞(表达端粒酶的永生化卵巢表面上皮细胞，或来自子宫内膜异位症的细胞系)的肿瘤转化中是否必要和/或充分。