characterization of ovarian cancer in a mouse model

小鼠模型卵巢癌的特征

• 批准号: 6890993
• 负责人: SANDRA ORSULIC
• 金额: $ 32.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890993
• 关键词: biochemistry; biological models; carcinogenesis; epithelium; gene expression; gene expression profiling; genetically modified animals; histology; immunocytochemistry; laboratory mouse; metastasis; molecular biology; neoplasm /cancer genetics; neoplastic cell; neoplastic process; ovary neoplasms; virus receptors

DESCRIPTION (provided by applicant): Biochemical pathways involved in ovarian carcinoma are poorly understood, mainly because of the lack of suitable models for the molecular characterization of ovarian carcinoma induction and progression. We developed a mouse model for ovarian carcinoma in which multiple genes can be introduced into mouse ovarian surface epithelial cells and give rise to tumors that largely resemble human ovarian carcinoma. We will use this system to identify additional combinations of genetic lesions that act in concert to induce ovarian carcinoma in mice. Defined sets of genetic lesions that are commonly present in human ovarian carcinomas will be introduced into mouse primary ovarian epithelial cells to determine which combinations of genetic lesions are capable of inducing a tumorigenic state in these cells. This knowledge will be used for the development of genetically defined mouse models in which the tumor phenotype can be correlated to the primary genetic events that trigger tumor formation. We will use expression profiling of genetically defined cell lines to determine whether specific combinations of genetic lesions activate specific biochemical pathways, and to identify downstream targets of genes that induce ovadan cancer. Metastatic tumors and cell lines will be derived from the primary transformed ovarian cell lines. We will then compare expression profiles between primary transformed cell lines and their corresponding metastatic cell lines in order to identify genes that are associated with the process of metastasis. Individual genes that are downregulated in metastatic cells will be re-introduced into these cells to test for their ability to suppress ovarian tumor growth and metastasis. Individual genes that are upregulated in metastatic cells will be introduced into primary cells to test their ability to induce growth and metastatic properties in these cells. We will compare expression profiles between metastatic cell lines with different genetic lesions to determine whether the molecular changes that occur during the metastatic process are universal or dependent upon the initiating genetic events. Activation of individual components of biochemical pathways in the mouse model will be validated by identification of these components in human ovarian carcinomas of different types and metastatic potential. Our expectation is that the knowledge from the molecular biology of ovarian cancer will be translated into improvements in diagnosis and the development of tumor therapy tailored to the causative genetic events in human ovarian cancer.

描述（由申请人提供）：对卵巢癌涉及的生化途径知之甚少，主要是因为缺乏卵巢癌诱导和进展的分子表征的合适模型。我们开发了一种卵巢癌小鼠模型，其中可以将多个基因引入小鼠卵巢表面上皮细胞，并产生与人类卵巢癌非常相似的肿瘤。我们将使用该系统来识别协同作用诱发小鼠卵巢癌的其他基因损伤组合。将人类卵巢癌中常见的一组确定的遗传损伤引入小鼠原代卵巢上皮细胞中，以确定哪些遗传损伤组合能够在这些细胞中诱导致瘤状态。这些知识将用于开发基因定义的小鼠模型，其中肿瘤表型可以与触发肿瘤形成的主要遗传事件相关联。我们将使用基因定义的细胞系的表达谱来确定基因损伤的特定组合是否激活特定的生化途径，并确定诱导 ovadan 癌的基因的下游靶标。转移性肿瘤和细胞系将源自原代转化的卵巢细胞系。然后，我们将比较原代转化细胞系和其相应的转移细胞系之间的表达谱，以鉴定与转移过程相关的基因。在转移细胞中下调的单个基因将被重新引入这些细胞中，以测试它们抑制卵巢肿瘤生长和转移的能力。在转移细胞中上调的单个基因将被引入原代细胞中，以测试它们诱导这些细胞生长和转移特性的能力。我们将比较具有不同遗传病变的转移细胞系之间的表达谱，以确定转移过程中发生的分子变化是普遍的还是取决于起始遗传事件。小鼠模型中生化途径的各个成分的激活将通过鉴定不同类型和转移潜力的人类卵巢癌中的这些成分来验证。我们的期望是，卵巢癌分子生物学知识将转化为诊断的改进和针对人类卵巢癌致病遗传事件的肿瘤治疗的开发。