Epithelial Positioning Organization and Ovarian Cancer

恶性实体瘤的一个突出标志是组织解体：在正常组织中，上皮细胞被破坏。 在肿瘤中，这种定位控制失去了。 上皮细胞衍生的癌细胞侵入基质并扩展超出正常组织结构， 损害和干扰器官的生理功能。Disabled-1和 Disabled-2可以在单元格的定位中起作用。上皮细胞表达的Disabled-2经常丢失， 乳腺和卵巢肿瘤细胞，并且被认为是与卵巢癌相关的肿瘤抑制因子。 因此，失活Disabled-2被认为导致定位控制的丧失，并促成了失活。 卵巢癌中上皮细胞的肿瘤生长。我们使用了一种基因靶向敲除小鼠模型， 检测Disabled-2在上皮细胞定位控制中的功能。在Disabled-2的小鼠中， 通过β-半乳糖苷酶（LacZ）的框内替换/插入而破坏， Disabled-2基因导致早期胚胎死亡，可能是由于其需要内脏内胚层细胞 定位组织。杂合子Dab 2突变小鼠易患子宫和卵巢癌。 增生和异型增生。 我们提出以下研究：1）确定Disabled-2和其他分子的作用 使用人卵巢肿瘤组织的上皮过渡区的形态转化中的事件; 2)研究Disabled-2在培养细胞中的细胞功能，特别是其在内吞和货物中的作用 靶向，其对于在体内建立极性是必需的; 3）产生卵巢特异性条件性Disabled-2 缺陷小鼠，以确定完全失活的残疾人-2导致肿瘤表型， 与卵巢癌发展中p53失活的协同作用。 研究的目的是验证上皮结构破坏的概念，包括 极性，是上皮肿瘤形态转化的关键组成部分， 卵巢肿瘤发生过程中的分子细节。这些研究将有助于更好地了解 癌症病因学，并将通过提供癌症预防策略和治疗为公共卫生做出贡献 疗法

A prominent hallmark of malignant solid tumors is disorganization: in normal tissues, epithelial cells are positionally organized along a sheet of basement membrane and in tumors, this positioning control is lost. The epithelial cell-derived cancer cells invade stroma and expand beyond the normal tissue structure, damaging and interfering with the physiological functions of the organs. Genes such as Disabled-1 and Disabled-2 may function in the positioning of cells. The epithelial-expressed Disabled-2 is frequently lost in breast and ovarian tumor cells and is believed to be a tumor suppressor of relevance in ovarian cancer. Thus, inactivation of Disabled-2 is thought to lead to loss of positioning control and contributes to the neoplastic growth of the epithelial cells in ovarian cancer. We used a gene targeted knockout mouse model to examine the function of Disabled-2 in positioning control of epithelial cells. In mice where Disabled-2 is disrupted by an in-frame replacement/insertion of beta-galactosidase (LacZ), disruption of both copies of Disabled-2 gene results in early embryonic lethality, likely due to its requirement in visceral endoderm cell positioning organization. The heterozygous Dab2 mutant mice are predisposed to uterine and ovarian hyperplasia and dysplasia. We propose the following investigations: 1) Determine the role of Disabled-2 and additional molecular events in morphological transformation using the epithelial transition zones of human ovarian tumor tissues; 2) Study the cellular function of Disabled-2 in cultured cells, particularly of its role in endocytosis and cargo targeting, which are essential to establish polarity in vivo; 3) Create ovarian-specific conditional Disabled-2 deficient mice to determine if complete Disabled-2 inactivation causes neoplastic phenotype, and the synergy with inactivation of p53 in ovarian cancer development. The goals of the research are to validate the concept that disruption of epithelial structure, including polarity, is a critical component in epithelial neoplastic morphological transformation and to uncover the molecular details in the process of ovarian tumorigenicity. Such studies will lead to a better understanding of cancer etiology and will contribute to public health by providing cancer preventive stratagy and treatment therapy.