Epithelial Positioning Organization and Ovarian Cancer

描述（由申请人提供）：恶性实体瘤的一个显著特征是组织紊乱：在正常组织中，上皮细胞沿基底膜定位组织，而在肿瘤中，这种定位控制丧失。上皮细胞来源的癌细胞侵入间质并扩展到正常组织结构之外，破坏和干扰器官的生理功能。像Disabled-1和Disabled-2这样的基因可能在细胞定位中起作用。上皮表达的Disabled-2在乳腺和卵巢肿瘤细胞中经常丢失，被认为是与卵巢癌相关的肿瘤抑制因子。因此，Disabled-2的失活被认为会导致定位控制的丧失，并有助于卵巢癌上皮细胞的肿瘤生长。我们使用基因靶向敲除小鼠模型来检测Disabled-2在上皮细胞定位控制中的功能。在被框架内替代/插入β -半乳糖苷酶（LacZ）破坏的小鼠中，两个拷贝的Disabled-2基因的破坏导致早期胚胎死亡，可能是由于其在内脏内胚层细胞定位组织中的需要。杂合子Dab2突变小鼠易患子宫和卵巢增生和不典型增生。我们建议进行以下研究：1)利用人卵巢肿瘤组织上皮过渡区确定Disabled-2和其他分子事件在形态转化中的作用；2)研究Disabled-2在培养细胞中的细胞功能，特别是其在胞吞作用和货物靶向中的作用，这是在体内建立极性所必需的；3)建立卵巢特异性条件型Disabled-2缺陷小鼠，以确定完全Disabled-2失活是否会导致肿瘤表型，以及与p53失活在卵巢癌发展中的协同作用。本研究的目的是验证上皮结构（包括极性）的破坏是上皮肿瘤形态转化的关键组成部分的概念，并揭示卵巢致瘤性过程中的分子细节。这些研究将有助于更好地了解癌症的病因，并将通过提供癌症预防战略和治疗方法来促进公共卫生。

DESCRIPTION (provided by applicant): 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.