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，上皮细胞沿沿着一片基底膜定位组织，而在肿瘤中，定位控制丧失。 上皮细胞来源的癌细胞侵入基质并扩展到组织结构之外，损害并干扰器官的生理功能。 Disabled-1和Disabled-2等基因可能在细胞的定位组织中起作用。 小鼠中的基因靶向敲除已经确立了Disabled- 1在脑细胞定位控制和所涉及的信号传导通路中的作用。 上皮表达的Disabled-2在乳腺和卵巢肿瘤细胞中经常丢失，被认为是卵巢癌的肿瘤抑制因子。 Disabled-2在结构和生化功能上与Disabled- 1相似，并且积累的信息支持Disabled-2在上皮细胞定位组织中的作用。 因此，认为卵巢癌中Disabled-2的失活导致定位控制的丧失并促成上皮细胞的恶性生长。 我们使用基因靶向敲除小鼠模型来检测Disabled-2在卵巢表面上皮细胞定位控制中的功能。 在通过β-半乳糖苷酶（LacZ）的框内替换/插入破坏Disabled-2的小鼠中，Disabled-2基因的两个拷贝的破坏导致早期胚胎死亡，这可能是由于其在内脏内胚层细胞定位组织中的需要。 我们提出以下研究：1）确定Disabled-2在早期胚胎发育中的作用; 2）使用杂合LacZ置换小鼠确定Disabled-2的组织表达模式和发育调控; 3）确定杂合Disabled-2突变小鼠是否具有发生卵巢恶性肿瘤的倾向; 4）产生组织特异性条件性Disabled-2缺陷小鼠以确定Disabled-2缺陷是否有助于卵巢表面上皮细胞组织和致瘤性的丧失。

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, the positioning control is lost. The epithelial cell- derived carcinoma cells invade stroma and expand beyond 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 organization of cells. Gene- targeted knockouts in mice have established the role of Disabled- 1 in brain cell positioning control and the signaling pathway involved. The epithelial-expressed Disabled-2 is frequently lost in breast and ovarian tumor cells and is believed to be a tumor suppressor of ovarian cancer. Disabled-2 is similar to Disabled- 1 in structure and biochemical function, and accumulating information supports a role for Disabled-2 in epithelial cell positioning organization. Thus, it is thought that inactivation of Disabled-2 in ovarian cancer leads to loss of positioning control and contributes to the malignant growth of the epithelial cells. We used a gene targeted knockout mouse model to examine the function of Disabled-2 in positioning control of ovarian surface epithelial cells. In mice that 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. We propose the following investigations: 1) Determine the role of Disabled-2 in early embryonic development; 2) Determine the tissue expression pattern and developmental regulation of Disabled-2 using heterozygous LacZ-replacement mice; 3) Determine if there is a predisposition in heterozygous Disabled-2 mutant mice to develop ovarian malignancy; 4) Create tissue-specific conditional Disabled-2 deficient mice to determine if Disabled-2 deficiency contributes to the loss of ovarian surface epithelial cell organization and tumorigenicity.