Epithelial Positioning Organization and Ovarian Cancer

恶性实体肿瘤的一个显著特征是组织紊乱：在正常组织中，上皮细胞沿着一层基底膜定位组织，而在肿瘤中，定位控制丢失。上皮细胞来源的癌细胞侵入间质并扩展到组织结构之外，破坏和干扰器官的生理功能。DISABLED-1和DISABLED-2等基因可能在细胞定位组织中发挥作用。小鼠的基因靶向敲除已经确立了Disable-1在脑细胞定位控制和涉及的信号通路中的作用。在乳腺和卵巢肿瘤细胞中，上皮性表达的Disable-2经常缺失，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，积累的信息支持DISABLED-2在上皮细胞定位组织中的作用。因此，人们认为卵巢癌中Disable-2的失活会导致定位控制的丧失，从而导致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Disable-2在卵巢表面上皮细胞定位控制中的作用。在禁用-2被框内替换/插入β-半乳糖苷酶(LacZ)干扰的小鼠中，禁用-2基因的两个拷贝的中断会导致早期胚胎死亡，这可能是因为它对内脏内胚层细胞定位组织的要求。我们建议进行以下研究：1)确定Disable-2在早期胚胎发育中的作用；2)利用杂合子LacZ替换小鼠确定Disable-2的组织表达模式和发育调节；3)确定杂合子Disable-2突变小鼠是否有发生卵巢恶性肿瘤的易感性；4)建立组织特异性条件性Disable-2缺陷小鼠，以确定Disable-2缺陷是否导致卵巢表面上皮细胞组织的丧失和致瘤性。

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.