Vincent Center for Reproductive Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Carcinogenesis. 2013 Apr;34(4):893-901. doi: 10.1093/carcin/bgs405. Epub 2012 Dec 31.
Epithelial ovarian cancer is a heterogeneous disease that is subdivided into five major histotypes but the mechanisms driving their differentiation are not clear. Mutations in adenomatous polyposis coli (APC) and β-catenin are commonly observed in the human ovarian endometrioid adenocarcinoma (OEA) patients. However, the mechanisms subsequent to APC deletion in ovarian tumorigenesis have not been well characterized. We have conditionally deleted APC in the murine ovarian surface epithelium (OSE) and showed that its loss leads to development of epithelial inclusion cysts. High-grade OEAs with tightly packed villoglandular histology were observed in older APC-deleted mice. Phosphatase and tensin homolog (PTEN) expression was elevated in the early lesions but lost after progression to the more advanced tumors. Knockdown of APC or expression of a gain-of-function β-catenin similarly induced human OSE cells to develop tumors with endometrioid histology in xenografts. Expression of HOXA10 was induced in both the advanced APC-deleted murine tumors and in the tumor xenografts of human OSE cells with knocked-down APC. These results show that reduced APC activity is sufficient to induce formation of epithelial inclusion cysts and support OEA development and suggest that induced HOXA10 expression and loss of PTEN are key mechanisms driving endometrioid histotype differentiation and progression.
卵巢上皮性癌是一种异质性疾病，可分为五个主要组织学类型，但驱动其分化的机制尚不清楚。在人类卵巢子宫内膜样腺癌（OEA）患者中，腺瘤性结肠息肉病基因（APC）和β-连环蛋白的突变很常见。然而，APC 缺失在卵巢肿瘤发生中的后续机制尚未得到很好的描述。我们已经在小鼠卵巢表面上皮（OSE）中条件性缺失 APC，并表明其缺失会导致上皮包涵囊肿的形成。在 APC 缺失的老年小鼠中观察到高级别 OEAs，其具有紧密排列的绒毛状组织学。在早期病变中，磷酸酶和张力蛋白同源物（PTEN）的表达升高，但在进展为更高级别的肿瘤后丢失。APC 的敲低或功能获得性β-连环蛋白的表达同样诱导人 OSE 细胞在异种移植物中形成具有子宫内膜样组织学的肿瘤。在晚期 APC 缺失的小鼠肿瘤和敲低 APC 的人 OSE 细胞的肿瘤异种移植物中均诱导 HOXA10 的表达。这些结果表明，降低 APC 活性足以诱导上皮包涵囊肿的形成，并支持 OEA 的发展，并表明诱导的 HOXA10 表达和 PTEN 的丢失是驱动子宫内膜样组织类型分化和进展的关键机制。
