Abstract 4878: The fallopian tube is the origin of high-grade serous ovarian carcinomas in a mouse model

Abstract

Abstract Ovarian cancer is a lethal disease primarily because it is often not detected until it spreads beyond the female reproductive tract. Early detection is thus the key to successful intervention in ovarian cancer. Yet it is not known how this cancer arises and metastasizes. In the last decade, new evidence has challenged the dogma that the ovary is the main source of these cancers. The fallopian tube has been proposed instead as the primary origin of high-grade serous ovarian cancer _ the subtype causing 70% of ovarian cancer deaths. To understand the origin and early progression of this serous cancer, we have generated double knockout (DKO) mice by conditionally disabling in the reproductive tract two critical genes _ Dicer, an essential gene for microRNA synthesis, and Pten, a tumor suppressor that negatively regulates the PI3K pathway. These DKO mice develop high-grade serous carcinomas that arise from the fallopian tube. These high-grade serous cancers spread to engulf the ovary and then extensively metastasize throughout the abdominal cavity, causing ascites and killing 100% of the mice by 13 months. This is the first mouse model demonstrating that the fallopian tube is capable of initiating and developing high-grade serous carcinomas with similar clinical manifestations shown in the human serous ovarian carcinomas. Intriguingly, analyzing these DKO tumors at early time points also reveals that these epithelial cancers begin in the stroma of the fallopian tube, suggesting that the cancers arise through a mesenchymal-to-epithelial transition (MET) _ a novel mechanism of carcinoma initiation. This study thus presents a new paradigm for the origin and initiation of deadly high-grade serous ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4878. doi:1538-7445.AM2012-4878