Abstract
Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in the world. Recent studies suggest that fallopian tubal secretory epithelial cells (FTSECs) are candidates for the origin of HGSOC. Several genetic alterations involved in the carcinogenesis have been reported in HGSOC, but their minimal requirement and the specific combinations remained unclear. To clarify these points, we established an in vitro stepwise carcinogenesis model using immortalized FTSECs with overexpressed cyclinD1/cdk4 and hTERT, in which we additionally mimicked selected genetic abnormalities frequently observed in clinical samples. Mutational analysis using clinical samples of HGSOCs identified frequent p53 mutations (96%). Furthermore, RAS/PI3K pathway is important signaling pathway and was deregulated in 45% of HGSOCs. PI3K/AKT pathway is also important pathway in HGSOCs. Thus, we introduced dominant negative form of p53 alone or in combination with oncogenic mutant KRAS allele into immortalized cells, but both failed to exhibit tumorigenic phenotypes. Additional introduction of genetic factors were attempted, and overexpression of c-Myc or phosphorylated Akt (p-Akt) were independently found to confer tumorigenic phenotypes. Importantly, all transformed FTSECs exhibited high-grade serous carcinomas that were grossly, histologically, and immunohistochemically similar to human HGSOCs. Thus, p53/KRAS/c-Myc or p53/KRAS/PI3K-AKT pathways were determined to be minimal required for carcinogenesis. The strength of our study is the use of immortalized FTSECs that have original characteristics of fallopian tube as well as the introduction of genetic mutations clinically observed in human HGSOCs. This experimental model provides a foundation for future studies of early events in carcinogenesis of HGSOCs and the identification of candidate targets for drug development and secreted biomarkers for early detection. It is also likely that a similar model can be broadly applied to studying the normal biology of other epithelial cells where precursor lesions and malignant counterparts are not entirely understood.
Citation Format: Kohei Nakamura, Kentaro Nakayama, Tohru Kiyono, Noriyoshi Ishikawa, Masako Ishikawa, Hiroshi Katagiri, Toshiko Minamoto, Tomoka Ishibashi, Emi Sato, Kaori Sanuki, Hitomi Yamashita, Kouji Iida, Razia Sultana, Satoru Kyo. Establishment of in vitro carcinogenic model of high-grade serous ovarian carcinoma using immortalized fallopian tubal secretory epithelial cell. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5160.