Research Papers:

Reconstitution of high-grade serous ovarian carcinoma from primary fallopian tube secretory epithelial cells

Kohei Nakamura, Kentaro Nakayama _, Noriyoshi Ishikawa, Masako Ishikawa, Razia Sultana, Tohru Kiyono and Satoru Kyo

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Oncotarget. 2018; 9:12609-12619. https://doi.org/10.18632/oncotarget.23035

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Kohei Nakamura1, Kentaro Nakayama1, Noriyoshi Ishikawa2, Masako Ishikawa1, Razia Sultana1, Tohru Kiyono3 and Satoru Kyo1

1Department of Obstetrics and Gynecology, Shimane University School of Medicine, 6938501, Izumo, Japan

2Department of Organ Pathology, Shimane University School of Medicine, 6938501, Izumo, Japan

3Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, 1040045, Tsukiji, Chuo-ku, Japan

Correspondence to:

Kentaro Nakayama, email: [email protected]

Tohru Kiyono, email: [email protected]

Keywords: carcinogenesis; high-grade serous ovarian carcinoma; fallopian tube; RAS/PI3K pathway; c-Myc

Received: July 02, 2017     Accepted: November 15, 2017     Published: December 08, 2017


Fallopian tube secretory epithelial cells (FTSECs) have been suggested to be the source of high-grade serous ovarian carcinoma (HGSOC). Although several genetic alterations are known to be involved in HGSOC development, the minimal requirements remain unclear. We aimed to identify oncogenic mutations indispensable for HGSOC development in a stepwise model, using immortalized FTSECs. FTSECs were isolated from clinical samples and immortalized by overexpression of cyclin D1, CDK4R24C, and hTERT. Oncogenic mutations in the p53, c-Myc, and RAS/PI3K pathways were mimicked by lentiviral transduction. We found two distinct patterns of gene alteration essential for HGSOC development: p53/KRAS/AKT and p53/KRAS/c-Myc. Dominant-negative p53, alone or combined with oncogenic KRAS (KRASV12), constitutively active AKT (CA-AKT), and c-Myc, did not induce tumorigenesis in immortalized cells; however, overexpression of CA-AKT or c-Myc, along with dominant-negative p53 and KRASV12, conferred tumorigenic potential. Transformed FTSECs formed tumors in nude mice that were grossly, histologically, and immunohistochemically similar to human HGSOCs. Interestingly, mice harboring tumors with c-Myc amplifications displayed extensive metastases, consistent with the increased dissemination in their human counterparts. Thus, aberrant p53/KRASV12/c-Myc or p53/KRASV12/PI3K-AKT signaling was the minimum requirement for FTSEC carcinogenesis. The model based on this evidence could shed light on the early stages of HGSOC development.

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