Evidence regarding intraductal papillary neoplasm of the bile duct (IPNB) as a new type of precancerous lesion of cholangiocarcinoma is limited. Moreover, a reproducible in vivo model is lacking and IPNB pathogenesis remains unclear. Here, we used a doxycycline-inducible Tet-on mice model facilitating the control of fibroblast growth factor 10 (FGF10) expression which contributes to branching and tubule formation. FGF10-induced IPNB mimicked the multifocal and divergent human IPNB phenotypes via the FGF10–FGFR2–RAS–ERK signalling pathway. A paracrine/autocrine growth factor was sufficient for the initiation and maintenance of IPNB originating from the peribiliary glands, including the biliary stem/progenitor cells. With KrasG12D, p53 and/or p16 gene alterations, Fgf10-induced IPNB showed stepwise carcinogenesis, causing associated invasive carcinoma. Fgf10-induced papillary changes were suppressed by FGF10–FGFR2–RAS–ERK signalling inhibition, which was inhibited with a MEK inhibitor, demonstrating that the signal is a novel therapeutic target for IPNB and associated carcinoma.
Tomita, Hiroyuki and Tanaka, Kaori and Hirata, Akihiro and Okada, Hideshi and Imai, Hisashi and Shirakami, Yohei and Ohnishi, Kotaro and Sugie, Shigeyuki and Aoki, Hitomi and Hatano, Yuichiro and Noguchi, Kei and Kanayama, Tomohiro and Niwa, Ayumi and Suzui, Natsuko and Miyazaki, Tatsuhiko and Tanaka, Takuji and Akiyama, Haruhiko and Shimizu, Masahito and Yoshida, Kazuhiro and Hara, Akira, FGF10/FGFR2/ERK Signal Activation is Required for the Initiation, Maintenance and Progression of Intraductal Papillary Neoplasm of the Bile Duct (November 7, 2019). Available at SSRN: https://ssrn.com/abstract=3481955 or http://dx.doi.org/10.2139/ssrn.3481955
This version of the paper has not been formally peer reviewed.
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