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FGF10/FGFR2/ERK Signal Activation is Required for the Initiation, Maintenance and Progression of Intraductal Papillary Neoplasm of the Bile Duct

61 Pages Posted: 8 Nov 2019 Sneak Peek Status: Review Complete

See all articles by Hiroyuki Tomita

Hiroyuki Tomita

Gifu University - Department of Tumor Pathology

Kaori Tanaka

Gifu University - Department of Tumor Pathology

Akihiro Hirata

Gifu University - Division of Animal Experiment

Hideshi Okada

Gifu University - Department of Emergency and Disaster Medicine

Hisashi Imai

Gifu University - Department of Surgical Oncology

Yohei Shirakami

Gifu University - Department of Gastroenterology

Kotaro Ohnishi

Gifu University - Department of Gastroenterology

Shigeyuki Sugie

Asahi University - Department of Pathology

Hitomi Aoki

Gifu University - Department of Tissue and Organ Development

Yuichiro Hatano

Gifu University - Department of Tumor Pathology

Kei Noguchi

Gifu University - Department of Tumor Pathology

Tomohiro Kanayama

Gifu University - Department of Tumor Pathology

Ayumi Niwa

Gifu University - Department of Tumor Pathology

Natsuko Suzui

Gifu University - Department of Pathology

Tatsuhiko Miyazaki

Gifu University - Department of Pathology

Takuji Tanaka

Gifu Municipal Hospital - Department of Diagnostic Pathology (DDP)

Haruhiko Akiyama

Gifu University - Department of Orthopedic Surgery

Masahito Shimizu

Gifu University - Department of Gastroenterology

Kazuhiro Yoshida

Gifu University - Department of Tumor Pathology

Akira Hara

Gifu University - Department of Tumor Pathology

More...

Abstract

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 KrasG12Dp53 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.

Keywords: Biliary tract cancer, Fibroblast growth factor 10, Intraductal papillary neoplasm, ERK, cholangiocarcinoma

Suggested Citation

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). CELL-REPORTS-D-19-04345. Available at SSRN: https://ssrn.com/abstract=3481955 or http://dx.doi.org/10.2139/ssrn.3481955
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Hiroyuki Tomita (Contact Author)

Gifu University - Department of Tumor Pathology ( email )

Japan

Kaori Tanaka

Gifu University - Department of Tumor Pathology

Japan

Akihiro Hirata

Gifu University - Division of Animal Experiment

Japan

Hideshi Okada

Gifu University - Department of Emergency and Disaster Medicine ( email )

Yanagido 1-1
Gifu 501-1193
Japan

Hisashi Imai

Gifu University - Department of Surgical Oncology

Japan

Yohei Shirakami

Gifu University - Department of Gastroenterology

Japan

Kotaro Ohnishi

Gifu University - Department of Gastroenterology

Japan

Shigeyuki Sugie

Asahi University - Department of Pathology

Japan

Hitomi Aoki

Gifu University - Department of Tissue and Organ Development

Japan

Yuichiro Hatano

Gifu University - Department of Tumor Pathology

Japan

Kei Noguchi

Gifu University - Department of Tumor Pathology

Japan

Tomohiro Kanayama

Gifu University - Department of Tumor Pathology

Japan

Ayumi Niwa

Gifu University - Department of Tumor Pathology

Japan

Natsuko Suzui

Gifu University - Department of Pathology

Japan

Tatsuhiko Miyazaki

Gifu University - Department of Pathology

Japan

Takuji Tanaka

Gifu Municipal Hospital - Department of Diagnostic Pathology (DDP)

Japan

Haruhiko Akiyama

Gifu University - Department of Orthopedic Surgery

Japan

Masahito Shimizu

Gifu University - Department of Gastroenterology

Japan

Kazuhiro Yoshida

Gifu University - Department of Tumor Pathology

Japan

Akira Hara

Gifu University - Department of Tumor Pathology

Japan

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