Inhibition of FGF10-ERK signal activation suppresses intraductal papillary neoplasm of the bile duct and its associated carcinomas
Hiroyuki Tomita,
Kaori Tanaka,
Akihiro Hirata,
Hideshi Okada,
Hisashi Imai,
Yohei Shirakami,
Kotaro Ohnishi,
Shigeyuki Sugie,
Hitomi Aoki,
Yuichiro Hatano,
Kei Noguchi,
Tomohiro Kanayama,
Ayumi Niwa,
Natsuko Suzui,
Tatsuhiko Miyazaki,
Takuji Tanaka,
Haruhiko Akiyama,
Masahito Shimizu,
Kazuhiro Yoshida,
Akira Hara
Affiliations
Hiroyuki Tomita
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Corresponding author
Kaori Tanaka
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Akihiro Hirata
Division of Animal Experiment, Life Science Research Center, Gifu University, Gifu 501-1194, Japan
Hideshi Okada
Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Hisashi Imai
Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Yohei Shirakami
Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Kotaro Ohnishi
Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Shigeyuki Sugie
Department of Pathology, Asahi University Hospital, Gifu 500-8523, Japan
Hitomi Aoki
Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Yuichiro Hatano
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Kei Noguchi
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Tomohiro Kanayama
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Ayumi Niwa
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Natsuko Suzui
Department of Pathology, Gifu University Hospital, Gifu 501-1194, Japan
Tatsuhiko Miyazaki
Department of Pathology, Gifu University Hospital, Gifu 501-1194, Japan
Takuji Tanaka
Department of Diagnostic Pathology (DDP) and Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, Gifu 500-8513, Japan
Haruhiko Akiyama
Department of Orthopedic Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Masahito Shimizu
Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Kazuhiro Yoshida
Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Akira Hara
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Summary: Evidence regarding intraductal papillary neoplasm of the bile duct (IPNB) as a type of precancerous lesion of cholangiocarcinoma is limited. Moreover, a reproducible in vivo model is lacking, and IPNB pathogenesis remains unclear. Here, we use a doxycycline-inducible tetracycline (Tet)-on mice model to control fibroblast growth factor 10 (FGF10) expression, which regulates branching and tubule formation. FGF10-induced IPNB mimics the multifocal and divergent human IPNB phenotypes via the FGF10-FGF receptor 2 (FGFR2)-RAS-extracellular-signal-regulated kinase (ERK) signaling pathway. A paracrine/autocrine growth factor is sufficient to initiate and maintain IPNB originating from the peribiliary glands, including biliary stem/progenitor cells. With KrasG12D, p53, or p16 mutations or both, Fgf10-induced IPNB shows stepwise carcinogenesis, causing associated invasive carcinoma. Fgf10-induced papillary changes and progression are suppressed by the inhibition of the FGF10-FGFR2-RAS-ERK signaling pathway, demonstrating that the signal is a therapeutic target for IPNB and associated carcinoma.
