RRC ID 63719
Author Tomita H, Tanaka K, Hirata A, Okada H, Imai H, Shirakami Y, Ohnishi K, Sugie S, Aoki H, Hatano Y, Noguchi K, Kanayama T, Niwa A, Suzui N, Miyazaki T, Tanaka T, Akiyama H, Shimizu M, Yoshida K, Hara A.
Title Inhibition of FGF10-ERK signal activation suppresses intraductal papillary neoplasm of the bile duct and its associated carcinomas.
Journal Cell Rep
Abstract 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.
Volume 34(8)
Pages 108772
Published 2021-2-23
DOI 10.1016/j.celrep.2021.108772
PII S2211-1247(21)00085-1
PMID 33626352
MeSH Aged Aged, 80 and over Animals Antineoplastic Agents / pharmacology Bile Duct Neoplasms / drug therapy Bile Duct Neoplasms / enzymology* Bile Duct Neoplasms / genetics Bile Duct Neoplasms / pathology Carcinoma, Papillary / drug therapy Carcinoma, Papillary / enzymology* Carcinoma, Papillary / genetics Carcinoma, Papillary / pathology Cells, Cultured Cholangiocarcinoma / drug therapy Cholangiocarcinoma / enzymology* Cholangiocarcinoma / genetics Cholangiocarcinoma / pathology Disease Progression Extracellular Signal-Regulated MAP Kinases / metabolism* Female Fibroblast Growth Factor 10 / genetics Fibroblast Growth Factor 10 / metabolism* Gene Expression Regulation, Neoplastic Genes, ras Humans Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Nude Mice, Transgenic Middle Aged Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors Mitogen-Activated Protein Kinase Kinases / metabolism Mutation Neoplastic Stem Cells / enzymology* Neoplastic Stem Cells / pathology Phosphorylation Precancerous Conditions / drug therapy Precancerous Conditions / enzymology* Precancerous Conditions / genetics Precancerous Conditions / pathology Protein Kinase Inhibitors / pharmacology Receptor, Fibroblast Growth Factor, Type 2 / genetics Receptor, Fibroblast Growth Factor, Type 2 / metabolism Signal Transduction
IF 8.109
Human and Animal Cells MC3T3-G2/PA6(RCB1127)