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.
Keywords:
bile duct stem/progenitor cell; cholangiocarcinoma; fibroblast growth factor 10; intraductal papillary neoplasm of the bile duct; peribiliary gland.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Aged, 80 and over
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Animals
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Antineoplastic Agents / pharmacology
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Bile Duct Neoplasms / drug therapy
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Bile Duct Neoplasms / enzymology*
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Bile Duct Neoplasms / genetics
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Bile Duct Neoplasms / pathology
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Carcinoma, Papillary / drug therapy
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Carcinoma, Papillary / enzymology*
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Carcinoma, Papillary / genetics
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Carcinoma, Papillary / pathology
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Cells, Cultured
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Cholangiocarcinoma / drug therapy
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Cholangiocarcinoma / enzymology*
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Cholangiocarcinoma / genetics
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Cholangiocarcinoma / pathology
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Disease Progression
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Female
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Fibroblast Growth Factor 10 / genetics
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Fibroblast Growth Factor 10 / metabolism*
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Gene Expression Regulation, Neoplastic
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Genes, ras
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Humans
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Nude
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Mice, Transgenic
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Middle Aged
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mutation
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Neoplastic Stem Cells / enzymology*
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Neoplastic Stem Cells / pathology
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Phosphorylation
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Precancerous Conditions / drug therapy
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Precancerous Conditions / enzymology*
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Precancerous Conditions / genetics
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Precancerous Conditions / pathology
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Protein Kinase Inhibitors / pharmacology
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Receptor, Fibroblast Growth Factor, Type 2 / genetics
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Receptor, Fibroblast Growth Factor, Type 2 / metabolism
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Signal Transduction
Substances
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Antineoplastic Agents
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FGF10 protein, human
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Fgf10 protein, mouse
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Fibroblast Growth Factor 10
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Protein Kinase Inhibitors
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Fgfr2 protein, mouse
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Receptor, Fibroblast Growth Factor, Type 2
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase Kinases