Inhibition of FGF10-ERK signal activation suppresses intraductal papillary neoplasm of the bile duct and its associated carcinomas
Male
0301 basic medicine
QH301-705.5
Mice, Nude
Antineoplastic Agents
bile duct stem/progenitor cell
Cholangiocarcinoma
Mice
03 medical and health sciences
peribiliary gland
Animals
Humans
Biology (General)
Extracellular Signal-Regulated MAP Kinases
Cells, Cultured
Aged
Aged, 80 and over
Mice, Inbred BALB C
fibroblast growth factor 10
Carcinoma, Papillary
3. Good health
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL
Genes, ras
intraductal papillary neoplasm of the bile duct
Bile Duct Neoplasms
Disease Progression
Female
cholangiocarcinoma
Fibroblast Growth Factor 10
DOI:
10.1016/j.celrep.2021.108772
Publication Date:
2021-02-23T23:05:07Z
AUTHORS (20)
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.
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CITATIONS (12)
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