Inhibition of FGF10-ERK signal activation suppresses intraductal papillary neoplasm of the bile duct and its associated carcinomas

Autor: Takuji Tanaka, Hiroyuki Tomita, Ayumi Niwa, Akira Hara, Kei Noguchi, Natsuko Suzui, Hisashi Imai, Hideshi Okada, Shigeyuki Sugie, Haruhiko Akiyama, Akihiro Hirata, Kaori Tanaka, Kazuhiro Yoshida, Yohei Shirakami, Tatsuhiko Miyazaki, Yuichiro Hatano, Masahito Shimizu, Tomohiro Kanayama, Kotaro Ohnishi, Hitomi Aoki
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
MAPK/ERK pathway
medicine.disease_cause
bile duct stem/progenitor cell
Mice
0302 clinical medicine
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
lcsh:QH301-705.5
Cells
Cultured
Aged
80 and over
Mice
Inbred BALB C
Chemistry
Bile duct
Middle Aged
Gene Expression Regulation
Neoplastic
medicine.anatomical_structure
intraductal papillary neoplasm of the bile duct
Disease Progression
Neoplastic Stem Cells
Female
Signal transduction
cholangiocarcinoma
Signal Transduction
Mice
Nude
Antineoplastic Agents
Mice
Transgenic
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Paracrine signalling
Carcinoma
medicine
Animals
Humans
peribiliary gland
Receptor
Fibroblast Growth Factor
Type 2
Progenitor cell
Protein Kinase Inhibitors
Aged
Mitogen-Activated Protein Kinase Kinases
FGF10
fibroblast growth factor 10
medicine.disease
Carcinoma
Papillary
Mice
Inbred C57BL
stomatognathic diseases
Genes
ras
030104 developmental biology
Bile Duct Neoplasms
lcsh:Biology (General)
Mutation
Cancer research
Carcinogenesis
Precancerous Conditions
030217 neurology & neurosurgery
Zdroj: Cell Reports, Vol 34, Iss 8, Pp 108772-(2021)
ISSN: 2211-1247
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: