Activation of biliary tree stem cells within peribiliary glands in primary sclerosing cholangitis

Carpino, Guido; Cardinale, Vincenzo; Renzi, Anastasia; Hov, Johannes R.; Berloco, P.B.; Rossi, Massimo; Karlsen, Tom H.; Alvaro, Domenico; Gaudio, Eugenio

doi:10.1016/j.jhep.2015.06.018

Cited by 103 publications

(146 citation statements)

References 35 publications

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“…This iCCA subtype displays immunohistochemistry, gene expression and a clinicopathological profile that can be super imposed on pCCA 17 and, in addition, shows (together with pCCA) large similarities to pancreatic ductal adenocarcinoma [47][48][49] . Consistently, the pattern of growth and the presence of preneoplastic lesions in cholangiocytes and peribiliary glands lining large intrahepatic bile ducts seem to indicate that these cells are candidate cells of origin 40,43 . The bile ductular (mixed)-type iCCAs show an immunohisto chemical and gene expression profile corresponding to mucin-negative cuboidal cholangiocytes that line the smaller bile ducts (interlobular bile ducts and ductules) 17 .…”

Section: Cells Of Originmentioning

confidence: 65%

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Bañales

Cardinale

Carpino

et al. 2016

Nat Rev Gastroenterol Hepatol

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1,107

1,139

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Section: Cells Of Originmentioning

confidence: 65%

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Bañales

Cardinale

Carpino

et al. 2016

Nat Rev Gastroenterol Hepatol

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1,107

1,139

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“…However, cells harboring mutations survived in the PBGs; therefore, the regenerative response to biliary injury resulted in ECC development from PBGs. Importantly, significant proliferation and hyperplasia of PBGs in response to biliary injury were observed in patients with primary sclerosing cholangitis and liver fluke infection (33,34). Furthermore, the PBGs of patients with hepatolithiasis frequently harbor Kras mutations (35).…”

Section: Discussionmentioning

confidence: 99%

Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands

Nakagawa

Suzuki

Hirata

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The carcinogenic mechanism of extrahepatic cholangiocarcinoma (ECC) is unclear, due at least in part to the lack of an appropriate mouse model. Because human studies have reported frequent genetic alterations in the Ras-and TGFβ/SMAD-signaling pathways in ECC, mice with tamoxifen-inducible, duct-cell-specific Kras activation and a TGFβ receptor type 2 (TGFβR2) deletion were first generated by crossing LSL-Kras G12D , Tgfbr2 flox/flox , and K19 CreERT mice (KT-K19 CreERT ). However, KT-K19 CreERT mice showed only mild hyperplasia of biliary epithelial cells (BECs) in the extrahepatic bile duct (EHBD) and died within 7 wk, probably a result of lung adenocarcinomas. Next, to analyze the additional effect of E-cadherin loss, KT-K19 CreERT mice were crossed with CDH1 flox/flox mice (KTC-K19 CreERT ). Surprisingly, KTC-K19 CreERT mice exhibited a markedly thickened EHBD wall accompanied by a swollen gallbladder within 4 wk after tamoxifen administration. Histologically, invasive periductal infiltrating-type ECC with lymphatic metastasis was observed. Time-course analysis of EHBD revealed that recombined BECs lining the bile duct lumen detached due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs), which are considered a BEC stem-cell niche. Detached dying BECs released high levels of IL-33, as determined by microarray analysis using biliary organoids, and stimulated inflammation and a regenerative response by PBGs, leading eventually to ECC development. Cell lineage tracing suggested PBGs as the cellular origin of ECC. IL-33 cooperated with Kras and TGFβR2 mutations in the development of ECC, and anti-IL-33 treatment suppressed ECC development significantly. Thus, this mouse model provided insight into the carcinogenic mechanisms, cellular origin, and potential therapeutic targets of ECC.extrahepatic cholangiocarcinoma | IL-33 | organoid | ILC2 | amphiregulin

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“…Recently, the involvement of biliary tree stem/progenitor cells (BTSCs) has been demonstrated in the progression of typical PSC duct lesions . BTSCs represent a stem/progenitor cell niche located within the glands of the biliary tree (peribiliary glands [PBGs]) .…”

mentioning

confidence: 99%

“…BTSCs represent a stem/progenitor cell niche located within the glands of the biliary tree (peribiliary glands [PBGs]) . A massive BTSC proliferation was revealed in PSC, and the subsequent PBG hyperplasia contributes to bile duct wall thickening, leading to obliterative fibrosis and strictures . In PSC, PBGs showed signs of dysplasia and have been suggested as a possible cell of origin for CCA and biliary intraductal papillary mucinous neoplasms …”

mentioning

confidence: 99%

Neoplastic Transformation of the Peribiliary Stem Cell Niche in Cholangiocarcinoma Arisen in Primary Sclerosing Cholangitis

et al. 2019

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Activation of biliary tree stem cells within peribiliary glands in primary sclerosing cholangitis

Cited by 103 publications

References 35 publications

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands

Neoplastic Transformation of the Peribiliary Stem Cell Niche in Cholangiocarcinoma Arisen in Primary Sclerosing Cholangitis

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