{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:49:19Z","timestamp":1790704159655,"version":"4.1.0"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2019,1,4]],"date-time":"2019-01-04T00:00:00Z","timestamp":1546560000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,1,4]],"date-time":"2019-01-04T00:00:00Z","timestamp":1546560000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:p>Primary sclerosing cholangitis (PSC) is a chronic inflammatory cholangiopathy frequently complicated by cholangiocarcinoma (CCA). Massive proliferation of biliary tree stem\/progenitor cells (BTSCs), expansion of peribiliary glands (PBGs), and dysplasia were observed in PSC. The aims of the present study were to evaluate the involvement of PBGs and BTSCs in CCA which emerged in PSC patients. Specimens from normal liver (n = 5), PSC (n = 20), and PSC\u2010associated CCA (n = 20) were included. Samples were processed for histology, immunohistochemistry, and immunofluorescence. <jats:italic toggle=\"yes\">In vitro <\/jats:italic>experiments were performed on human BTSCs, human mucinous primary CCA cell cultures, and human cholangiocyte cell lines (H69). Our results indicated that all CCAs emerging in PSC patients were mucin\u2010producing tumors characterized by PBG involvement and a high expression of stem\/progenitor cell markers. Ducts with neoplastic lesions showed higher inflammation, wall thickness, and PBG activation compared to nonneoplastic PSC\u2010affected ducts. CCA showed higher microvascular density and higher expression of nuclear factor kappa B, interleukin\u20106, interleukin\u20108, transforming growth factor \u03b2, and vascular endothelial growth factor\u20101 compared to nonneoplastic ducts. CCA cells were characterized by a higher expression of epithelial\u2010to\u2010mesenchymal transition (EMT) traits and by the absence of primary cilia compared to bile ducts and PBG cells in controls and patients with PSC. Our <jats:italic toggle=\"yes\">in vitro<\/jats:italic> study demonstrated that lipopolysaccharide and oxysterols (PSC\u2010related stressors) induced the expression of EMT traits, the nuclear factor kappa B pathway, autophagy, and the loss of primary cilia in human BTSCs. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: CCA arising in patients with PSC is characterized by extensive PBG involvement and by activation of the BTSC niche in these patients, the presence of duct lesions at different stages suggests a progressive tumorigenesis.<\/jats:p>","DOI":"10.1002\/hep.30210","type":"journal-article","created":{"date-parts":[[2018,8,13]],"date-time":"2018-08-13T20:08:43Z","timestamp":1534190923000},"page":"622-638","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":60,"title":["Neoplastic Transformation of the Peribiliary Stem Cell Niche in Cholangiocarcinoma Arisen in Primary Sclerosing Cholangitis"],"prefix":"10.1097","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8570-2519","authenticated-orcid":false,"given":"Guido","family":"Carpino","sequence":"first","affiliation":[{"name":"Department of Movement, Human and Health Sciences, Division of Health Sciences,University of Rome \"Foro Italico\",Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Cardinale","sequence":"additional","affiliation":[{"name":"Department of Medico\u2010Surgical Sciences and Biotechnologies,Sapienza University of Rome,Latina,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trine","family":"Folseraas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3561-8903","authenticated-orcid":false,"given":"Diletta","family":"Overi","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Grzyb","sequence":"additional","affiliation":[{"name":"Department of Pathology,Oslo University Hospital,Oslo,Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7438-4578","authenticated-orcid":false,"given":"Daniele","family":"Costantini","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialties,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale Bartolomeo","family":"Berloco","sequence":"additional","affiliation":[{"name":"Department of General Surgery and Organ Transplantation,Sapsienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Di Matteo","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialties,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom Hemming","family":"Karlsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Alvaro","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialties,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Gaudio","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,1,4]]},"reference":[{"key":"hep30210-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrgastro.2016.51","article-title":"Expert consensus document: cholangiocarcinoma: current 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