Neoplastic transformation of peribiliary stem cell niche in cholangiocarcinoma arisen in primary sclerosing cholangitis.

Carpino G , Cardinale V , Folseraas T , Overi D , Grzyb K , Costantini D , Berloco PB , Di Matteo S , Karlsen TH , Alvaro D , Gaudio E
Hepatology (Baltimore, Md.)
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-associated CCA (N=20) were included. Samples were processed for histology, immunohistochemistry and immunofluorescence. In vitro 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-producing 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 non-neoplastic PSC-affected ducts. CCA showed higher microvascular density and higher expressions of nuclear factor-κB, interleukin-6, interleukin-8, transforming growth factor β, and vascular endothelial growth factor-1, compared to non-neoplastic ducts. CCA cells were characterized by a higher expression of epithelial-to-mesenchymal transition (EMT) traits and by the absence of primary cilia compared to bile ducts and PBG cells in controls and PSC. Our in vitro study demonstrated that lipopolysaccharide and oxysterols (PSC-related stressors) induced the expression of EMT traits, nuclear factor-κB pathway, autophagy, and the loss of primary cilia in human BTSCs.

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