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

Carpino, Guido; Cardinale, Vincenzo; Folseraas, Trine; Overi, Diletta; Grzyb, Krzysztof; Costantini, D.; Berloco, P.B.; Matteo, Sabina Di; Karlsen, Tom H.; Alvaro, Domenico; Gaudio, Eugenio

doi:10.1002/hep.30210

Cited by 53 publications

(71 citation statements)

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“…PBGs can produce Notch ligands themselves, thus suggesting an autocrine effect and a further paracrine effect on neighboring (myo‐)fibroblasts. Interestingly, previous evidence indicated that, in human biliary disease, PBGs can secrete vascular endothelial growth factors (VEGFs), influencing the modification of peribiliary vascular plexus in PSC and hypoxic conditions . Taken together with previous studies, our results indicate that the activation of PBG niche represents a consequence of toxic or inflammatory biliary damage (Fig.…”

Section: Discussionsupporting

confidence: 84%

“…Interestingly, PBGs are also involved in the pathogenesis of biliary strictures in patients with PSC; in this disease, chronic biliary inflammation stimulates PBG stem cell niche with subsequent myofibroblast activation, leading to biliary fibrosis and strictures. Furthermore, PBG stem cell niche gives rise to a secondary regenerative response, leading to biliary carcinogenesis in human patients with PSC and in experimental genetically induced biliary injury . Generally, the emerging concept is that PBG stem cell niche can be activated in the context of pathologies affecting larger IHBDs and EHBDs, despite the well‐recognized proliferative capability of mature cholangiocytes .…”

Section: Discussionmentioning

confidence: 99%

“…The in vitro effects of signaling pathways on hBTSC were evaluated by supplementing the KM with specific Notch and Wnt activators and inhibitors. The following conditions have been tested: Notch pathway‐stimulation medium (Notch‐M) Wnt pathway‐stimulation medium (Wnt‐M) Wnt‐M plus Wnt inhibitor (Wnt‐M+Block) KM supplemented with lipopolysaccharides (LPS) …”

Section: Methodsmentioning

confidence: 99%

“…The exact composition of analyzed conditions is provided in the Supporting Information. Cell proliferation was assessed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2 H ‐tetrazolium (MTS) assay, DNA Quantification (see the Supporting Information), and population doubling time (PDT) . Cell migration has been assessed by a scratch test …”

Section: Methodsmentioning

confidence: 99%

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Peribiliary Gland Niche Participates in Biliary Tree Regeneration in Mouse and in Human Primary Sclerosing Cholangitis

et al. 2019

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Background and Aims Mechanisms underlying the repair of extrahepatic biliary tree (EHBT) after injury have been scarcely explored. The aims of this study were to evaluate, by using a lineage tracing approach, the contribution of peribiliary gland (PBG) niche in the regeneration of EHBT after damage and to evaluate, in vivo and in vitro, the signaling pathways involved. Approach and Results Bile duct injury was induced by the administration of 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) diet for 14 days to Krt19CreTdTomatoLSL mice. Human biliary tree stem/progenitor cells (BTSC) within PBGs were isolated from EHBT obtained from liver donors. Hepatic duct samples (n = 10) were obtained from patients affected by primary sclerosing cholangitis (PSC). Samples were analyzed by histology, immunohistochemistry, western blotting, and polymerase chain reaction. DDC administration causes hyperplasia of PBGs and periductal fibrosis in EHBT. A PBG cell population (Cytokeratin19‐/SOX9+) is involved in the renewal of surface epithelium in injured EHBT. The Wnt signaling pathway triggers human BTSC proliferation in vitro and influences PBG hyperplasia in vivo in the DDC‐mediated mouse biliary injury model. The Notch signaling pathway activation induces BTSC differentiation in vitro toward mature cholangiocytes and is associated with PBG activation in the DDC model. In human PSC, inflammatory and stromal cells trigger PBG activation through the up‐regulation of the Wnt and Notch signaling pathways. Conclusions We demonstrated the involvement of PBG cells in regenerating the injured biliary epithelium and identified the signaling pathways driving BTSC activation. These results could have relevant implications on the pathophysiology and treatment of cholangiopathies.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Peribiliary Gland Niche Participates in Biliary Tree Regeneration in Mouse and in Human Primary Sclerosing Cholangitis

et al. 2019

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“…In diabetes, biliary tree stem/progenitor cell (BTSC) activation in humans and mice has also been observed . PSC represents a human model of biliary carcinogenesis . PBG cell proliferation, mucinous metaplasia and dysplasia to cancer progression take place within bile ducts and along the biliary tree in PSC, mimicking the cancerization field (“field defect”) described in ulcerative colitis .…”

Section: Cells Of Origin Cancer Stem Cells and Models Of Carcinogenesismentioning

confidence: 98%

Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma

Vicent

Lieshout

Verstegen

et al. 2019

Liver International

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Human cholangiocarcinoma (CCA) is an aggressive tumour entity arising from the biliary tree, whose molecular pathogenesis remains largely undeciphered. Over the last decade, the advent of high‐throughput and cell‐based techniques has significantly increased our knowledge on the molecular mechanisms underlying this disease while, at the same time, unravelling CCA complexity. In particular, it becomes clear that CCA displays pronounced inter‐ and intratumoural heterogeneity, which is presumably the consequence of the interplay between distinct tissues and cells of origin, the underlying diseases, and the associated molecular alterations. To better characterize these events and to design novel and more effective therapeutic strategies, a number of CCA experimental and preclinical models have been developed and are currently generated. This review summarizes the current knowledge and understanding of these models, critically underlining their translational usefulness and limitations. Furthermore, this review aims to provide a comprehensive overview on cells of origin, cancers stem cells and their dynamic interplay within CCA tissue.

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Integrative Analysis Defines Distinct Prognostic Subgroups of Intrahepatic Cholangiocarcinoma

et al. 2019

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Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer. It is defined by cholangiocytic differentiation and has poor prognosis. Recently, epigenetic processes have been shown to play an important role in cholangiocarcinogenesis. We performed an integrative analysis on 52 iCCAs using both genetic and epigenetic data with a specific focus on DNA methylation components. We found recurrent isocitrate dehydrogenase 1 (IDH1) and IDH2 (28%) gene mutations, recurrent arm‐length copy number alterations (CNAs), and focal alterations such as deletion of 3p21 or amplification of 12q15, which affect BRCA1 Associated Protein 1, polybromo 1, and mouse double minute 2 homolog. DNA methylome analysis revealed excessive hypermethylation of iCCA, affecting primarily the bivalent genomic regions marked with both active and repressive histone modifications. Integrative clustering of genetic and epigenetic data identified four iCCA subgroups with prognostic relevance further designated as IDH, high (H), medium (M), and low (L) alteration groups. The IDH group consisted of all samples with IDH1 or IDH2 mutations and showed, together with the H group, a highly disrupted genome, characterized by frequent deletions of chromosome arms 3p and 6q. Both groups showed excessive hypermethylation with distinct patterns. The M group showed intermediate characteristics regarding both genetic and epigenetic marks, whereas the L group exhibited few methylation changes and mutations and a lack of CNAs. Methylation‐based latent component analysis of cell‐type composition identified differences among these four groups. Prognosis of the H and M groups was significantly worse than that of the L group. Conclusion: Using an integrative genomic and epigenomic analysis approach, we identified four major iCCA subgroups with widespread genomic and epigenomic differences and prognostic implications. Furthermore, our data suggest differences in the cell‐of‐origin of the iCCA subtypes.

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

Abstract: CCA arising in PSC patients is characterized by extensive PBG involvement and by the activation of the BTSC niche. In these patients, the presence of duct lesions at different stages suggests a progressive tumorigenesis. This article is protected by copyright. All rights reserved.

Cited by 53 publications

References 39 publications

Peribiliary Gland Niche Participates in Biliary Tree Regeneration in Mouse and in Human Primary Sclerosing Cholangitis

Peribiliary Gland Niche Participates in Biliary Tree Regeneration in Mouse and in Human Primary Sclerosing Cholangitis

Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma

Integrative Analysis Defines Distinct Prognostic Subgroups of Intrahepatic Cholangiocarcinoma

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