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Fibroinflammatory Liver Injuries as Preneoplastic Condition in Cholangiopathies

1
Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Corso Raffaello 30, 10125 Torino, Italy
2
School of Medicine and Surgery, University of Milan-Bicocca, Via Cadore 48, 20900 Monza, Italy
3
Department of Medicine (DIMED), Internal Medicine and Hepatology Unit, University of Padova, Via Giustiniani 2, 35121 Padova, Italy
4
International Center for Digestive Health (ICDH), University of Milan-Bicocca, Via Cadore 48, 20900 Monza, Italy
5
Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
6
Department of Molecular Medicine (DMM), University of Padova, via Gabelli 63, 35121 Padova, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(12), 3875; https://doi.org/10.3390/ijms19123875
Received: 5 November 2018 / Revised: 29 November 2018 / Accepted: 1 December 2018 / Published: 4 December 2018
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Abstract

The cholangipathies are a class of liver diseases that specifically affects the biliary tree. These pathologies may have different etiologies (genetic, autoimmune, viral, or toxic) but all of them are characterized by a stark inflammatory infiltrate, increasing overtime, accompanied by an excess of periportal fibrosis. The cellular types that mount the regenerative/reparative hepatic response to the damage belong to different lineages, including cholagiocytes, mesenchymal and inflammatory cells, which dynamically interact with each other, exchanging different signals acting in autocrine and paracrine fashion. Those messengers may be proinflammatory cytokines and profibrotic chemokines (IL-1, and 6; CXCL1, 10 and 12, or MCP-1), morphogens (Notch, Hedgehog, and WNT/β-catenin signal pathways) and finally growth factors (VEGF, PDGF, and TGFβ, among others). In this review we will focus on the main molecular mechanisms mediating the establishment of a fibroinflammatory liver response that, if perpetuated, can lead not only to organ dysfunction but also to neoplastic transformation. Primary Sclerosing Cholangitis and Congenital Hepatic Fibrosis/Caroli’s disease, two chronic cholangiopathies, known to be prodrome of cholangiocarcinoma, for which several murine models are also available, were also used to further dissect the mechanisms of fibroinflammation leading to tumor development. View Full-Text
Keywords: cholangiocytes; neoplastic transformation; cholangiocarcinoma; primary sclerosing cholangitis; Caroli’s disease cholangiocytes; neoplastic transformation; cholangiocarcinoma; primary sclerosing cholangitis; Caroli’s disease
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Cannito, S.; Milani, C.; Cappon, A.; Parola, M.; Strazzabosco, M.; Cadamuro, M. Fibroinflammatory Liver Injuries as Preneoplastic Condition in Cholangiopathies. Int. J. Mol. Sci. 2018, 19, 3875.

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