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Molecular and Cellular Interactions in Biliary Tree Development, Diseases and Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 August 2018) | Viewed by 66446

Special Issue Editors

1. Department of Molecular Medicine (DMM), University of Padua School of Medicine, Viale G. Colombo, 3, 35131 Padua, Italy
2. Section of Digestive Diseases, Yale Liver Center (YLC), Yale University, 300 Cedar Street, New Haven, CT 06520, USA
Interests: biliary disease pathophysiology; epithelial-mesenchymal interactions; liver repair; tumor microenvironment
Section of Digestive Diseases, Yale Liver Center (YLC), Yale University, 300 Cedar Street, New Haven, CT 06520, USA
Clinic of Gastroenterology and Hepatology, University-Hospital of Zurich, Rämistrasse 100, 8091 Zürich, Switzerland

Special Issue Information

Dear Colleagues,

Primary diseases of the biliary epithelium (i.e., cholangiopathies) are a heterogeneous group of chronic liver diseases frequently affecting children or young adult individuals. Cholangiopathies are characterized by bile duct damage evolving into ductopenia, with progressive cholestasis and portal fibrosis. Although actively investigated since the early 1990s, most of them still lack effective therapies. Treatment for cholangiopathies is limited to ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) in primary biliary cholangitis, and to liver transplantation in the most advanced diseases.

In cholangiopathies, the fundamental mechanism targeting the biliary epithelium is inflammation, often associated to peribiliary fibrogenesis that may progress to biliary cirrhosis and eventually malignant transformation. It is now recognized that inflammation is part of a highly-orchestrated process in which biliary epithelial cells (i.e., cholangiocytes), by reactivating a phenotype typically displayed during the embryonic development, establish with mesenchymal cells intimate contacts and mutually exchange a variety of signals. This Special Issue will highlight in both development and pathology conditions, the different settings featuring these cell interactions along with the multiple cell types involved and the paracrine signals mediating the cell communications. A range of primary cholangiopathies, from developmental (biliary atresia, congenital hepatic fibrosis, polycystic liver disease, cystic fibrosis, Alagille syndrome), to immune-mediated (primary biliary cirrhosis, primary sclerosing cholangitis) and malignant (cholangiocarcinoma) bear witness to the pathophysiological relevance of these cellular interactions.

The main goal of the studies that will be included in this Special Issue is to pinpoint the translational potential of this approach, and the identification of novel therapeutic targets to inhibit progression to cirrhosis and cancer.

Prof. Dr. Luca Fabris
Prof. Dr. Carlo Spirli
Prof. Dr. Joachim Mertens
Guest Editors

Manuscript Submission Information

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Keywords

  • Cholangiocytes
  • Myofibroblasts
  • Macrophages
  • Endothelial cells
  • Lymphocytes
  • NK cells
  • Hepatic progenitor cells
  • Ductular reaction
  • Chemokines
  • Cytokines
  • Growth factors
  • Morphogens
  • Primary biliary cholangitis
  • Primary sclerosing cholangitis
  • Biliary atresia
  • Cystic Fibrosis
  • Fibropolycystic liver disease
  • Cholangiocarcinoma

Published Papers (12 papers)

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Editorial

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5 pages, 175 KiB  
Editorial
Cell Interactions in Biliary Diseases: Clues from Pathophysiology and Repair Mechanisms to Foster Early Assessment
by Luca Fabris, Carlo Spirli and Joachim Mertens
Int. J. Mol. Sci. 2019, 20(16), 3961; https://doi.org/10.3390/ijms20163961 - 14 Aug 2019
Viewed by 1806
Abstract
In modern hepatology, diseases of the biliary epithelium, currently termed cholangiopathies, represent one of the main gaps in knowledge, both on experimental and clinical grounds, though they started to draw attention since the late 80s [...] Full article

Research

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20 pages, 6890 KiB  
Article
YAP Activation Drives Liver Regeneration after Cholestatic Damage Induced by Rbpj Deletion
by Umesh Tharehalli, Michael Svinarenko, Johann M. Kraus, Silke D. Kühlwein, Robin Szekely, Ute Kiesle, Annika Scheffold, Thomas F.E. Barth, Alexander Kleger, Reinhold Schirmbeck, Hans A. Kestler, Thomas Seufferlein, Franz Oswald, Sarah-Fee Katz and André Lechel
Int. J. Mol. Sci. 2018, 19(12), 3801; https://doi.org/10.3390/ijms19123801 - 29 Nov 2018
Cited by 20 | Viewed by 6607
Abstract
Liver cholestasis is a chronic liver disease and a major health problem worldwide. Cholestasis is characterised by a decrease in bile flow due to impaired secretion by hepatocytes or by obstruction of bile flow through intra- or extrahepatic bile ducts. Thereby cholestasis can [...] Read more.
Liver cholestasis is a chronic liver disease and a major health problem worldwide. Cholestasis is characterised by a decrease in bile flow due to impaired secretion by hepatocytes or by obstruction of bile flow through intra- or extrahepatic bile ducts. Thereby cholestasis can induce ductal proliferation, hepatocyte injury and liver fibrosis. Notch signalling promotes the formation and maturation of bile duct structures. Here we investigated the liver regeneration process in the context of cholestasis induced by disruption of the Notch signalling pathway. Liver-specific deletion of recombination signal binding protein for immunoglobulin kappa j region (Rbpj), which represents a key regulator of Notch signalling, induces severe cholestasis through impaired intra-hepatic bile duct (IHBD) maturation, severe necrosis and increased lethality. Deregulation of the biliary compartment and cholestasis are associated with the change of several signalling pathways including a Kyoto Encyclopedia of Genes and Genomes (KEGG) gene set representing the Hippo pathway, further yes-associated protein (YAP) activation and upregulation of SRY (sex determining region Y)-box 9 (SOX9), which is associated with transdifferentiation of hepatocytes. SOX9 upregulation in cholestatic liver injury in vitro is independent of Notch signalling. We could comprehensively address that in vivo Rbpj depletion is followed by YAP activation, which influences the transdifferentiation of hepatocytes and thereby contributing to liver regeneration. Full article
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19 pages, 4570 KiB  
Article
Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis
by Pamela S. Tietz-Bogert, Minsuk Kim, Angela Cheung, James H. Tabibian, Julie K. Heimbach, Charles B. Rosen, Madhumitha Nandakumar, Konstantinos N. Lazaridis, Nicholas F. LaRusso, Jaeyun Sung and Steven P. O’Hara
Int. J. Mol. Sci. 2018, 19(10), 3188; https://doi.org/10.3390/ijms19103188 - 16 Oct 2018
Cited by 26 | Viewed by 7278
Abstract
Primary sclerosing cholangitis (PSC) is a pathogenically complex, chronic, fibroinflammatory disorder of the bile ducts without known etiology or effective pharmacotherapy. Emerging in vitro and in vivo evidence support fundamental pathophysiologic mechanisms in PSC centered on enterohepatic circulation. To date, no studies have [...] Read more.
Primary sclerosing cholangitis (PSC) is a pathogenically complex, chronic, fibroinflammatory disorder of the bile ducts without known etiology or effective pharmacotherapy. Emerging in vitro and in vivo evidence support fundamental pathophysiologic mechanisms in PSC centered on enterohepatic circulation. To date, no studies have specifically interrogated the chemical footprint of enterohepatic circulation in PSC. Herein, we evaluated the metabolome and lipidome of portal venous blood and bile obtained at the time of liver transplantation in patients with PSC (n = 7) as compared to individuals with noncholestatic, end-stage liver disease (viral, metabolic, etc. (disease control, DC, n = 19)) and to nondisease controls (NC, living donors, n = 12). Global metabolomic and lipidomic profiling was performed on serum derived from portal venous blood (portal serum) and bile using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and differential mobility spectroscopy-mass spectroscopy (DMS-MS; complex lipid platform). The Mann–Whitney U test was used to identify metabolites that significantly differed between groups. Principal-component analysis (PCA) showed significant separation of both PSC and DC from NC for both portal serum and bile. Metabolite set enrichment analysis of portal serum and bile demonstrated that the liver-disease cohorts (PSC and DC) exhibited similar enrichment in several metabolite categories compared to NC. Interestingly, the bile in PSC was uniquely enriched for dipeptide and polyamine metabolites. Finally, analysis of patient-matched portal serum and biliary metabolome revealed that these biological fluids were more homogeneous in PSC than in DC or NC, suggesting aberrant bile formation and enterohepatic circulation. In summary, PSC and DC patients exhibited alterations in several metabolites in portal serum and bile, while PSC patients exhibited a unique bile metabolome. These specific alterations in PSC are amenable to hypothesis testing and, potentially, therapeutic pharmacologic manipulation. Full article
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13 pages, 1785 KiB  
Article
Serum and Hepatic Autofluorescence as a Real-Time Diagnostic Tool for Early Cholestasis Assessment
by Anna C. Croce, Giovanni Bottiroli, Laura G. Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Mariapia Vairetti and Andrea Ferrigno
Int. J. Mol. Sci. 2018, 19(9), 2634; https://doi.org/10.3390/ijms19092634 - 05 Sep 2018
Cited by 4 | Viewed by 3160
Abstract
While it is well established that various factors can impair the production and flow of bile and lead to cholestatic disease in hepatic and extrahepatic sites, an enhanced assessment of the biomarkers of the underlying pathophysiological mechanisms is still needed to improve early [...] Read more.
While it is well established that various factors can impair the production and flow of bile and lead to cholestatic disease in hepatic and extrahepatic sites, an enhanced assessment of the biomarkers of the underlying pathophysiological mechanisms is still needed to improve early diagnosis and therapeutic strategies. Hence, we investigated fluorescing endogenous biomolecules as possible intrinsic biomarkers of molecular and cellular changes in cholestasis. Spectroscopic autofluorescence (AF) analysis was performed using a fiber optic probe (366 nm excitation), under living conditions and in serum, on the livers of male Wistar rats submitted to bile duct ligation (BDL, 24, 48, and 72 h). Biomarkers of liver injury were assayed biochemically. In the serum, AF analysis distinctly detected increased bilirubin at 24 h BDL. A continuous, significant increase in red-fluorescing porphyrin derivatives indicated the subversion of heme metabolism, consistent with an almost twofold increase in the serum iron at 72 h BDL. In the liver, changes in the AF of NAD(P)H and flavins, as well as lipopigments, indicated the impairment of mitochondrial functionality, oxidative stress, and the accumulation of oxidative products. A serum/hepatic AF profile can be thus proposed as a supportive diagnostic tool for the in situ, real-time study of bio-metabolic alterations in bile duct ligation (BDL) in experimental hepatology, with the potential to eventually translate to clinical diagnosis. Full article
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10 pages, 12438 KiB  
Communication
Microsatellite Instability Occurs Rarely in Patients with Cholangiocarcinoma: A Retrospective Study from a German Tertiary Care Hospital
by Ria Winkelmann, Markus Schneider, Sylvia Hartmann, Andreas A. Schnitzbauer, Stefan Zeuzem, Jan Peveling-Oberhag, Martin Leo Hansmann and Dirk Walter
Int. J. Mol. Sci. 2018, 19(5), 1421; https://doi.org/10.3390/ijms19051421 - 09 May 2018
Cited by 45 | Viewed by 4015
Abstract
Immune-modulating therapy is a promising therapy for patients with cholangiocarcinoma (CCA). Microsatellite instability (MSI) might be a favorable predictor for treatment response, but comprehensive data on the prevalence of MSI in CCA are missing. The aim of the current study was to determine [...] Read more.
Immune-modulating therapy is a promising therapy for patients with cholangiocarcinoma (CCA). Microsatellite instability (MSI) might be a favorable predictor for treatment response, but comprehensive data on the prevalence of MSI in CCA are missing. The aim of the current study was to determine the prevalence of MSI in a German tertiary care hospital. Formalin-fixed paraffin-embedded tissue samples, obtained in the study period from 2007 to 2015 from patients with CCA undergoing surgical resection with curative intention at Johann Wolfgang Goethe University hospital, were examined. All samples were investigated immunohistochemically for the presence of MSI (expression of MLH1, PMS2, MSH2, and MSH6) as well as by pentaplex polymerase chain reaction for five quasimonomorphic mononucleotide repeats (BAT-25, BAT-26, NR-21, NR-22, and NR-24). In total, 102 patients were included, presenting intrahepatic (n = 35, 34.3%), perihilar (n = 42, 41.2%), and distal CCA (n = 25, 24.5%). In the immunohistochemical analysis, no loss of expression of DNA repair enzymes was observed. In the PCR-based analysis, one out of 102 patients was found to be MSI-high and one out of 102 was found to be MSI-low. Thus, MSI seems to appear rarely in CCA in Germany. This should be considered when planning immune-modulating therapy trials for patients with CCA. Full article
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Review

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11 pages, 533 KiB  
Review
Calcium Signaling in Cholangiocytes: Methods, Mechanisms, and Effects
by Michele Angela Rodrigues, Dawidson Assis Gomes and Michael Harris Nathanson
Int. J. Mol. Sci. 2018, 19(12), 3913; https://doi.org/10.3390/ijms19123913 - 06 Dec 2018
Cited by 13 | Viewed by 6171
Abstract
Calcium (Ca2+) is a versatile second messenger that regulates a number of cellular processes in virtually every type of cell. The inositol 1,4,5-trisphosphate receptor (ITPR) is the only intracellular Ca2+ release channel in cholangiocytes, and is therefore responsible for Ca [...] Read more.
Calcium (Ca2+) is a versatile second messenger that regulates a number of cellular processes in virtually every type of cell. The inositol 1,4,5-trisphosphate receptor (ITPR) is the only intracellular Ca2+ release channel in cholangiocytes, and is therefore responsible for Ca2+-mediated processes in these cells. This review will discuss the machinery responsible for Ca2+ signals in these cells, as well as experimental models used to investigate cholangiocyte Ca2+ signaling. We will also discuss the role of Ca2+ in the normal and abnormal regulation of secretion and apoptosis in cholangiocytes, two of the best characterized processes mediated by Ca2+ in this cell type. Full article
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22 pages, 965 KiB  
Review
Fibroinflammatory Liver Injuries as Preneoplastic Condition in Cholangiopathies
by Stefania Cannito, Chiara Milani, Andrea Cappon, Maurizio Parola, Mario Strazzabosco and Massimiliano Cadamuro
Int. J. Mol. Sci. 2018, 19(12), 3875; https://doi.org/10.3390/ijms19123875 - 04 Dec 2018
Cited by 21 | Viewed by 4115
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 [...] Read more.
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. Full article
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15 pages, 5107 KiB  
Review
Impact of Machine Perfusion on Biliary Complications after Liver Transplantation
by Andrea Schlegel and Philipp Dutkowski
Int. J. Mol. Sci. 2018, 19(11), 3567; https://doi.org/10.3390/ijms19113567 - 12 Nov 2018
Cited by 26 | Viewed by 7642
Abstract
We describe in this review the different types of injuries caused to the biliary tree after liver transplantation. Furthermore, we explain underlying mechanisms and why oxygenated perfusion concepts could not only protect livers, but also repair high-risk grafts to prevent severe biliary complications [...] Read more.
We describe in this review the different types of injuries caused to the biliary tree after liver transplantation. Furthermore, we explain underlying mechanisms and why oxygenated perfusion concepts could not only protect livers, but also repair high-risk grafts to prevent severe biliary complications and graft loss. Accordingly, we summarize experimental studies and clinical applications of machine liver perfusion with a focus on biliary complications after liver transplantation. Key points: (1) Acute inflammation with subsequent chronic ongoing liver inflammation and injury are the main triggers for cholangiocyte injury and biliary tree transformation, including non-anastomotic strictures; (2) Hypothermic oxygenated perfusion (HOPE) protects livers from initial oxidative injury at normothermic reperfusion after liver transplantation. This is a unique feature of a cold oxygenation approach, which is effective also end-ischemically, e.g., after cold storage, due to mitochondrial repair mechanisms. In contrast, normothermic oxygenated perfusion concepts protect by reducing cold ischemia, and are therefore most beneficial when applied instead of cold storage; (3) Due to less downstream activation of cholangiocytes, hypothermic oxygenated perfusion also significantly reduces the development of biliary strictures after liver transplantation. Full article
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18 pages, 1686 KiB  
Review
Inflammation and the Gut-Liver Axis in the Pathophysiology of Cholangiopathies
by Debora Maria Giordano, Claudio Pinto, Luca Maroni, Antonio Benedetti and Marco Marzioni
Int. J. Mol. Sci. 2018, 19(10), 3003; https://doi.org/10.3390/ijms19103003 - 01 Oct 2018
Cited by 30 | Viewed by 6111
Abstract
Cholangiocytes, the epithelial cells lining the bile ducts, represent the unique target of a group of progressive diseases known as cholangiopathies whose pathogenesis remain largely unknown. In normal conditions, cholangiocytes are quiescent and participate to the final bile volume and composition. Following exogenous [...] Read more.
Cholangiocytes, the epithelial cells lining the bile ducts, represent the unique target of a group of progressive diseases known as cholangiopathies whose pathogenesis remain largely unknown. In normal conditions, cholangiocytes are quiescent and participate to the final bile volume and composition. Following exogenous or endogenous stimuli, cholangiocytes undergo extensive modifications of their phenotype. Reactive cholangiocytes actively proliferate and release a set of proinflammatory molecules, which act in autocrine/paracrine manner mediating the cross-talk with other liver cell types and innate and adaptive immune cells. Cholangiocytes themselves activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Gut microbiota has been implicated in the development and progression of the two most common cholangiopathies, i.e., primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), which have distinctive microbiota composition compared to healthy individuals. The impairment of intestinal barrier functions or gut dysbiosis expose cholangiocytes to an increasing amount of microorganisms and may exacerbate inflammatory responses thus leading to fibrotic remodeling of the organ. The present review focuses on the complex interactions between the activation of innate immune responses in reactive cholangiocytes, dysbiosis, and gut permeability to bacterial products in the pathogenesis of PSC and PBC. Full article
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16 pages, 1999 KiB  
Review
Contribution of Resident Stem Cells to Liver and Biliary Tree Regeneration in Human Diseases
by Diletta Overi, Guido Carpino, Vincenzo Cardinale, Antonio Franchitto, Samira Safarikia, Paolo Onori, Domenico Alvaro and Eugenio Gaudio
Int. J. Mol. Sci. 2018, 19(10), 2917; https://doi.org/10.3390/ijms19102917 - 25 Sep 2018
Cited by 32 | Viewed by 7719
Abstract
Two distinct stem/progenitor cell populations of biliary origin have been identified in the adult liver and biliary tree. Hepatic Stem/progenitor Cells (HpSCs) are bipotent progenitor cells located within the canals of Hering and can be differentiated into mature hepatocytes and cholangiocytes; Biliary Tree [...] Read more.
Two distinct stem/progenitor cell populations of biliary origin have been identified in the adult liver and biliary tree. Hepatic Stem/progenitor Cells (HpSCs) are bipotent progenitor cells located within the canals of Hering and can be differentiated into mature hepatocytes and cholangiocytes; Biliary Tree Stem/progenitor Cells (BTSCs) are multipotent stem cells located within the peribiliary glands of large intrahepatic and extrahepatic bile ducts and able to differentiate into hepatic and pancreatic lineages. HpSCs and BTSCs are endowed in a specialized niche constituted by supporting cells and extracellular matrix compounds. The actual contribution of these stem cell niches to liver and biliary tree homeostatic regeneration is marginal; this is due to the high replicative capabilities and plasticity of mature parenchymal cells (i.e., hepatocytes and cholangiocytes). However, the study of human liver and biliary diseases disclosed how these stem cell niches are involved in the regenerative response after extensive and/or chronic injuries, with the activation of specific signaling pathways. The present review summarizes the contribution of stem/progenitor cell niches in human liver diseases, underlining mechanisms of activation and clinical implications, including fibrogenesis and disease progression. Full article
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16 pages, 576 KiB  
Review
The Role of Stroma in Cholangiocarcinoma: The Intriguing Interplay between Fibroblastic Component, Immune Cell Subsets and Tumor Epithelium
by Alessandra Gentilini, Mirella Pastore, Fabio Marra and Chiara Raggi
Int. J. Mol. Sci. 2018, 19(10), 2885; https://doi.org/10.3390/ijms19102885 - 22 Sep 2018
Cited by 53 | Viewed by 5248
Abstract
Cholangiocarcinoma (CCA) is a severe and mostly intractable adenocarcinoma of biliary epithelial cells. A typical feature of CCA is its highly desmoplastic microenvironment containing fibrogenic connective tissue and an abundance of immune cells (T lymphocytes, Natural Killer (NK) cells, and macrophages) infiltrating tumor [...] Read more.
Cholangiocarcinoma (CCA) is a severe and mostly intractable adenocarcinoma of biliary epithelial cells. A typical feature of CCA is its highly desmoplastic microenvironment containing fibrogenic connective tissue and an abundance of immune cells (T lymphocytes, Natural Killer (NK) cells, and macrophages) infiltrating tumor epithelium. This strong desmoplasia is orchestrated by various soluble factors and signals, suggesting a critical role in shaping a tumor growth-permissive microenvironment that is responsible for CCA poor clinical outcome. Indeed stroma not only provides an abundance of factors that facilitate CCA initiation, growth and progression, but also a prejudicial impact on therapeutic outcome. This review will give an overview of tumor-stroma signaling in a microenvironment critically regulating CCA development and progression. Identification of CCA secreted factors by both the fibroblast component and immune cell subsets might provide ample opportunities for pharmacological targeting of this type of cancer. Full article
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16 pages, 1361 KiB  
Review
Peribiliary Glands as the Cellular Origin of Biliary Tract Cancer
by Hayato Nakagawa, Yuki Hayata, Tomoharu Yamada, Satoshi Kawamura, Nobumi Suzuki and Kazuhiko Koike
Int. J. Mol. Sci. 2018, 19(6), 1745; https://doi.org/10.3390/ijms19061745 - 12 Jun 2018
Cited by 16 | Viewed by 5591
Abstract
The identification of the cellular origin of cancer is important for our understanding of the mechanisms regulating carcinogenesis, thus the cellular origin of cholangiocarcinoma (CCA) is a current topic of interest. Although CCA has been considered to originate from biliary epithelial cells, recent [...] Read more.
The identification of the cellular origin of cancer is important for our understanding of the mechanisms regulating carcinogenesis, thus the cellular origin of cholangiocarcinoma (CCA) is a current topic of interest. Although CCA has been considered to originate from biliary epithelial cells, recent studies have suggested that multiple cell types can develop into CCA. With regard to the hilar and extrahepatic bile ducts, peribiliary glands (PBGs), a potential stem cell niche of biliary epithelial cells, have attracted attention as the cellular origin of biliary tract cancer. Recent histopathological and experimental studies have suggested that some kinds of inflammation-induced CCA and intraductal papillary neoplasms of the bile duct are more likely to originate from PBGs. During inflammation-mediated cholangiocarcinogenesis, the biliary epithelial injury-induced regenerative response by PBGs is considered a key process. Thus, in this review, we discuss recent advances in our understanding of cholangiocarcinogenesis from the viewpoint of inflammation and the cellular origin of CCA, especially focusing on PBGs. Full article
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