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      Cholangiocarcinoma 2020: the next horizon in mechanisms and management

      review-article
      1 , 2 , 3 , , 2 , 4 , 5 , 6 , 1 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 1 , 2 , 14 , 15 , 16 , 2 , 4 , 17 , 18 , 19 , 14 , 15 , 20 , 21 , 22 , 23 , 24 , 25 , 25 , 8 , 26 , 27 , 2 , 28 , 2 , 28 , 29 , 5 , 6 , 8
      Nature Reviews. Gastroenterology & Hepatology
      Nature Publishing Group UK
      Biliary tract cancer, Cancer

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          Abstract

          Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.

          Abstract

          Cholangiocarcinoma (CCA) comprises heterogeneous biliary malignant tumours, and their incidence is increasing worldwide. This expert Consensus Statement, endorsed by the ENS-CCA, summarizes the latest advances in CCA, including classification, genetics and treatment, and provides recommendations for CCA management and priorities across basic, translational and clinical research.

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          Most cited references326

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          Epithelial-mesenchymal transitions in development and disease.

          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions.

            Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue's homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to "bad luck," that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes. Copyright © 2015, American Association for the Advancement of Science.
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              Human Primary Liver Cancer -derived Organoid Cultures for disease modelling and drug screening

              Human liver cancer research currently lacks in vitro models that faithfully recapitulate the pathophysiology of the original tumour. We recently described a novel, near-physiological organoid culture system, where primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here, we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumours. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumour, allowing discrimination between different tumour tissues and subtypes, even after long term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumourogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug screening testing and lead to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized medicine approaches for the disease.
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                Author and article information

                Contributors
                jesus.banales@biodonostia.org
                Journal
                Nat Rev Gastroenterol Hepatol
                Nat Rev Gastroenterol Hepatol
                Nature Reviews. Gastroenterology & Hepatology
                Nature Publishing Group UK (London )
                1759-5045
                1759-5053
                30 June 2020
                30 June 2020
                2020
                : 17
                : 9
                : 557-588
                Affiliations
                [1 ]GRID grid.11480.3c, ISNI 0000000121671098, Department of Liver and Gastrointestinal Diseases, , Biodonostia Health Research Institute – Donostia University Hospital, University of the Basque Country (UPV/EHU), ; San Sebastian, Spain
                [2 ]National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, “Instituto de Salud Carlos III”), San Sebastian, Spain
                [3 ]GRID grid.424810.b, ISNI 0000 0004 0467 2314, Ikerbasque, Basque Foundation for Science, ; Bilbao, Spain
                [4 ]GRID grid.11762.33, ISNI 0000 0001 2180 1817, Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, , University of Salamanca, ; Salamanca, Spain
                [5 ]GRID grid.412917.8, ISNI 0000 0004 0430 9259, Department of Medical Oncology, , The Christie NHS Foundation Trust, ; Manchester, UK
                [6 ]GRID grid.5379.8, ISNI 0000000121662407, Division of Cancer Sciences, , University of Manchester, ; Manchester, UK
                [7 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Department of Surgery and Cancer, , Imperial College London, Hammersmith Hospital, ; London, UK
                [8 ]Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN USA
                [9 ]GRID grid.7841.a, Department of Medico-Surgical Sciences and Biotechnologies, , Sapienza University of Rome, ; Rome, Italy
                [10 ]GRID grid.412756.3, ISNI 0000 0000 8580 6601, Department of Movement, Human and Health Sciences, Division of Health Sciences, , University of Rome “Foro Italico”, ; Rome, Italy
                [11 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, Denmark
                [12 ]GRID grid.8756.c, ISNI 0000 0001 2193 314X, Institute of Cancer Sciences, , University of Glasgow, ; Glasgow, UK
                [13 ]GRID grid.7727.5, ISNI 0000 0001 2190 5763, Institute of Pathology, University of Regensburg, ; Regensburg, Germany
                [14 ]GRID grid.5608.b, ISNI 0000 0004 1757 3470, Department of Molecular Medicine, , University of Padua School of Medicine, ; Padua, Italy
                [15 ]GRID grid.47100.32, ISNI 0000000419368710, Digestive Disease Section, , Yale University School of Medicine, ; New Haven, CT USA
                [16 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, MRC-Human Genetics Unit, Institute of Genetics and Molecular Medicine, , University of Edinburgh, ; Edinburgh, UK
                [17 ]GRID grid.7841.a, Division of Human Anatomy, Department of Anatomical, , Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, ; Rome, Italy
                [18 ]GRID grid.7841.a, Department of Medicine and Medical Specialties, , Sapienza University of Rome, ; Rome, Italy
                [19 ]GRID grid.17635.36, ISNI 0000000419368657, The Hormel Institute, , University of Minnesota, ; Austin, MN USA
                [20 ]GRID grid.7010.6, ISNI 0000 0001 1017 3210, Clinic of Gastroenterology and Hepatology, , Universita Politecnica delle Marche, ; Ancona, Italy
                [21 ]GRID grid.410368.8, ISNI 0000 0001 2191 9284, INSERM, Université de Rennes, ; Rennes, France
                [22 ]GRID grid.7429.8, ISNI 0000000121866389, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), ; Paris, France
                [23 ]GRID grid.8404.8, ISNI 0000 0004 1757 2304, Department of Experimental and Clinical Medicine, , University of Florence, ; Florence, Italy
                [24 ]GRID grid.4708.b, ISNI 0000 0004 1757 2822, Division of Gastroenterology and Center of Autoimmune Liver Diseases, Department of Medicine and Surgery, San Gerardo Hospital, , University of Milano, ; Bicocca, Italy
                [25 ]GRID grid.412004.3, ISNI 0000 0004 0478 9977, Department of Gastroenterology and Hepatology, , University Hospital Zurich and University of Zurich, ; Zürich, Switzerland
                [26 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Department of Surgery, , Mayo Clinic, ; Rochester, MN USA
                [27 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Surgery, , Erasmus Medical Center, ; Rotterdam, Netherlands
                [28 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, , University of Barcelona, ; Barcelona, Spain
                [29 ]GRID grid.83440.3b, ISNI 0000000121901201, Department of Medical Oncology, , UCL Cancer Institute, ; London, UK
                Author information
                http://orcid.org/0000-0002-5224-2373
                http://orcid.org/0000-0003-1186-6849
                http://orcid.org/0000-0001-9696-6122
                http://orcid.org/0000-0001-6193-7436
                http://orcid.org/0000-0001-7885-8574
                http://orcid.org/0000-0001-8570-2519
                http://orcid.org/0000-0003-1760-5244
                http://orcid.org/0000-0003-4835-1259
                http://orcid.org/0000-0001-8538-6317
                http://orcid.org/0000-0002-7954-6705
                http://orcid.org/0000-0002-4748-0326
                http://orcid.org/0000-0002-1995-6331
                http://orcid.org/0000-0001-6377-5610
                http://orcid.org/0000-0003-3262-1998
                http://orcid.org/0000-0003-1917-6973
                http://orcid.org/0000-0002-9014-4950
                http://orcid.org/0000-0001-9186-1604
                http://orcid.org/0000-0002-1999-0863
                http://orcid.org/0000-0003-3151-009X
                Article
                310
                10.1038/s41575-020-0310-z
                7447603
                32606456
                ab14ea9c-bddb-412a-994e-3ee208a962ab
                © The author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 29 April 2020
                Categories
                Consensus Statement
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                © Springer Nature Limited 2020

                biliary tract cancer,cancer
                biliary tract cancer, cancer

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