{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T15:40:40Z","timestamp":1790005240754,"version":"4.0.1"},"reference-count":97,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T00:00:00Z","timestamp":1594771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cholangiocarcinoma (CCA) comprises a heterogeneous group of primary liver tumors. They emerge from different hepatic (progenitor) cell populations, typically via sporadic mutations. Chronic biliary inflammation, as seen in primary sclerosing cholangitis (PSC), may trigger CCA development. Although several efforts were made in the last decade to better understand the complex processes of biliary carcinogenesis, it was only recently that new therapeutic advances have been achieved. Animal models are a crucial bridge between in vitro findings on molecular or genetic alterations, pathophysiological understanding, and new therapeutic strategies for the clinic. Nevertheless, it is inherently difficult to recapitulate simultaneously the stromal microenvironment (e.g., immune-competent cells, cholestasis, inflammation, PSC-like changes, fibrosis) and the tumor biology (e.g., mutational burden, local growth, and metastatic spread) in an animal model, so that it would reflect the full clinical reality of CCA. In this review, we highlight available data on animal models for CCA. We discuss if and how these models reflect human disease and whether they can serve as a tool for understanding the pathogenesis, or for predicting a treatment response in patients. In addition, open issues for future developments will be discussed.<\/jats:p>","DOI":"10.3390\/ijms21144993","type":"journal-article","created":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T10:35:18Z","timestamp":1594809318000},"page":"4993","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["In Vivo Models for Cholangiocarcinoma\u2014What Can We Learn for Human Disease?"],"prefix":"10.3390","volume":"21","author":[{"given":"Raphael","family":"Mohr","sequence":"first","affiliation":[{"name":"Department of Hepatology &amp; Gastroenterology, Campus Virchow Klinikum and Campus Charit\u00e9 Mitte, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8885-737X","authenticated-orcid":false,"given":"Burcin","family":"\u00d6zdirik","sequence":"additional","affiliation":[{"name":"Department of Hepatology &amp; Gastroenterology, Campus Virchow Klinikum and Campus Charit\u00e9 Mitte, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Knorr","sequence":"additional","affiliation":[{"name":"Department of Hepatology &amp; Gastroenterology, Campus Virchow Klinikum and Campus Charit\u00e9 Mitte, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3426-5421","authenticated-orcid":false,"given":"Alexander","family":"Wree","sequence":"additional","affiliation":[{"name":"Department of Hepatology &amp; Gastroenterology, Campus Virchow Klinikum and Campus Charit\u00e9 Mitte, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00fcnevver","family":"Demir","sequence":"additional","affiliation":[{"name":"Department of Hepatology &amp; Gastroenterology, Campus Virchow Klinikum and Campus Charit\u00e9 Mitte, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6206-0226","authenticated-orcid":false,"given":"Frank","family":"Tacke","sequence":"additional","affiliation":[{"name":"Department of Hepatology &amp; Gastroenterology, Campus Virchow Klinikum and Campus Charit\u00e9 Mitte, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Roderburg","sequence":"additional","affiliation":[{"name":"Department of Hepatology &amp; Gastroenterology, Campus Virchow Klinikum and Campus Charit\u00e9 Mitte, Charit\u00e9 University Medicine Berlin, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1053\/j.gastro.2013.10.013","article-title":"Pathogenesis, diagnosis, and management of cholangiocarcinoma","volume":"145","author":"Rizvi","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.21037\/cco.2016.10.09","article-title":"Biliary tract cancers: Epidemiology, molecular pathogenesis and genetic risk associations","volume":"5","author":"Mohamed","year":"2016","journal-title":"Chin. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1111\/liv.13954","article-title":"Cholangiocarcinoma in Germany: Epidemiologic trends and impact of misclassification","volume":"39","author":"Walter","year":"2019","journal-title":"Liver Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.3109\/00365521.2011.589472","article-title":"Epidemiological trends in incidence and mortality of hepatobiliary cancers in Germany","volume":"46","author":"Ciesek","year":"2011","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.jhep.2019.11.020","article-title":"Liver resection and transplantation for intrahepatic cholangiocarcinoma","volume":"72","author":"Mazzaferro","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"417","DOI":"10.3389\/fonc.2019.00417","article-title":"Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics","volume":"9","author":"Golub","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1007\/s00262-019-02386-w","article-title":"Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer","volume":"68","author":"Sun","year":"2019","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/S1470-2045(20)30157-1","article-title":"Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): A multicentre, randomised, double-blind, placebo-controlled, phase 3 study","volume":"21","author":"Macarulla","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/S1470-2045(20)30109-1","article-title":"Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: A multicentre, open-label, phase 2 study","volume":"21","author":"Sahai","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6153","DOI":"10.1158\/0008-5472.CAN-16-1260","article-title":"Humanized Mouse Xenograft Models: Narrowing the Tumor-Microenvironment Gap","volume":"76","author":"Morton","year":"2016","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/17474124.2020.1765771","article-title":"Contemporary role of liver transplantation for the treatment of cholangiocarcinoma","volume":"14","author":"Hand","year":"2020","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s11894-017-0542-4","article-title":"Update on the Diagnosis and Treatment of Cholangiocarcinoma","volume":"19","author":"Doherty","year":"2017","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1097\/01.sla.0000251366.62632.d3","article-title":"Cholangiocarcinoma: Thirty-one-year experience with 564 patients at a single institution","volume":"245","author":"DeOliveira","year":"2007","journal-title":"Ann. Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1200\/JCO.2011.40.5381","article-title":"Adjuvant therapy in the treatment of biliary tract cancer: A systematic review and meta-analysis","volume":"30","author":"Horgan","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/S1470-2045(18)30915-X","article-title":"Capecitabine compared with observation in resected biliary tract cancer (BILCAP): A randomised, controlled, multicentre, phase 3 study","volume":"20","author":"Primrose","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1200\/JCO.18.00050","article-title":"Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study","volume":"37","author":"Edeline","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1002\/bjs.10776","article-title":"Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer","volume":"105","author":"Ebata","year":"2018","journal-title":"Br. J. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1200\/JCO.18.02178","article-title":"Adjuvant Therapy for Resected Biliary Tract Cancer: ASCO Clinical Practice Guideline","volume":"37","author":"Shroff","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1056\/NEJMoa0908721","article-title":"Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer","volume":"362","author":"Valle","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/sj.bjc.6605779","article-title":"Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: A comparative multicentre study in Japan","volume":"103","author":"Okusaka","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1093\/annonc\/mdt540","article-title":"Cisplatin and gemcitabine for advanced biliary tract cancer: A meta-analysis of two randomised trials","volume":"25","author":"Valle","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1093\/annonc\/mdz402","article-title":"Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced\/recurrent biliary tract cancer: The FUGA-BT (JCOG1113) randomized phase III clinical trial","volume":"30","author":"Morizane","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1001\/jamaoncol.2019.0270","article-title":"Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial","volume":"5","author":"Shroff","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.2217\/fon-2020-0247","article-title":"NUC-1031\/cisplatin versus gemcitabine\/cisplatin in untreated locally advanced\/metastatic biliary tract cancer (NuTide:121)","volume":"16","author":"McNamara","year":"2020","journal-title":"Future Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1007\/s00280-020-04079-z","article-title":"Evaluation of NUC-1031: A first-in-class ProTide in biliary tract cancer","volume":"6","author":"Arora","year":"2020","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1016\/S0168-8278(97)80467-9","article-title":"Heterogeneity of the \u201coval-cell\u201d response in the hamster liver during cholangiocarcinogenesis following Clonorchis sinensis infection and dimethylnitrosamine treatment","volume":"26","author":"Lee","year":"1997","journal-title":"J. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.bbadis.2018.03.026","article-title":"Animal models of cholangiocarcinoma","volume":"1","author":"Loeuillard","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/bjc.1976.66","article-title":"Carcinogenic effects of different nitroso-compounds in Chinese hamsters. I. Dimethylnitrosamine and N-diethylnitrosamine","volume":"33","author":"Reznik","year":"1976","journal-title":"Br. J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0232-1513(84)80063-8","article-title":"Histogenesis of cholangiomas and cholangiocarcinomas in thioacetamide fed rats","volume":"26","author":"Praet","year":"1984","journal-title":"Exp. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1093\/carcin\/bgh037","article-title":"Thioacetamide-induced intestinal-type cholangiocarcinoma in rat: An animal model recapitulating the multi-stage progression of human cholangiocarcinoma","volume":"25","author":"Yeh","year":"2004","journal-title":"Carcinogenesis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1177\/019262339101900401","article-title":"Furan-induced hepatic cholangiocarcinomas in Fischer 344 rats","volume":"19","author":"Maronpot","year":"1991","journal-title":"Toxicol. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1177\/0192623309357946","article-title":"Evidence of oxidative stress and associated DNA damage, increased proliferative drive, and altered gene expression in rat liver produced by the cholangiocarcinogenic agent furan","volume":"38","author":"Hickling","year":"2010","journal-title":"Toxicol. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1177\/019262339602400113","article-title":"Biliary proliferation and adaptation in furan-induced rat liver injury and carcinogenesis","volume":"24","author":"Sirica","year":"1996","journal-title":"Toxicol. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1111\/j.1365-2559.1999.00654.x","article-title":"p53 but not bcl-2 is expressed by most cholangiocarcinomas: A study of 28 cases","volume":"34","author":"Arora","year":"1999","journal-title":"Histopathology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1046\/j.1365-2559.1999.00705.x","article-title":"Protein expression and genetic alterations of p53 and ras in intrahepatic cholangiocarcinoma","volume":"35","author":"Furubo","year":"1999","journal-title":"Histopathology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1046\/j.1440-1827.1999.00821.x","article-title":"K-ras codon 12 and p53 mutations in biopsy specimens and bile from biliary tract cancers","volume":"49","author":"Itoi","year":"1999","journal-title":"Pathol. Int."},{"key":"ref_37","first-page":"477","article-title":"Mutation of p53 and K-ras, and loss of heterozygosity of APC in intrahepatic cholangiocarcinoma","volume":"79","author":"Kang","year":"1999","journal-title":"Lab. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1136\/gut.47.5.721","article-title":"Frequency of p16(INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver","volume":"47","author":"Tannapfel","year":"2000","journal-title":"Gut"},{"key":"ref_39","first-page":"1685","article-title":"NEU overexpression in the furan rat model of cholangiocarcinogenesis compared with biliary ductal cell hyperplasia","volume":"151","author":"Sirica","year":"1997","journal-title":"Am. J. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.clinre.2018.04.008","article-title":"Animal models of cholangiocarcinoma: What they teach us about the human disease","volume":"42","author":"Cadamuro","year":"2018","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1159\/000129007","article-title":"Thioacetamide- and carbon tetrachloride-induced liver cirrhosis","volume":"21","author":"Dashti","year":"1989","journal-title":"Eur. Surg. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1021\/tx3002719","article-title":"Metabolism and toxicity of thioacetamide and thioacetamide S-oxide in rat hepatocytes","volume":"25","author":"Hajovsky","year":"2012","journal-title":"Chem. Res. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.dld.2012.10.008","article-title":"Liver carcinogenesis: Rodent models of hepatocarcinoma and cholangiocarcinoma","volume":"45","author":"Kisseleva","year":"2013","journal-title":"Dig. Liver Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.dld.2011.06.014","article-title":"An oestrogen receptor beta-selective agonist exerts anti-neoplastic effects in experimental intrahepatic cholangiocarcinoma","volume":"44","author":"Marzioni","year":"2012","journal-title":"Dig. Liver Dis."},{"key":"ref_45","first-page":"318","article-title":"Altered microsome function during acute thioacetamide poisoning","volume":"8","author":"Barker","year":"1972","journal-title":"Mol. Pharmacol."},{"key":"ref_46","first-page":"4634","article-title":"Effects of dimethylnitrosamine on induction of cholangiocarcinoma in Opisthorchis viverrini-infected Syrian golden hamsters","volume":"38","author":"Thamavit","year":"1978","journal-title":"Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1053\/j.gastro.2011.03.044","article-title":"A mouse model of cholestasis-associated cholangiocarcinoma and transcription factors involved in progression","volume":"141","author":"Yang","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"46750","DOI":"10.18632\/oncotarget.8775","article-title":"The landscape of targeted therapies for cholangiocarcinoma: Current status and emerging targets","volume":"7","author":"Chong","year":"2016","journal-title":"Oncotarget"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1002\/em.20368","article-title":"Evaluating genotoxicity data to identify a mode of action and its application in estimating cancer risk at low doses: A case study involving carbon tetrachloride","volume":"49","author":"Eastmond","year":"2008","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1538\/expanim.58.141","article-title":"Genetic differences among C57BL\/6 substrains","volume":"58","author":"Mekada","year":"2009","journal-title":"Exp. Anim."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6622","DOI":"10.1158\/0008-5472.CAN-05-4609","article-title":"Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarcinoma in p53-deficient mice","volume":"66","author":"Farazi","year":"2006","journal-title":"Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"236","DOI":"10.5009\/gnl17102","article-title":"Liver Fluke-Associated Biliary Tract Cancer","volume":"12","author":"Prueksapanich","year":"2018","journal-title":"Gut Liver"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1002\/hep.23134","article-title":"Advanced periductal fibrosis from infection with the carcinogenic human liver fluke Opisthorchis viverrini correlates with elevated levels of interleukin-6","volume":"50","author":"Sripa","year":"2009","journal-title":"Hepatology"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Sripa, B., Thinkhamrop, B., Mairiang, E., Laha, T., Kaewkes, S., Sithithaworn, P., Periago, M.V., Bhudhisawasdi, V., Yonglitthipagon, P., and Mulvenna, J. (2012). Elevated plasma IL-6 associates with increased risk of advanced fibrosis and cholangiocarcinoma in individuals infected by Opisthorchis viverrini. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/journal.pntd.0001654"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.parint.2011.07.013","article-title":"A novel carbohydrate antigen expression during development of Opisthorchis viverrini-associated cholangiocarcinoma in golden hamster: A potential marker for early diagnosis","volume":"61","author":"Sawanyawisuth","year":"2012","journal-title":"Parasitol. Int."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/mc.20094","article-title":"Altered gene expression in Opisthorchis viverrini-associated cholangiocarcinoma in hamster model","volume":"45","author":"Loilome","year":"2006","journal-title":"Mol. Carcinog."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.parint.2011.07.003","article-title":"Expression of oxysterol binding protein isoforms in opisthorchiasis-associated cholangiocarcinoma: A potential molecular marker for tumor metastasis","volume":"61","author":"Loilome","year":"2012","journal-title":"Parasitol. Int."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/nrc2192","article-title":"Maximizing mouse cancer models","volume":"7","author":"Frese","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1126\/science.1957168","article-title":"Transgenic models of tumor development","volume":"254","author":"Adams","year":"1991","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1172\/JCI73742","article-title":"Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation","volume":"124","author":"Li","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/S0140-6736(05)67530-7","article-title":"Cholangiocarcinoma","volume":"366","author":"Khan","year":"2005","journal-title":"Lancet"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1053\/hupa.2002.127444","article-title":"Expression of G1-S modulators (p53, p16, p27, cyclin D1, Rb) and Smad4\/Dpc4 in intrahepatic cholangiocarcinoma","volume":"33","author":"Kang","year":"2002","journal-title":"Hum. Pathol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2954","DOI":"10.1200\/JCO.2004.02.141","article-title":"The biology and clinical relevance of the PTEN tumor suppressor pathway","volume":"22","author":"Sansal","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/(SICI)1526-968X(200002)26:2<149::AID-GENE16>3.0.CO;2-V","article-title":"DNA excision in liver by an albumin-Cre transgene occurs progressively with age","volume":"26","author":"Postic","year":"2000","journal-title":"Genesis"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1053\/j.gastro.2011.12.005","article-title":"Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors","volume":"142","author":"Andersen","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1016\/j.humpath.2013.07.026","article-title":"The frequency of KRAS and BRAF mutations in intrahepatic cholangiocarcinomas and their correlation with clinical outcome","volume":"44","author":"Robertson","year":"2013","journal-title":"Hum. Pathol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"23899","DOI":"10.1038\/srep23899","article-title":"A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion","volume":"6","author":"Ikenoue","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.canlet.2018.02.017","article-title":"Combination of Kras activation and PTEN deletion contributes to murine hepatopancreatic ductal malignancy","volume":"421","author":"Lin","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1158\/0008-5472.CAN-11-3596","article-title":"Kras(G12D) and p53 mutation cause primary intrahepatic cholangiocarcinoma","volume":"72","author":"Huang","year":"2012","journal-title":"Cancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nature13441","article-title":"Mutant IDH inhibits HNF-4alpha to block hepatocyte differentiation and promote biliary cancer","volume":"513","author":"Saha","year":"2014","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/S2468-1253(19)30189-X","article-title":"Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: A phase 1 study","volume":"4","author":"Lowery","year":"2019","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6115","DOI":"10.1038\/sj.onc.1203972","article-title":"Overexpression of ErbB2 in cancer and ErbB2-targeting strategies","volume":"19","author":"Yu","year":"2000","journal-title":"Oncogene"},{"key":"ref_73","first-page":"6971","article-title":"Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma","volume":"61","author":"Kiguchi","year":"2001","journal-title":"Cancer Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4061","DOI":"10.1242\/dev.052118","article-title":"Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: Insights into Alagille syndrome","volume":"137","author":"Hofmann","year":"2010","journal-title":"Development"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.ccr.2013.04.019","article-title":"A critical role for notch signaling in the formation of cholangiocellular carcinomas","volume":"23","author":"Zender","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.1172\/JCI63212","article-title":"Cholangiocarcinomas can originate from hepatocytes in mice","volume":"122","author":"Fan","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1002\/hep.27687","article-title":"IL-33 facilitates oncogene-induced cholangiocarcinoma in mice by an interleukin-6-sensitive mechanism","volume":"61","author":"Yamada","year":"2015","journal-title":"Hepatology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1002\/hep.26468","article-title":"Adjuvant gemcitabine therapy improves survival in a locally induced, R0-resectable model of metastatic intrahepatic cholangiocarcinoma","volume":"58","author":"Gurlevik","year":"2013","journal-title":"Hepatology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/0002-9610(89)90582-5","article-title":"Response to exogenous cholecystokinin of six human gastrointestinal cancers xenografted in nude mice","volume":"157","author":"Hudd","year":"1989","journal-title":"Am. J. Surg."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"11437","DOI":"10.1158\/0008-5472.CAN-05-1470","article-title":"gamma-Aminobutyric acid inhibits cholangiocarcinoma growth by cyclic AMP-dependent regulation of the protein kinase A\/extracellular signal-regulated kinase 1\/2 pathway","volume":"65","author":"Fava","year":"2005","journal-title":"Cancer Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"85492","DOI":"10.18632\/oncotarget.13408","article-title":"Synergistic antitumor activity of the combination of salubrinal and rapamycin against human cholangiocarcinoma cells","volume":"7","author":"Zhao","year":"2016","journal-title":"Oncotarget"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"65077","DOI":"10.18632\/oncotarget.17779","article-title":"Targeting SHP-1-STAT3 signaling: A promising therapeutic approach for the treatment of cholangiocarcinoma","volume":"8","author":"Hu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1158\/1535-7163.MCT-16-0922","article-title":"JQ1 Induces DNA Damage and Apoptosis, and Inhibits Tumor Growth in a Patient-Derived Xenograft Model of Cholangiocarcinoma","volume":"17","author":"Garcia","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1038\/labinvest.2011.97","article-title":"Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma","volume":"91","author":"Hou","year":"2011","journal-title":"Lab. Investig."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1007\/s00535-013-0748-7","article-title":"WTAP regulates migration and invasion of cholangiocarcinoma cells","volume":"48","author":"Jo","year":"2013","journal-title":"J. Gastroenterol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.jhep.2005.10.030","article-title":"Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes","volume":"44","author":"Meng","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jhep.2017.02.017","article-title":"SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma","volume":"67","author":"Lozano","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s12967-017-1342-1","article-title":"Autocrine parathyroid hormone-like hormone promotes intrahepatic cholangiocarcinoma cell proliferation via increased ERK\/JNK-ATF2-cyclinD1 signaling","volume":"15","author":"Tang","year":"2017","journal-title":"J. Transl. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1002\/hep.24591","article-title":"MicroRNA down-regulated in human cholangiocarcinoma control cell cycle through multiple targets involved in the G1\/S checkpoint","volume":"54","author":"Olaru","year":"2011","journal-title":"Hepatology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1053\/j.gastro.2012.03.045","article-title":"MicroRNA-26a promotes cholangiocarcinoma growth by activating \u03b2-catenin","volume":"143","author":"Zhang","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2828","DOI":"10.1016\/j.ajpath.2014.06.024","article-title":"miR-17\u201392 cluster promotes cholangiocarcinoma growth: Evidence for PTEN as downstream target and IL-6\/Stat3 as upstream activator","volume":"184","author":"Zhu","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/liv.13495","article-title":"Neuropilin-1 regulated by miR-320 contributes to the growth and metastasis of cholangiocarcinoma cells","volume":"38","author":"Zhu","year":"2018","journal-title":"Liver Int."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"100068","DOI":"10.1016\/j.jhepr.2020.100068","article-title":"Biliary tract cancer patient-derived xenografts: Surgeon impact on individualized medicine","volume":"2","author":"Leiting","year":"2020","journal-title":"JHEP Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1002\/hep.22088","article-title":"A novel \u201cpatient-like\u201d model of cholangiocarcinoma progression based on bile duct inoculation of tumorigenic rat cholangiocyte cell lines","volume":"47","author":"Sirica","year":"2008","journal-title":"Hepatology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/hep.23729","article-title":"A smac mimetic reduces TNF related apoptosis inducing ligand (TRAIL)-induced invasion and metastasis of cholangiocarcinoma cells","volume":"52","author":"Fingas","year":"2010","journal-title":"Hepatology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5892","DOI":"10.18632\/oncotarget.23638","article-title":"YAP-associated chromosomal instability and cholangiocarcinoma in mice","volume":"9","author":"Rizvi","year":"2018","journal-title":"Oncotarget"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Banales, J.M., Marin, J.J.G., Lamarca, A., Rodrigues, P.M., Khan, S.A., Roberts, L.R., Cardinale, V., Carpino, G., Andersen, J.B., and Braconi, C. (2020). Cholangiocarcinoma 2020: The next horizon in mechanisms and management. Nat. Rev. Gastroenterol. Hepatol.","DOI":"10.1038\/s41575-020-0310-z"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/14\/4993\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:48:46Z","timestamp":1760176126000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/14\/4993"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,15]]},"references-count":97,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["ijms21144993"],"URL":"https:\/\/doi.org\/10.3390\/ijms21144993","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,15]]}}}