{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T14:02:47Z","timestamp":1790344967995,"version":"4.1.0"},"reference-count":144,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,10,29]],"date-time":"2019-10-29T00:00:00Z","timestamp":1572307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI16\/00598"],"award-info":[{"award-number":["PI16\/00598"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI19\/00819"],"award-info":[{"award-number":["PI19\/00819"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["SAF2016-75197-R"],"award-info":[{"award-number":["SAF2016-75197-R"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Asociaci\u00f3n Espa\u00f1ola Contra el Cancer","award":["AECC-Cancer raros 2017\/2020"],"award-info":[{"award-number":["AECC-Cancer raros 2017\/2020"]}]},{"name":"Centro Internacional sobre el Envejecimiento, Spain","award":["OLD-HEPAMARKER, 0348_CIE_6_E"],"award-info":[{"award-number":["OLD-HEPAMARKER, 0348_CIE_6_E"]}]},{"DOI":"10.13039\/501100000921","name":"European Cooperation in Science and Technology","doi-asserted-by":"publisher","award":["EURO-CHOLANGIO-NET (OC-2018-1-22912)"],"award-info":[{"award-number":["EURO-CHOLANGIO-NET (OC-2018-1-22912)"]}],"id":[{"id":"10.13039\/501100000921","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The lack of response to pharmacological treatment constitutes a substantial limitation in the handling of patients with primary liver cancers (PLCs). The existence of active mechanisms of chemoresistance (MOCs) in hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma hampers the usefulness of chemotherapy. A better understanding of MOCs is needed to develop strategies able to overcome drug refractoriness in PLCs. With this aim, several experimental models are commonly used. These include in vitro cell-free assays using subcellular systems; studies with primary cell cultures; cancer cell lines or heterologous expression systems; multicellular models, such as spheroids and organoids; and a variety of in vivo models in rodents, such as subcutaneous and orthotopic tumor xenografts or chemically or genetically induced liver carcinogenesis. Novel methods to perform programmed genomic edition and more efficient techniques to isolate circulating microvesicles offer new opportunities for establishing useful experimental tools for understanding the resistance to chemotherapy in PLCs. In the present review, using three criteria for information organization: (1) level of research; (2) type of MOC; and (3) type of PLC, we have summarized the advantages and limitations of the armamentarium available in the field of pharmacological investigation of PLC chemoresistance.<\/jats:p>","DOI":"10.3390\/cancers11111677","type":"journal-article","created":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T05:18:26Z","timestamp":1572499106000},"page":"1677","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Models for Understanding Resistance to Chemotherapy in Liver Cancer"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1186-6849","authenticated-orcid":false,"given":"Jose J. G.","family":"Marin","sequence":"first","affiliation":[{"name":"Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, 37007 Salamanca, Spain"},{"name":"Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9271-3320","authenticated-orcid":false,"given":"Elisa","family":"Herraez","sequence":"additional","affiliation":[{"name":"Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, 37007 Salamanca, Spain"},{"name":"Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Lozano","sequence":"additional","affiliation":[{"name":"Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, 37007 Salamanca, Spain"},{"name":"Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4748-0326","authenticated-orcid":false,"given":"Rocio I. R.","family":"Macias","sequence":"additional","affiliation":[{"name":"Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, 37007 Salamanca, Spain"},{"name":"Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Briz","sequence":"additional","affiliation":[{"name":"Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, 37007 Salamanca, Spain"},{"name":"Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.clinre.2017.12.006","article-title":"Molecular bases of the poor response of liver cancer to chemotherapy","volume":"42","author":"Marin","year":"2018","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1021\/mp300028a","article-title":"No correlation between the expression of FXR and genes involved in multidrug resistance phenotype of primary liver tumors","volume":"9","author":"Vaquero","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3580","DOI":"10.1073\/pnas.85.10.3580","article-title":"ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells","volume":"85","author":"Horio","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","first-page":"620","article-title":"Rational use of in vitro P-glycoprotein assays in drug discovery","volume":"299","author":"Polli","year":"2001","journal-title":"J. Pharm. Exp. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1126\/science.168.3928.255","article-title":"Inside-out red cell membrane vesicles: preparation and purification","volume":"168","author":"Steck","year":"1970","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1517\/17425255.4.6.721","article-title":"Utilization of membrane vesicle preparations to study drug-ABC transporter interactions","volume":"4","author":"Glavinas","year":"2008","journal-title":"Expert Opin. Drug Metab. Toxic."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3394","DOI":"10.1021\/bi0619526","article-title":"P-Glycoprotein kinetics measured in plasma membrane vesicles and living cells","volume":"46","author":"Aanismaa","year":"2007","journal-title":"Biochemistry"},{"key":"ref_8","first-page":"929","article-title":"Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells","volume":"55","author":"Cui","year":"1999","journal-title":"Mol. Pharm."},{"key":"ref_9","first-page":"4779","article-title":"Transport of amphipathic anions by human multidrug resistance protein 3","volume":"60","author":"Zeng","year":"2000","journal-title":"Cancer Res."},{"key":"ref_10","first-page":"60","article-title":"A structure-activity relationship study of ABCC2 inhibitors","volume":"103","author":"Wissel","year":"2017","journal-title":"Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci."},{"key":"ref_11","first-page":"104963","article-title":"Endogenous, cholesterol-activated ATP-dependent transport in membrane vesicles from Spodoptera frugiperda cells","volume":"137","author":"Sjostedt","year":"2019","journal-title":"Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1042\/bj3110479","article-title":"Reconstitution and characterization of ATP-dependent bile acid transport in human and rat placenta","volume":"311 Pt. 2","author":"Bravo","year":"1995","journal-title":"Biochem. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/nprot.2007.519","article-title":"Membrane reconstitution of ABC transporters and assays of translocator function","volume":"3","author":"Geertsma","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4854","DOI":"10.1016\/S0021-9258(18)42909-2","article-title":"Expression of the human multidrug resistance cDNA in insect cells generates a high activity drug-stimulated membrane ATPase","volume":"267","author":"Sarkadi","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/emm.2003.3","article-title":"Enzymatic method for assaying calcium in serum with Ca++ -ATPase","volume":"35","author":"Javed","year":"2003","journal-title":"Exp. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8262","DOI":"10.1021\/bi00193a013","article-title":"Direct, real-time measurement of rapid inorganic phosphate release using a novel fluorescent probe and its application to actomyosin subfragment 1 ATPase","volume":"33","author":"Brune","year":"1994","journal-title":"Biochemistry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1046\/j.1432-1327.1999.00735.x","article-title":"Purification of the human apical conjugate export pump MRP2 reconstitution and functional characterization as substrate-stimulated ATPase","volume":"265","author":"Hagmann","year":"1999","journal-title":"Eur. J. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/0165-022X(82)90031-8","article-title":"Inorganic phosphate assay with malachite green: An improvement and evaluation","volume":"7","author":"Carter","year":"1982","journal-title":"J. Biochem. Biophys. Methods"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1152\/physrev.00037.2005","article-title":"Human multidrug resistance ABCB and ABCG transporters: Participation in a chemoimmunity defense system","volume":"86","author":"Sarkadi","year":"2006","journal-title":"Physiol. Rev."},{"key":"ref_20","first-page":"1010","article-title":"Cabozantinib reverses multidrug resistance of human hepatoma HepG2\/adr cells by modulating the function of P-glycoprotein","volume":"35","author":"Xiang","year":"2015","journal-title":"Liver Int. Off. J. Int. Assoc. Study Liver"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.ejmech.2015.06.049","article-title":"Reversal of P-gp and BCRP-mediated MDR by tariquidar derivatives","volume":"101","author":"Li","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","first-page":"635","article-title":"Beneficial effect of cepharanthine on overcoming drug-resistance of hepatocellular carcinoma","volume":"24","author":"Nakajima","year":"2004","journal-title":"Int. J. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.3892\/ijo.2015.2925","article-title":"Ganoderma lucidum derived ganoderenic acid B reverses ABCB1-mediated multidrug resistance in HepG2\/ADM cells","volume":"46","author":"Liu","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/0065-2571(94)90023-X","article-title":"ATP-dependent export pumps and their inhibition by cyclosporins","volume":"34","author":"Bohme","year":"1994","journal-title":"Adv. Enzyme Regul."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"52629","DOI":"10.1074\/jbc.M308175200","article-title":"Transition state analysis of the coupling of drug transport to ATP hydrolysis by P-glycoprotein","volume":"278","author":"Polar","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"19383","DOI":"10.1074\/jbc.270.33.19383","article-title":"P-glycoprotein is stably inhibited by vanadate-induced trapping of nucleotide at a single catalytic site","volume":"270","author":"Urbatsch","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Royo, F., and Falcon-Perez, J.M. (2012). Liver extracellular vesicles in health and disease. J. Extracell. Vesicles, 1.","DOI":"10.3402\/jev.v1i0.18825"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s12943-019-0965-7","article-title":"Extracellular vesicles-mediated intercellular communication: Roles in the tumor microenvironment and anti-cancer drug resistance","volume":"18","author":"Maacha","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/978-1-4939-6824-4_2","article-title":"Isolation of Functional Mitochondria from Cultured Cells and Mouse Tissues","volume":"1567","author":"Wettmarshausen","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3881","DOI":"10.2147\/OTT.S193433","article-title":"Mitochondria P-glycoprotein confers paclitaxel resistance on ovarian cancer cells","volume":"12","author":"Guo","year":"2019","journal-title":"OncoTargets Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4070","DOI":"10.1016\/j.yexcr.2006.09.005","article-title":"P-gp localization in mitochondria and its functional characterization in multiple drug-resistant cell lines","volume":"312","author":"Solazzo","year":"2006","journal-title":"Exp. Cell Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7235","DOI":"10.1158\/0008-5472.CAN-08-4315","article-title":"Mitochondrial expression and functional activity of breast cancer resistance protein in different multiple drug-resistant cell lines","volume":"69","author":"Solazzo","year":"2009","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/s41467-018-07922-3","article-title":"The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis","volume":"10","author":"Baechler","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"545","DOI":"10.7150\/ijms.4648","article-title":"Role of mitochondrial translocation of telomerase in hepatocellular carcinoma cells with multidrug resistance","volume":"9","author":"Ling","year":"2012","journal-title":"Int. J. Med. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1111\/jcmm.12528","article-title":"Mitochondria of a human multidrug-resistant hepatocellular carcinoma cell line constitutively express inducible nitric oxide synthase in the inner membrane","volume":"19","author":"Fantappie","year":"2015","journal-title":"J. Cell. Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Serrano, F.A., Matsuo, A.L., Monteforte, P.T., Bechara, A., Smaili, S.S., Santana, D.P., Rodrigues, T., Pereira, F.V., Silva, L.S., and Machado, J. (2011). A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells. BMC Cancer, 11.","DOI":"10.1186\/1471-2407-11-296"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"G54","DOI":"10.1152\/ajpgi.00592.2007","article-title":"Cytosol-nucleus traffic and colocalization with FXR of conjugated bile acids in rat hepatocytes","volume":"295","author":"Monte","year":"2008","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1016\/j.bcp.2012.09.029","article-title":"ABCC2 is involved in the hepatocyte perinuclear barrier for small organic compounds","volume":"84","author":"Rosales","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"765794","DOI":"10.1155\/2014\/765794","article-title":"Heparin and liver heparan sulfate can rescue hepatoma cells from topotecan action","volume":"2014","author":"Dudas","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/ng0501-29","article-title":"SOCS-1, a negative regulator of the JAK\/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity","volume":"28","author":"Yoshikawa","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/978-1-4939-3756-1_19","article-title":"Isolation of Lysosomes from Mammalian Tissues and Cultured Cells","volume":"1449","author":"Aguado","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.3324\/haematol.2009.008631","article-title":"ABC transporter A3 facilitates lysosomal sequestration of imatinib and modulates susceptibility of chronic myeloid leukemia cell lines to this drug","volume":"94","author":"Chapuy","year":"2009","journal-title":"Haematologica"},{"key":"ref_43","first-page":"23","article-title":"Lysosomes as mediators of drug resistance in cancer","volume":"24","author":"Zhitomirsky","year":"2016","journal-title":"Drug Resist. Updates Rev. Comment. Antimicrob. Anticancer Chemother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1124\/dmd.112.050054","article-title":"Lysosomal sequestration (trapping) of lipophilic amine (cationic amphiphilic) drugs in immortalized human hepatocytes (Fa2N-4 cells)","volume":"41","author":"Kazmi","year":"2013","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"27411","DOI":"10.1038\/srep27411","article-title":"Hepatocellular carcinoma cell lines retain the genomic and transcriptomic landscapes of primary human cancers","volume":"6","author":"Qiu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3389\/fped.2016.00022","article-title":"Hepatoblastoma: A Need for Cell Lines and Tissue Banks to Develop Targeted Drug Therapies","volume":"4","author":"Rikhi","year":"2016","journal-title":"Front. Pediatr."},{"key":"ref_47","first-page":"10","article-title":"Primary Cholangiocellular Carcinoma Cell Lines","volume":"2","author":"Zach","year":"2015","journal-title":"J. Stem Cell Res. Transplant."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Jouan, E., Le Vee, M., Denizot, C., Parmentier, Y., and Fardel, O. (2016). Drug Transporter Expression and Activity in Human Hepatoma HuH-7 Cells. Pharmaceutics, 9.","DOI":"10.3390\/pharmaceutics9010003"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"743","DOI":"10.18632\/oncotarget.23142","article-title":"Organic cation transporter 3 mediates cisplatin and copper cross-resistance in hepatoma cells","volume":"9","author":"Guttmann","year":"2018","journal-title":"Oncotarget"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1038\/aps.2009.85","article-title":"The expression of efflux and uptake transporters are regulated by statins in Caco-2 and HepG2 cells","volume":"30","author":"Rodrigues","year":"2009","journal-title":"Acta Pharmacologica Sinica"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1002\/hep.26425","article-title":"Expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib","volume":"58","author":"Herraez","year":"2013","journal-title":"Hepatology"},{"key":"ref_52","first-page":"S90","article-title":"Role of transportome in chemoresistance of hepatoblastoma","volume":"74","author":"Asensio","year":"2018","journal-title":"J. Physiol. Biochem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1097\/00029330-200704020-00017","article-title":"Establishment of hepatocellular carcinoma multidrug resistant monoclone cell line HepG2\/mdr1","volume":"120","author":"Chen","year":"2007","journal-title":"Ch. Med. J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1742-7843.2007.00199.x","article-title":"Chemosensitivity determinants of irinotecan hydrochloride in hepatocellular carcinoma cell lines","volume":"102","author":"Takahata","year":"2008","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_55","first-page":"1465","article-title":"The combination of glycyrrhizin and lamivudine can reverse the cisplatin resistance in hepatocellular carcinoma cells through inhibition of multidrug resistance-associated proteins","volume":"31","author":"Wakamatsu","year":"2007","journal-title":"Int. J. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.3748\/wjg.v11.i18.2748","article-title":"Drug sensitivity and drug resistance profiles of human intrahepatic cholangiocarcinoma cell lines","volume":"11","author":"Tepsiri","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1124\/dmd.114.062380","article-title":"Induction of human UDP-Glucuronosyltransferase 2B7 gene expression by cytotoxic anticancer drugs in liver cancer HepG2 cells","volume":"43","author":"Hu","year":"2015","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1756-9966-33-11","article-title":"Suppression of NAD(P)H-quinone oxidoreductase 1 enhanced the susceptibility of cholangiocarcinoma cells to chemotherapeutic agents","volume":"33","author":"Zeekpudsa","year":"2014","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1124\/jpet.103.052696","article-title":"Reversal of multiple drug resistance in cholangiocarcinoma by the glutathione S-transferase-pi-specific inhibitor O1-hexadecyl-gamma-glutamyl-S-benzylcysteinyl-D-phenylglycine ethylester","volume":"306","author":"Nakajima","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1200\/JCO.1999.17.3.1061","article-title":"Mechanisms of action of and resistance to antitubulin agents: Microtubule dynamics, drug transport, and cell death","volume":"17","author":"Dumontet","year":"1999","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/labinvest.3700254","article-title":"Karyotypic imbalances and differential gene expressions in the acquired doxorubicin resistance of hepatocellular carcinoma cells","volume":"85","author":"Pang","year":"2005","journal-title":"Lab. Investig. J. Tech. Methods Pathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1007\/s00280-004-0767-4","article-title":"Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line","volume":"53","author":"Chan","year":"2004","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_63","first-page":"76","article-title":"Wild type p53 increased chemosensitivity of drug-resistant human hepatocellular carcinoma Bel7402\/5-FU cells","volume":"25","author":"Li","year":"2004","journal-title":"Acta Pharmacologica Sinica"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1248\/bpb.30.1400","article-title":"Irinotecan-induced apoptosis is inhibited by increased P-glycoprotein expression and decreased p53 in human hepatocellular carcinoma cells","volume":"30","author":"Takeba","year":"2007","journal-title":"Biol. Pharm. Bull."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1159\/000151541","article-title":"Characterization of 5-fluorouracil-resistant cholangiocarcinoma cell lines","volume":"54","author":"Namwat","year":"2008","journal-title":"Chemotherapy"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.bbrc.2004.01.118","article-title":"Bcl-2 and Bcl-xL are important for the induction of paclitaxel resistance in human hepatocellular carcinoma cells","volume":"315","author":"Chun","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.bbrc.2010.11.130","article-title":"Acquisition of chemoresistance in intrahepatic cholangiocarcinoma cells by activation of AKT and extracellular signal-regulated kinase (ERK)1\/2","volume":"405","author":"Yoon","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"398","DOI":"10.3892\/ijo.2015.3019","article-title":"Establishment and characterization of gemcitabine-resistant human cholangiocarcinoma cell lines with multidrug resistance and enhanced invasiveness","volume":"47","author":"Wattanawongdon","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_69","first-page":"25","article-title":"Mcl-1 is an anti-apoptotic factor for human hepatocellular carcinoma","volume":"28","author":"Fleischer","year":"2006","journal-title":"Int. J. Oncol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.yexmp.2010.10.003","article-title":"Invasion and EMT-associated genes are up-regulated in B viral hepatocellular carcinoma with high expression of CD133-human and cell culture study","volume":"90","author":"Na","year":"2011","journal-title":"Exp. Mol. Pathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s12935-014-0103-y","article-title":"Establishment and characterization of a novel primary hepatocellular carcinoma cell line with metastatic ability in vivo","volume":"14","author":"Cheung","year":"2014","journal-title":"Cancer Cell Int."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.biopha.2012.04.001","article-title":"Genes responsible for the characteristics of primary cultured invasive phenotype hepatocellular carcinoma cells","volume":"66","author":"Lin","year":"2012","journal-title":"Biomed. Pharmacother. Biomed. Pharmacotherapie"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2782","DOI":"10.1002\/ijc.32026","article-title":"Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification","volume":"144","author":"Castven","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Hou, J., Hong, Z., Feng, F., Chai, Y., Zhang, Y., Jiang, Q., Hu, Y., Wu, S., Wu, Y., and Gao, X. (2017). A novel chemotherapeutic sensitivity-testing system based on collagen gel droplet embedded 3D-culture methods for hepatocellular carcinoma. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3706-6"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1111\/jgh.12693","article-title":"Clinical utility of a simple primary culture method in hepatocellular carcinoma patients","volume":"30","author":"Lin","year":"2015","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Fraveto, A., Cardinale, V., Bragazzi, M.C., Giuliante, F., De Rose, A.M., Grazi, G.L., Napoletano, C., Semeraro, R., Lustri, A.M., and Costantini, D. (2015). Sensitivity of Human Intrahepatic Cholangiocarcinoma Subtypes to Chemotherapeutics and Molecular Targeted Agents: A Study on Primary Cell Cultures. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0142124"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/ncponc1110","article-title":"Mechanisms of Disease: Cancer stem cells\u2014Targeting the evil twin","volume":"5","author":"Trumpp","year":"2008","journal-title":"Nat. Clin. Pract. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrc1590","article-title":"Tumour stem cells and drug resistance","volume":"5","author":"Dean","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/978-3-030-14366-4_4","article-title":"Heterogeneity of Hepatic Cancer Stem Cells","volume":"1139","author":"Sukowati","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1172\/JCI66024","article-title":"Cancer stem cells in the development of liver cancer","volume":"123","author":"Yamashita","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1038\/s41416-018-0338-9","article-title":"SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance","volume":"119","author":"Yuan","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1002\/hep.30404","article-title":"ID3 Promotes Stem Cell Features and Predicts Chemotherapeutic Response of Intrahepatic Cholangiocarcinoma","volume":"69","author":"Huang","year":"2019","journal-title":"Hepatology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"632","DOI":"10.3892\/ijo.2015.3024","article-title":"Protective effects of hepatic stellate cells against cisplatin-induced apoptosis in human hepatoma G2 cells","volume":"47","author":"Zhang","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_84","first-page":"3209","article-title":"Expression of P53 and HSP70 in Chronic Hepatitis, Liver Cirrhosis, and Early and Advanced Hepatocellular Carcinoma Tissues and Their Diagnostic Value in Hepatocellular Carcinoma: An Immunohistochemical Study","volume":"21","author":"Wang","year":"2015","journal-title":"Med. Sci. Monit. Int. Med. J. Exp. Clin. Res."},{"key":"ref_85","first-page":"764981","article-title":"Hepatic stellate cell coculture enables sorafenib resistance in Huh7 cells through HGF\/c-Met\/Akt and Jak2\/Stat3 pathways","volume":"2014","author":"Chen","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/dmd.115.066712","article-title":"Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride","volume":"44","author":"Fujita","year":"2016","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1124\/mol.64.6.1452","article-title":"Functional characterization of human breast cancer resistance protein (BCRP, ABCG2) expressed in the oocytes of Xenopus laevis","volume":"64","author":"Nakanishi","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1002\/humu.20694","article-title":"6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA) transport altered by two missense mutations in the drug transporter gene ABCC4","volume":"29","author":"Janke","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_89","first-page":"113","article-title":"Growth of multicell spheroids in tissue culture as a model of nodular carcinomas","volume":"46","author":"Sutherland","year":"1971","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1053\/j.gastro.2016.11.048","article-title":"Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis","volume":"152","author":"Sia","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.jhep.2016.08.012","article-title":"Cholangiocarcinoma stem-like subset shapes tumor-initiating niche by educating associated macrophages","volume":"66","author":"Raggi","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4233","DOI":"10.1039\/C9AN00612E","article-title":"Microfluidic co-culture of liver tumor spheroids with stellate cells for the investigation of drug resistance and intercellular interactions","volume":"144","author":"Chen","year":"2019","journal-title":"Analyst"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neo.2014.12.004","article-title":"Spherical cancer models in tumor biology","volume":"17","author":"Weiswald","year":"2015","journal-title":"Neoplasia"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1053\/j.gastro.2011.07.050","article-title":"Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett\u2019s epithelium","volume":"141","author":"Sato","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.cell.2014.08.016","article-title":"Organoid cultures derived from patients with advanced prostate cancer","volume":"159","author":"Gao","year":"2014","journal-title":"Cell"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/j.cell.2015.03.053","article-title":"Prospective derivation of a living organoid biobank of colorectal cancer patients","volume":"161","author":"Francies","year":"2015","journal-title":"Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1038\/nm.4438","article-title":"Human primary liver cancer-derived organoid cultures for disease modeling and drug screening","volume":"23","author":"Broutier","year":"2017","journal-title":"Nat. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/j.celrep.2018.07.001","article-title":"Organoid Models of Human Liver Cancers Derived from Tumor Needle Biopsies","volume":"24","author":"Nuciforo","year":"2018","journal-title":"Cell Rep."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1053\/j.gastro.2017.10.043","article-title":"MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma","volume":"154","author":"Lampis","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1080\/15476278.2017.1322243","article-title":"Microenvironment of a tumor-organoid system enhances hepatocellular carcinoma malignancy-related hallmarks","volume":"13","author":"Wang","year":"2017","journal-title":"Organogenesis"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"E3806","DOI":"10.1073\/pnas.1619416114","article-title":"Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands","volume":"114","author":"Nakagawa","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_102","first-page":"2280","article-title":"Facts and theories concerning the mechanisms of carcinogenesis","volume":"5","author":"Pitot","year":"1991","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_103","first-page":"367","article-title":"CCL4-induced liver cirrhosis and hepatocellular carcinoma in rats: Relationship to plasma zinc, copper and estradiol levels","volume":"41","author":"Frezza","year":"1994","journal-title":"Hepato-Gastroenterol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1093\/carcin\/20.1.59","article-title":"Inhibition of hepatocellular carcinoma by glycyrrhizin in diethylnitrosamine-treated mice","volume":"20","author":"Shiota","year":"1999","journal-title":"Carcinogenesis"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3953","DOI":"10.1158\/1078-0432.CCR-16-1464","article-title":"In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3-Mediated Apoptosis","volume":"23","author":"Fornari","year":"2017","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_106","first-page":"477","article-title":"Newer insights into the pathogenesis of liver cancer","volume":"89","author":"Farber","year":"1977","journal-title":"Am. J. Pathol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1111\/bph.14563","article-title":"Epigenetic events involved in organic cation transporter 1-dependent impaired response of hepatocellular carcinoma to sorafenib","volume":"176","author":"Lozano","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1093\/carcin\/bgh285","article-title":"Role of peroxisome proliferator-activated receptor-alpha (PPARalpha) in bezafibrate-induced hepatocarcinogenesis and cholestasis","volume":"26","author":"Hays","year":"2005","journal-title":"Carcinogenesis"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1093\/toxsci\/kfr087","article-title":"Aflatoxin B1-DNA adduct formation and mutagenicity in livers of neonatal male and female B6C3F1 mice","volume":"122","author":"Woo","year":"2011","journal-title":"Toxic. Sci. Off. J. Soc. Toxicol."},{"key":"ref_110","first-page":"4594","article-title":"Susceptibility to aflatoxin B1-related primary hepatocellular carcinoma in mice and humans","volume":"63","author":"McGlynn","year":"2003","journal-title":"Cancer Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1084\/jem.192.12.1809","article-title":"Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice","volume":"192","author":"Knight","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.ebiom.2018.12.047","article-title":"TNF-alpha is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma","volume":"40","author":"Tan","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"8397","DOI":"10.1158\/0008-5472.CAN-04-1612","article-title":"Phosphatidylinositol 3\u2032-kinase activation leads to multidrug resistance protein-1 expression and subsequent chemoresistance in advanced prostate cancer cells","volume":"64","author":"Lee","year":"2004","journal-title":"Cancer Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"28867","DOI":"10.18632\/oncotarget.4814","article-title":"MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN\/Akt pathway","volume":"6","author":"He","year":"2015","journal-title":"Oncotarget"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1593\/neo.10804","article-title":"Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy","volume":"12","author":"Tang","year":"2010","journal-title":"Neoplasia"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1124\/mol.63.3.742","article-title":"Usefulness of liposomes loaded with cytostatic bile acid derivatives to circumvent chemotherapy resistance of enterohepatic tumors","volume":"63","author":"Briz","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"ref_117","first-page":"509","article-title":"Accelerated orthotopic hepatocellular carcinomas growth is linked to increased expression of pro-angiogenic and prometastatic factors in murine liver fibrosis","volume":"28","author":"Kornek","year":"2008","journal-title":"Liver Int. Off. J. Int. Assoc. Study Liver"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/0024-3205(95)00254-4","article-title":"In vivo cultivation of tumor cells in hollow fibers","volume":"57","author":"Hollingshead","year":"1995","journal-title":"Life Sci."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.jhep.2012.06.017","article-title":"Liver specific deletion of CYLDexon7\/8 induces severe biliary damage, fibrosis and increases hepatocarcinogenesis in mice","volume":"57","author":"Urbanik","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_120","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_121","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/labinvest.2009.15","article-title":"Expression of stem cell factor and its receptor c-Kit during the development of intrahepatic cholangiocarcinoma","volume":"89","author":"Mansuroglu","year":"2009","journal-title":"Lab. Investig. J. Tech. Methods Pathol."},{"key":"ref_122","first-page":"566","article-title":"Nab-paclitaxel is effective against intrahepatic cholangiocarcinoma via disruption of desmoplastic stroma","volume":"16","author":"Chang","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1158\/1541-7786.MCR-13-0503","article-title":"Cocarcinogenic effects of intrahepatic bile acid accumulation in cholangiocarcinoma development","volume":"12","author":"Lozano","year":"2014","journal-title":"Mol. Cancer Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1016\/j.ajpath.2018.05.015","article-title":"Conjugated Bile Acids Promote Invasive Growth of Esophageal Adenocarcinoma Cells and Cancer Stem Cell Expansion via Sphingosine 1-Phosphate Receptor 2-Mediated Yes-Associated Protein Activation","volume":"188","author":"Liu","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_125","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_126","first-page":"1536","article-title":"Cisplatin, camptothecin, and taxol sensitivities of cells with p53-associated multidrug resistance","volume":"50","author":"Vasey","year":"1996","journal-title":"Mol. Pharm."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1172\/JCI6863","article-title":"Disruption of p53 in human cancer cells alters the responses to therapeutic agents","volume":"104","author":"Bunz","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"33","DOI":"10.4137\/JCM.S40549","article-title":"KRAS Mutation as a Potential Prognostic Biomarker of Biliary Tract Cancers","volume":"7","author":"Yokoyama","year":"2016","journal-title":"Jpn. Clin. Med."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"90185","DOI":"10.18632\/oncotarget.21624","article-title":"Role of drug-dependent transporter modulation on the chemosensitivity of cholangiocarcinoma","volume":"8","author":"Urtasun","year":"2017","journal-title":"Oncotarget"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"3602","DOI":"10.3892\/mmr.2016.5701","article-title":"Upregulation of retinoic acid receptor-beta reverses drug resistance in cholangiocarcinoma cells by enhancing susceptibility to apoptosis","volume":"14","author":"Ren","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Hong, Z.F., Zhao, W.X., Yin, Z.Y., Xie, C.R., Xu, Y.P., Chi, X.Q., Zhang, S., and Wang, X.M. (2015). Capsaicin Enhances the Drug Sensitivity of Cholangiocarcinoma through the Inhibition of Chemotherapeutic-Induced Autophagy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121538"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"23857","DOI":"10.18632\/oncotarget.4408","article-title":"Lovastatin overcomes gefitinib resistance through TNF-alpha signaling in human cholangiocarcinomas with different LKB1 statuses in vitro and in vivo","volume":"6","author":"Yang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Lozano, E., Macias, R.I.R., Monte, M.J., Asensio, M., Del Carmen, S., Sanchez-Vicente, L., Alonso-Pena, M., Al-Abdulla, R., Munoz-Garrido, P., and Satriano, L. (2019). Causes of hOCT1-Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor-Selective Gene Therapy. Hepatology.","DOI":"10.1002\/hep.30656"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1053\/jhep.2000.8535","article-title":"Growth control of human biliary epithelial cells by interleukin 6, hepatocyte growth factor, transforming growth factor beta1, and activin A: comparison of a cholangiocarcinoma cell line with primary cultures of non-neoplastic biliary epithelial cells","volume":"32","author":"Yokomuro","year":"2000","journal-title":"Hepatology"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.jhep.2018.12.004","article-title":"Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma","volume":"70","author":"Cadamuro","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1002\/hep.24466","article-title":"Nuclear expression of S100A4 calcium-binding protein increases cholangiocarcinoma invasiveness and metastasization","volume":"54","author":"Fabris","year":"2011","journal-title":"Hepatology"},{"key":"ref_137","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_138","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1002\/hep.28621","article-title":"Patient-derived mouse xenografts from pediatric liver cancer predict tumor recurrence and advise clinical management","volume":"64","author":"Nicolle","year":"2016","journal-title":"Hepatology"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1002\/cncr.10858","article-title":"The role of the MDR1 gene in the development of multidrug resistance in human hepatoblastoma: Clinical course and in vivo model","volume":"95","author":"Warmann","year":"2002","journal-title":"Cancer"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1080\/08880010590964192","article-title":"Effects of P-glycoprotein modulation on the chemotherapy of xenotransplanted human hepatoblastoma","volume":"22","author":"Warmann","year":"2005","journal-title":"Pediatr. Hematol. Oncol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.yexcr.2013.12.007","article-title":"BH3-mimetic drugs prevent tumour onset in an orthotopic mouse model of hepatoblastoma","volume":"322","author":"Lieber","year":"2014","journal-title":"Exp. Cell Res."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1038\/ncomms3126","article-title":"Evaluating cell lines as tumour models by comparison of genomic profiles","volume":"4","author":"Domcke","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"18708","DOI":"10.1073\/pnas.1111840108","article-title":"Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance","volume":"108","author":"Gillet","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/1476-4598-5-55","article-title":"Pathway-specific differences between tumor cell lines and normal and tumor tissue cells","volume":"5","author":"Ertel","year":"2006","journal-title":"Mol. Cancer"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/11\/1677\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:30:06Z","timestamp":1760189406000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/11\/1677"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,29]]},"references-count":144,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["cancers11111677"],"URL":"https:\/\/doi.org\/10.3390\/cancers11111677","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,29]]}}}