EXPERIMENTAL RODENT MODELS FOR HEPATOCELLULAR CARCINOMA AND CHOLANGIOCARCINOMA: A PRE-CLINICAL FRAMEWORK FOR LIVER CANCER RESEARCH

Authors

  • LOKESHVAR RAVIKUMAR Department of Pharmacology, Saveetha College of Pharmacy, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India.
  • RAMAIYAN VELMURUGAN Department of Pharmacology, Saveetha College of Pharmacy, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India. https://orcid.org/0000-0001-6869-3446
  • YOKESH S Department of Pharmacology, Saveetha College of Pharmacy, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India.
  • MAHA SWETHA K Department of Pharmacology, Saveetha College of Pharmacy, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India.

DOI:

https://doi.org/10.22159/ajpcr.2025v18i5.54026

Keywords:

Liver carcinogenesis, Hepatocellular carcinoma,, Cholangiocarcinoma, Rodent models, Experimental oncology

Abstract

Every year, more people die from primary liver malignancies such Cholangiocarcinoma and Hepatocellular carcinoma. For physicians, this is a major issue. Numerous in vivo models of malignant malignancies have lately been established, yielding vital new insights into their development. These models are especially important for preclinical testing of novel therapeutic agents in order to evaluate newly developed compounds as potential treatments for primary liver malignancies. To correctly analyse study results and plan future research, the technical components of each model must be carefully considered, as they are an essential aspect of the research process. The primary goal of this review is to provide a thorough description of the technical and experimental features of the most important rodent models, with an emphasis on highlighting the similarities and differences between these models and the corresponding human diseases. This will aid in the development of novel therapeutic strategies. This review is divided into two main sections. The first section investigates hepatocellular carcinoma models developed by a range of strategies, including genetic modification, nutritional manipulation, and the use of toxic chemicals. To provide a comprehensive overview of the various methods used to study these liver cancers, the second section will go into detail about cholangiocarcinoma models established in rodents, such as rats and mice, using a variety of techniques, including xenograft and syngeneic models, bile duct cannulation, genetic manipulation, toxin administration, and surgical interventions.

Downloads

Download data is not yet available.

References

El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011 Sep 22;365(12):1118-27. doi: 10.1056/NEJMra1001683. PMID: 21992124

Lavanya M, Srinivasan P, Padmini R. Unveiling the anticancer effect of syringic acid and its derivatives in hepatocellular carcinoma. Int J Appl Pharm. 2023;15(4):114-24. doi: 10.22159/ijap.2023v15i4.47773

Acharya NS, Shah UR, Shah RG, Acharya S, Hingorani L. Evaluation of in vitro anticancer activity of Symplocos racemosa bark against hepatocellular carcinoma. Int J Pharm Pharm Sci. 2015 Nov;7(11):384-5.

Jayaraman MR, V L, Grace Priyadarshini S. An Unusual Case of Hepatocellular Carcinoma in a Healthy Adolescent Male. Cureus. 2024 Apr 15;16(4):e58357. doi: 10.7759/cureus.58357. PMID: 38756304.

Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet. 2005 Oct 8;366(9493):1303-14. Erratum in: Lancet. 2006 May 20;367(9523):1656. doi: 10.1016/S0140- 6736(05)67530-7. PMID: 16214602

Wolpin BM, Mayer RJ. A step forward in the treatment of advanced biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1335-7. doi: 10.1056/NEJMe1001183. PMID: 20375411

Blechacz B, Gores GJ. Cholangiocarcinoma: Advances in pathogenesis, diagnosis, and treatment. Hepatology. 2008 Jul;48(1):308-21. doi: 10.1002/hep.22310. PMID: 18536057; PMC2547491

Pitot HC, Dragan YP. Facts and theories concerning the mechanisms of carcinogenesis. FASEB J. 1991 Jun;5(9):2280-6. PMID: 1860619

Pandey P, Elsori D, Kumar R, Lakhanpal S, Rautela I, Alqahtani TM, et al. Ferroptosis targeting natural compounds as a promising approach for developing potent liver cancer agents. Front Pharmacol. 2024 Apr 26;15:1399677. doi: 10.3389/fphar.2024.1399677. PMID: 38738178

Gray R, Peto R, Brantom P, Grasso P. Chronic nitrosamine ingestion in 1040 rodents: The effect of the choice of nitrosamine, the species studied, and the age of starting exposure. Cancer Res. 1991 Dec 1;51(23 Pt 2):6470-91. PMID: 1933908

Kawanishi S, Hiraku Y, Murata M, Oikawa S. The role of metals in site-specific DNA damage with reference to carcinogenesis. Free Radic Biol Med. 2002 May 1;32(9):822-32. doi: 10.1016/s0891-5849(02)00779-7. PMID: 11978484

Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006 Mar 10;160(1):1-40. doi: 10.1016/j.cbi.2005.12.009. PMID: 16430879

Lampimukhi M, Qassim T, Venu R, Pakhala N, Mylavarapu S, Perera T, et al. A Review of incidence and related risk factors in the development of hepatocellular carcinoma. Cureus. 2023 Nov 26;15(11):e49429. doi: 10.7759/cureus.49429. PMID: 38149129

Park TJ, Kim JY, Oh SP, Kang SY, Kim BW, Wang HJ, et al. TIS21 negatively regulates hepatocarcinogenesis by disruption of cyclin B1- Forkhead box M1 regulation loop. Hepatology. 2008 May;47(5):1533- 43. doi: 10.1002/hep.22212. PMID: 18393292

Teoh NC, Dan YY, Swisshelm K, Lehman S, Wright JH, Haque J, et al. Defective DNA strand break repair causes chromosomal instability and accelerates liver carcinogenesis in mice. Hepatology. 2008 Jun;47(6):2078-88. doi: 10.1002/hep.22194. PMID: 18506893

Williams GM, Iatropoulos MJ, Jeffrey AM. Mechanistic basis for nonlinearities and thresholds in rat liver carcinogenesis by the DNA-reactive carcinogens 2-acetylaminofluorene and diethylnitrosamine. Toxicol Pathol. 2000 May-Jun;28(3):388-95. doi: 10.1177/019262330002800306. PMID: 10862555

Zimmers TA, Jin X, Gutierrez JC, Acosta C, McKillop IH, Pierce RH, et al. Effect of in vivo loss of GDF-15 on hepatocellular carcinogenesis. J Cancer Res Clin Oncol. 2008 Jul;134(7):753-9. doi: 10.1007/s00432- 007-0336-4, PMID: 18210153

Finnberg N, Stenius U, Högberg J. Heterozygous p53-deficient (+/-) mice develop fewer p53-negative preneoplastic focal liver lesions in response to treatment with diethylnitrosamine than do wild-type (+/+) mice. Cancer Lett. 2004 Apr 30;207(2):149-55. doi: 10.1016/j. canlet.2003.11.013. PMID: 15072823

Shiota G, Harada K, Ishida M, Tomie Y, Okubo M, Katayama S, et al. Inhibition of hepatocellular carcinoma by glycyrrhizin in diethylnitrosamine-treated mice. Carcinogenesis. 1999 Jan;20(1):59- 63. doi: 10.1093/carcin/20.1.59. PMID: 9934850

Hsu HC, Jeng YM, Mao TL, Chu JS, Lai PL, Peng SY. Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am J Pathol. 2000 Sep;157(3):763-70. doi: 10.1016/s0002- 9440(10)64590-7. PMID: 10980116; PMCID: PMC1885685

Mao TL, Chu JS, Jeng YM, Lai PL, Hsu HC. Expression of mutant nuclear beta-catenin correlates with non-invasive hepatocellular carcinoma, absence of portal vein spread, and good prognosis. J Pathol. 2001 Jan;193(1):95-101. doi: 10.1002/1096-9896(2000)9999:9999<:AID-PATH720>3.0.CO;2-3. PMID: 11169521

Farber E, Solt D, Cameron R, Laishes B, Ogawa K, Medline A. Newer insights into the pathogenesis of liver cancer. Am J Pathol. 1977 Nov;89(2):477-82. PMID: 920780; PMC2032235

Klinman NR, Erslev AJ. Cellular response to partial hepatectomy. Proc Soc Exp Biol Med. 1963 Feb;112:338-40. doi: 10.3181/00379727-112- 28037. PMID: 14033567

Rignall B, Braeuning A, Buchmann A, Schwarz M. Tumor formation in liver of conditional β-catenin-deficient mice exposed to a diethylnitrosamine/phenobarbital tumor promotion regimen. Carcinogenesis. 2011 Jan;32(1):52-7. doi: 10.1093/carcin/bgq226, PMID: 21047994

Puatanachokchai R, Kakuni M, Wanibuchi H, Kinoshita A, Kang JS, Salim EI, et al. Lack of promoting effects of phenobarbital at low dose on diethylnitrosamine-induced hepatocarcinogenesis in TGF-alpha transgenic mice. Asian Pac J Cancer Prev. 2006 Apr-Jun;7(2):274-8. PMID: 16839222

Baek HJ, Lim SC, Kitisin K, Jogunoori W, Tang Y, Marshall MB, et al. Hepatocellular cancer arises from loss of transforming growth factor beta signaling adaptor protein embryonic liver fodrin through abnormal angiogenesis. Hepatology. 2008 Oct;48(4):1128-37. doi: 10.1002/ hep.22460. PMID: 18704924; PMC2747753

Lakhtakia R, Kumar V, Reddi H, Mathur M, Dattagupta S, Panda SK. Hepatocellular carcinoma in a hepatitis B “x” transgenic mouse model: A sequential pathological evaluation. J Gastroenterol Hepatol. 2003 Jan;18(1):80-91. doi: 10.1046/j.1440-1746.2003.02902.x. PMID: 12519229

Xiong J, Yao YC, Zi XY, Li JX, Wang XM, Ye XT, et al. Expression of hepatitis B virus X protein in transgenic mice. World J Gastroenterol. 2003 Jan;9(1):112-6. doi: 10.3748/wjg.v9.i1.112. PMID: 12508363; PMC4728222

Hays T, Rusyn I, Burns AM, Kennett MJ, Ward JM, Gonzalez FJ, et al. Role of peroxisome proliferator-activated receptor-alpha (PPARalpha) in bezafibrate-induced hepatocarcinogenesis and cholestasis. Carcinogenesis. 2005 Jan;26(1):219-27. doi: 10.1093/carcin/bgh285. PMID: 15447978

Zhao W, Iskandar S, Kooshki M, Sharpe JG, Payne V, Robbins ME. Knocking out peroxisome proliferator-activated receptor (PPAR) alpha inhibits radiation-induced apoptosis in the mouse kidney through activation of NF-kappaB and increased expression of IAPs. Radiat Res. 2007 May;167(5):581-91. doi: 10.1667/RR0814.1. PMID: 17474796

Yin PH, Lee HC, Chau GY, Wu YT, Li SH, Lui WY, et al. Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma. Br J Cancer. 2004 Jun 14;90(12):2390-6. doi: 10.1038/sj.bjc.6601838. PMID: 15150555; PMC2409531

Liu SP, Li YS, Chen YJ, Chiang EP, Li AF, Lee YH, et al. Glycine N-methyltransferase-/-mice develop chronic hepatitis and glycogen storage disease in the liver. Hepatology. 2007 Nov;46(5):1413- 25. Erratum in: Hepatology. 2008 Feb;47(2):769. Hwang, Shiu- Feng [corrected to Huang, Shiu-Feng]. doi: 10.1002/hep.21863. PMID: 17937387

Woo LL, Egner PA, Belanger CL, Wattanawaraporn R, Trudel LJ, Croy RG, et al. Aflatoxin B1-DNA adduct formation and mutagenicity in livers of neonatal male and female B6C3F1 mice. Toxicol Sci. 2011 Jul;122(1):38-44. Erratum in: Toxicol Sci. 2012 Jan;125(1):326. Bouhenguel, Jason T [added]. doi: 10.1093/toxsci/kfr087. PMID: 21507988; PMC3143467

Hulla JE, Chen ZY, Eaton DL. Aflatoxin B1-induced rat hepatic hyperplastic nodules do not exhibit a site-specific mutation within the p53 gene. Cancer Res. 1993 Jan 1;53(1):9-11. PMID: 8380129

Naas T, Ghorbani M, Alvarez-Maya I, Lapner M, Kothary R, De Repentigny Y, et al. Characterization of liver histopathology in a transgenic mouse model expressing genotype 1a hepatitis C virus core and envelope proteins 1 and 2. J Gen Virol. 2005 Aug;86(Pt 8):2185- 2196. doi: 10.1099/vir.0.80969-0. PMID: 16033966

Kamegaya Y, Hiasa Y, Zukerberg L, Fowler N, Blackard JT, Lin W, et al. Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis. Hepatology. 2005 Mar;41(3):660-7. doi: 10.1002/hep.20621. PMID: 15723444

Domenicali M, Caraceni P, Principe A, Pertosa AM, Ros J, Chieco P, et al. A novel sodium overload test predicting ascites decompensation in rats with CCl4-induced cirrhosis. J Hepatol. 2005 Jul;43(1):92-7. doi: 10.1016/j.jhep.2005.01.034. PMID: 15893844

Sheweita SA, Abd El-Gabar M, Bastawy M. Carbon tetrachloride-induced changes in the activity of phase II drug-metabolizing enzyme in the liver of male rats: Role of antioxidants. Toxicology. 2001 Aug 28;165(2-3):217-24. doi: 10.1016/s0300-483x(01)00429-2. PMID: 11522380

Farazi PA, Glickman J, Horner J, Depinho RA. Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res. 2006 May 1;66(9):4766-73. doi: 10.1158/0008-5472.CAN-05-4608. PMID: 16651430

Frezza EE, Gerunda GE, Farinati F, DeMaria N, Galligioni A, Plebani F, et al. CCL4-induced liver cirrhosis and hepatocellular carcinoma in rats: Relationship to plasma zinc, copper and estradiol levels. Hepatogastroenterology. 1994 Aug;41(4):367-9. PMID: 7959573

Knight B, Yeoh GC, Husk KL, Ly T, Abraham LJ, Yu C, et al. Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice. J Exp Med. 2000 Dec 18;192(12):1809-18. doi: 10.1084/jem.192.12.1809. PMID: 11120777; PMC2213505

Hasmall SC, James NH, Macdonald N, Gonzalez FJ, Peters JM, Roberts RA. Suppression of mouse hepatocyte apoptosis by peroxisome proliferators: Role of PPARalpha and TNFalpha. Mutat Res. 2000 Mar 17;448(2):193-200. doi: 10.1016/s0027-5107(99)00236-5. PMID: 10725472

Reddy JK, Rao S, Moody DE. Hepatocellular carcinomas in acatalasemic mice treated with nafenopin, a hypolipidemic peroxisome proliferator. Cancer Res. 1976 Apr;36(4):1211-7. PMID: 177202

Newell P, Villanueva A, Friedman SL, Koike K, Llovet JM. Experimental models of hepatocellular carcinoma. J Hepatol. 2008 May;48(5):858- 79. doi: 10.1016/j.jhep.2008.01.008. PMID: 18314222; PMC2990959

McGlynn KA, Hunter K, LeVoyer T, Roush J, Wise P, Michielli RA, et al. Susceptibility to aflatoxin B1-related primary hepatocellular carcinoma in mice and humans. Cancer Res. 2003 Aug 1;63(15):4594- 601. PMID: 12907637

Weisburger EK. Carcinogenicity studies on halogenated hydrocarbons. Environ Health Perspect. 1977 Dec;21:7-16. doi: 10.1289/ehp.77217. PMID: 206428; PMC1475344

Campo GM, Avenoso A, Campo S, Nastasi G, Traina P, D’Ascola A, et al. The antioxidant activity of chondroitin-4-sulphate, in carbon tetrachloride-induced acute hepatitis in mice, involves NF-kappaB and caspase activation. Br J Pharmacol. 2008 Nov;155(6):945-56. doi: 10.1038/bjp.2008.338. PMID: 18724385; PMC2597242

Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, et al. A mouse model of hepatocellular carcinoma: Ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol. 2002 Jun;160(6):2295-307. doi: 10.1016/S0002- 9440(10)61177-7. PMID: 12057932; PMC1850847

Watanabe S, Horie Y, Kataoka E, Sato W, Dohmen T, Ohshima S, et al. Non-alcoholic steatohepatitis and hepatocellular carcinoma: Lessons from hepatocyte-specific phosphatase and tensin homolog (PTEN)- deficient mice. J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S96-100. doi: 10.1111/j.1440-1746.2006.04665.x. Erratum in: J Gastroenterol Hepatol. 2008 Mar;23(3):501-2. PMID: 17567478

Seki E, Brenner DA. The role of NF-kappaB in hepatocarcinogenesis: Promoter or suppressor? J Hepatol. 2007 Aug;47(2):307-9. doi: 10.1016/j.jhep.2007.05.006. PMID: 17566588; PMC2739234

Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest. 2004 Jun;113(12):1774-83. doi: 10.1172/JCI20513. PMID: 15199412; PMC420505

Inokuchi S, Aoyama T, Miura K, Osterreicher CH, Kodama Y, Miyai K, et al. Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis. Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):844-9. doi: 10.1073/pnas.0909781107. PMID: 20080763; PMC2818947

Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R, et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell. 2007 Feb;11(2):119-32. doi: 10.1016/j.ccr.2006.12.016. PMID: 17292824

Nakano T, Cheng YF, Lai CY, Hsu LW, Chang YC, Deng JY, et al. Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats. J Hepatol. 2011 Aug;55(2):415-25. doi: 10.1016/j.jhep.2010.11.028. PMID: 21184788

de Lima VM, Oliveira CP, Alves VA, Chammas MC, Oliveira EP, Stefano JT, et al. A rodent model of NASH with cirrhosis, oval cell proliferation and hepatocellular carcinoma. J Hepatol. 2008 Dec;49(6):1055-61. doi: 10.1016/j.jhep.2008.07.024. PMID: 18929425

Zhong B, Zhou Q, Toivola DM, Tao GZ, Resurreccion EZ, Omary MB. Organ-specific stress induces mouse pancreatic keratin overexpression in association with NF-kappaB activation. J Cell Sci. 2004 Apr 1;117(Pt 9):1709-19. doi: 10.1242/jcs.01016. PMID: 15075232

Guest I, Ilic Z, Sell S. Age dependence of oval cell responses and bile duct carcinomas in male Fischer 344 rats fed a cyclic choline-deficient, ethionine-supplemented diet. Hepatology. 2010 Nov;52(5):1750-7. doi: 10.1002/hep.23880. PMID: 20842700; PMC2967670

Kodama Y, Kisseleva T, Iwaisako K, Miura K, Taura K, De Minicis S, et al. c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice. Gastroenterology. 2009 Oct;137(4):1467-77.e5. doi: 10.1053/j. gastro.2009.06.045. PMID: 19549522; PMC2757473

Yang MC, Chang CP, Lei HY. Induction of liver fibrosis in a murine hepatoma model by thioacetamide is associated with enhanced tumor growth and suppressed antitumor immunity. Lab Invest. 2010 Dec;90(12):1782-93. doi: 10.1038/labinvest.2010.139. PMID: 20680008

Rygaard J, Povlsen CO. Heterotransplantation of a human malignant tumour to “Nude” mice. Acta Pathol Microbiol Scand. 1969;77(4):758- 60. doi: 10.1111/j.1699-0463.1969.tb04520.x. PMID: 5383844

Sun FX, Tang ZY, Lui KD, Ye SL, Xue Q, Gao DM, et al. Establishment of a metastatic model of human hepatocellular carcinoma in nude mice via orthotopic implantation of histologically intact tissues. Int J Cancer. 1996 Apr 10;66(2):239-43. doi: 10.1002/(SICI)1097- 0215(19960410)66:2<239:AID-IJC17>3.0.CO;2-7. PMID: 8603818

Huynh H, Soo KC, Chow PK, Panasci L, Tran E. Xenografts of human hepatocellular carcinoma: A useful model for testing drugs. Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4306-14. doi: 10.1158/1078-0432.CCR- 05-2568. PMID: 16857806

Matsuo M, Sakurai H, Saiki I. ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, shows antimetastatic activity using a hepatocellular carcinoma model. Mol Cancer Ther. 2003 Jun;2(6):557-61. PMID: 12813135

Kornek M, Raskopf E, Tolba R, Becker U, Klöckner M, Sauerbruch T, et al. Accelerated orthotopic hepatocellular carcinomas growth is linked to increased expression of pro-angiogenic and prometastatic factors in murine liver fibrosis. Liver Int. 2008 Apr;28(4):509-18. doi: 10.1111/j.1478-3231.2008.01670.x. PMID: 18339078

Tang TC, Man S, Xu P, Francia G, Hashimoto K, Emmenegger U, et al. Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy. Neoplasia. 2010 Nov;12(11):928-40. doi: 10.1593/neo.10804. PMID: 21076618; PMC2978915

Shao DM, Wang QH, Chen C, Shen ZH, Yao M, Zhou XD, et al. N-acetylglucosaminyltransferase V activity in metastatic models of human hepatocellular carcinoma in nude mice. J Exp Clin Cancer Res. 1999 Sep;18(3):331-5. PMID: 10606178

Hollingshead MG, Alley MC, Camalier RF, Abbott BJ, Mayo JG, Malspeis L, et al. In vivo cultivation of tumor cells in hollow fibers. Life Sci. 1995;57(2):131-41. doi: 10.1016/0024-3205(95)00254-4. PMID: 7603295

Suggitt M, Bibby MC. 50 years of preclinical anticancer drug screening: Empirical to target-driven approaches. Clin Cancer Res. 2005 Feb 1;11(3):971-81. PMID: 15709162

Shnyder SD, Cooper PA, Scally AJ, Bibby MC. Reducing the cost of screening novel agents using the hollow fibre assay. Anticancer Res. 2006 May-Jun;26(3A):2049-52. PMID: 16827143

Frese KK, Tuveson DA. Maximizing mouse cancer models. Nat Rev Cancer. 2007 Sep;7(9):645-58. doi: 10.1038/nrc2192. PMID: 17687385

Tuveson DA, Jacks T. Technologically advanced cancer modeling in mice. Curr Opin Genet Dev. 2002 Feb;12(1):105-10. doi: 10.1016/ s0959-437x(01)00272-6. PMID: 11790563

Koo JS, Seong JK, Park C, Yu DY, Oh BK, Oh SH, et al. Large liver cell dysplasia in hepatitis B virus x transgenic mouse liver and human chronic hepatitis B virus-infected liver. Intervirology. 2005;48(1):16- 22. doi: 10.1159/000082090. PMID: 15785085

Beraza N, Malato Y, Sander LE, Al-Masaoudi M, Freimuth J, Riethmacher D, et al. Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. J Exp Med. 2009 Aug 3;206(8):1727-37. doi: 10.1084/jem.20082152. PMID: 19635861; PMC2722179

Harada N, Oshima H, Katoh M, Tamai Y, Oshima M, Taketo MM. Hepatocarcinogenesis in mice with beta-catenin and Ha-ras gene mutations. Cancer Res. 2004 Jan 1;64(1):48-54. doi: 10.1158/0008- 5472.can-03-2123. PMID: 14729607

Merle P, Kim M, Herrmann M, Gupte A, Lefrançois L, Califano S, et al. Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma. J Hepatol. 2005 Nov;43(5):854-62. doi: 10.1016/j. jhep.2005.05.018. PMID: 16098625

Sirica AE, Zhang Z, Lai GH, Asano T, Shen XN, Ward DJ, et al. A novel “patient-like” model of cholangiocarcinoma progression based on bile duct inoculation of tumorigenic rat cholangiocyte cell lines. Hepatology. 2008 Apr;47(4):1178-90. doi: 10.1002/hep.22088. PMID: 18081149

Fava G, Marzioni M, Benedetti A, Glaser S, DeMorrow S, Francis H, et al. Molecular pathology of biliary tract cancers. Cancer Lett. 2007 Jun 8;250(2):155-67. doi: 10.1016/j.canlet.2006.09.011. PMID: 17069969

Fingas CD, Blechacz BR, Smoot RL, Guicciardi ME, Mott J, Bronk SF, et al. A smac mimetic reduces TNF related apoptosis inducing ligand (TRAIL)-induced invasion and metastasis of cholangiocarcinoma cells. Hepatology. 2010 Aug;52(2):550-61. doi: 10.1002/hep.23729. PMID: 20683954; PMC2957364

Blechacz BR, Smoot RL, Bronk SF, Werneburg NW, Sirica AE, Gores GJ. Sorafenib inhibits signal transducer and activator of transcription-3 signaling in cholangiocarcinoma cells by activating the phosphatase shatterproof 2. Hepatology. 2009 Dec;50(6):1861-70. doi: 10.1002/hep.23214. PMID: 19821497; PMC2891152

Praet MM, Roels HJ. Histogenesis of cholangiomas and cholangiocarcinomas in thioacetamide fed rats. Exp Pathol. 1984;26(1):3-14. doi: 10.1016/s0232-1513(84)80063-8. PMID: 6207043

Dashti H, Jeppsson B, Hägerstrand I, Hultberg B, Srinivas U, Abdulla M, et al. Thioacetamide-and carbon tetrachloride-induced liver cirrhosis. Eur Surg Res. 1989;21(2):83-91. doi: 10.1159/000129007. PMID: 2767088

Al-Bader A, Mathew TC, Abul H, Al-Sayer H, Singal PK, Dashti HM. Cholangiocarcinoma and liver cirrhosis in relation to changes due to thioacetamide. Mol Cell Biochem. 2000 May;208(1-2):1-10. doi: 10.1023/a:1007082515548. PMID: 10939622

Jan YY, Yeh TS, Yeh JN, Yang HR, Chen MF. Expression of epidermal growth factor receptor, apomucins, matrix metalloproteinases, and p53 in rat and human cholangiocarcinoma: Appraisal of an animal model of cholangiocarcinoma. Ann Surg. 2004 Jul;240(1):89-94. doi: 10.1097/01.sla.0000129492.95311.f2. PMID: 15213623; PMC1356379

Yeh CN, Maitra A, Lee KF, Jan YY, Chen MF. Thioacetamide-induced intestinal-type cholangiocarcinoma in rat: An animal model recapitulating the multi-stage progression of human cholangiocarcinoma. Carcinogenesis. 2004 Apr;25(4):631-6. doi: 10.1093/carcin/bgh037. PMID: 14656942

Fava G, Alpini G, Rychlicki C, Saccomanno S, DeMorrow S, Trozzi L, et al. Leptin enhances cholangiocarcinoma cell growth. Cancer Res. 2008 Aug 15;68(16):6752-61. doi: 10.1158/0008-5472.CAN-07-6682. PMID: 18701500; PMC2556377

Marzioni M, Torrice A, Saccomanno S, Rychlicki C, Agostinelli L, Pierantonelli I, et al. An oestrogen receptor β-selective agonist exerts anti-neoplastic effects in experimental intrahepatic cholangiocarcinoma. Dig Liver Dis. 2012 Feb;44(2):134-42. doi: 10.1016/j.dld.2011.06.014. PMID: 21782536

Liu KH, Liao LM, Ro LS, Wu YL, Yeh TS. Thalidomide attenuates tumor growth and preserves fast-twitch skeletal muscle fibers in cholangiocarcinoma rats. Surgery. 2008 Mar;143(3):375-83. doi: 10.1016/j.surg.2007.09.035. PMID: 18291259

Mansuroglu T, Ramadori P, Dudás J, Malik I, Hammerich K, Füzesi L, et al. Expression of stem cell factor and its receptor c-Kit during the development of intrahepatic cholangiocarcinoma. Lab Invest. 2009 May;89(5):562-74. doi: 10.1038/labinvest.2009.15. PMID: 19255573

Laverman P, Blokx WA, Te Morsche RH, Frielink C, Boerman OC, Oyen WJ, et al. [(18)F]FDG accumulation in an experimental model of multistage progression of cholangiocarcinoma. Hepatol Res. 2007 Feb;37(2):127-32. doi: 10.1111/j.1872-034X.2007.00016.x. PMID: 17300708

Yeh CN, Lin KJ, Hsiao IT, Yen TC, Chen TW, Jan YY, et al. Animal PET for thioacetamide-induced rat cholangiocarcinoma: A novel and reliable platform. Mol Imaging Biol. 2008 Jul-Aug;10(4):209-16. doi: 10.1007/s11307-008-0141-8. PMID: 18491193

Xu X, Kobayashi S, Qiao W, Li C, Xiao C, Radaeva S, et al. Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. J Clin Invest. 2006 Jul;116(7):1843-52. doi: 10.1172/JCI27282. PMID: 16767220; PMCID: PMC1474816

Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004 Jul 15;22(14):2954-63. doi: 10.1200/JCO.2004.02.141. PMID: 15254063

Kang YK, Kim WH, Jang JJ. Expression of G1-S modulators (p53, p16, p27, cyclin D1, Rb) and Smad4/Dpc4 in intrahepatic cholangiocarcinoma. Hum Pathol. 2002 Sep;33(9):877-83. doi: 10.1053/hupa.2002.127444. PMID: 12378511

Kobayashi S, Werneburg NW, Bronk SF, Kaufmann SH, Gores GJ. Interleukin-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells. Gastroenterology. 2005 Jun;128(7):2054-65. doi: 10.1053/j. gastro.2005.03.010. PMID: 15940637

Tanno S, Yanagawa N, Habiro A, Koizumi K, Nakano Y, Osanai M, et al. Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance. Cancer Res. 2004 May 15;64(10):3486-90. doi: 10.1158/0008-5472.CAN-03- 1788. PMID: 15150102

Taura K, Miura K, Iwaisako K, Osterreicher CH, Kodama Y, Penz-Osterreicher M, et al. Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology. 2010 Mar;51(3):1027-36. doi: 10.1002/hep.23368. PMID: 20052656; PMC2906231

Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem. 2007 Aug 10;282(32):23337- 47. doi: 10.1074/jbc.M700194200. PMID: 17562716

Farazi PA, Zeisberg M, Glickman J, Zhang Y, Kalluri R, DePinho RA. Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarcinoma in p53-deficient mice. Cancer Res. 2006 Jul 1;66(13):6622-7. doi: 10.1158/0008-5472. CAN-05-4609. PMID: 16818635

Momoi H, Itoh T, Nozaki Y, Arima Y, Okabe H, Satoh S, et al. Microsatellite instability and alternative genetic pathway in intrahepatic cholangiocarcinoma. J Hepatol. 2001 Aug;35(2):235-44. doi: 10.1016/ s0168-8278(01)00106-4. PMID: 11580146

Furubo S, Harada K, Shimonishi T, Katayanagi K, Tsui W, Nakanuma Y. Protein expression and genetic alterations of p53 and ras in intrahepatic cholangiocarcinoma. Histopathology. 1999 Sep;35(3):230-40. doi: 10.1046/j.1365-2559.1999.00705.x. PMID: 10469215

Tullo A, D’Erchia AM, Honda K, Kelly MD, Habib NA, Saccone C, et al. New p53 mutations in hilar cholangiocarcinoma. Eur J Clin Invest. 2000 Sep;30(9):798-803. doi: 10.1046/j.1365-2362.2000.00717.x. PMID: 10998080

Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: Recent progress. Part 2: Molecular pathology and treatment. J Gastroenterol Hepatol. 2002 Oct;17(10):1056-63. doi: 10.1046/j.1440- 1746.2002.02780.x. PMID: 12201864

Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: Recent progress. Part 1: Epidemiology and etiology. J Gastroenterol Hepatol. 2002 Oct;17(10):1049-55. doi: 10.1046/j.1440-1746.2002.02781.x. PMID: 12201863

Endo K, Yoon BI, Pairojkul C, Demetris AJ, Sirica AE. ERBB- 2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions. Hepatology. 2002 Aug;36(2):439-50. doi: 10.1053/jhep.2002.34435. PMID: 12143054

Hudd C, Euhus DM, LaRegina MC, Herbold DR, Palmer DC, Johnson FE. Effect of cholecystokinin on human cholangiocarcinoma xenografted into nude mice. Cancer Res. 1985 Mar;45(3):1372-7. PMID: 2982488

Wang M, Xiao J, Shen M, Yahong Y, Tian R, Zhu F, et al. Isolation and characterization of tumorigenic extrahepatic cholangiocarcinoma cells with stem cell-like properties. Int J Cancer. 2011 Jan 1;128(1):72-81. doi: 10.1002/ijc.25317. PMID: 20232394

Lu D, Han C, Wu T. Microsomal prostaglandin E synthase-1 inhibits PTEN and promotes experimental cholangiocarcinogenesis and tumor progression. Gastroenterology. 2011 Jun;140(7):2084-94. doi: 10.1053/j.gastro.2011.02.056. PMID: 21354147; PMC3109169

Rozich RA, Mills DR, Brilliant KE, Callanan HM, Yang D, Tantravahi U, et al. Accumulation of neoplastic traits prior to spontaneous in vitro transformation of rat cholangiocytes determines susceptibility to activated ErbB-2/Neu. Exp Mol Pathol. 2010 Dec;89(3):248-59. doi: 10.1016/j.yexmp.2010.07.005. PMID: 20655306; PMC4012332

Shiraso S, Katayose Y, Yamamoto K, Mizuma M, Yabuuchi S, Oda A, et al. Overexpression of adenovirus-mediated p27kip1 lacking the Jab1- binding region enhances cytotoxicity and inhibits xenografted human cholangiocarcinoma growth. Anticancer Res. 2009 Jun;29(6):2015-24. PMID: 19528460

Fava G, Demorrow S, Gaudio E, Franchitto A, Onori P, Carpino G, et al. Endothelin inhibits cholangiocarcinoma growth by a decrease in the vascular endothelial growth factor expression. Liver Int. 2009 Aug;29(7):1031-42. doi: 10.1111/j.1478-3231.2009.01997.x. PMID: 19291182; PMC2706939

Fava G, Marucci L, Glaser S, Francis H, De Morrow S, Benedetti A, et al. gamma-Aminobutyric acid inhibits cholangiocarcinoma growth by cyclic AMP-dependent regulation of the protein kinase A/extracellular signal-regulated kinase 1/2 pathway. Cancer Res. 2005 Dec 15;65(24):11437-46. doi: 10.1158/0008-5472.CAN-05- 1470. PMID: 16357152

Francis H, Onori P, Gaudio E, Franchitto A, DeMorrow S, Venter J, et al. H3 histamine receptor-mediated activation of protein kinase Calpha inhibits the growth of cholangiocarcinoma in vitro and in vivo. Mol Cancer Res. 2009 Oct;7(10):1704-13. doi: 10.1158/1541-7786. MCR-09-0261. PMID: 19825989; PMC2788765

Braconi C, Huang N, Patel T. MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes. Hepatology. 2010 Mar;51(3):881-90. doi: 10.1002/hep.23381. PMID: 20146264; PMC3902044

Jing G, Yuan K, Turk AN, Jhala NC, Arnoletti JP, Zhang K, et al. Tamoxifen enhances therapeutic effects of gemcitabine on cholangiocarcinoma tumorigenesis. Lab Invest. 2011 Jun;91(6):896- 904. doi: 10.1038/labinvest.2011.60. PMID: 21464824

Huang L, Ramirez JC, Frampton GA, Golden LE, Quinn MA, Pae HY, et al. Anandamide exerts its antiproliferative actions on cholangiocarcinoma by activation of the GPR55 receptor. Lab Invest. 2011 Jul;91(7):1007-17. doi: 10.1038/labinvest.2011.62. PMID: 21464819; PMC3126905

DeMorrow S, Onori P, Venter J, Invernizzi P, Frampton G, White M, et al. Neuropeptide Y inhibits cholangiocarcinoma cell growth and invasion. Am J Physiol Cell Physiol. 2011 May;300(5):C1078-89. doi: 10.1152/ajpcell.00358.2010. PMID: 21270292; PMC3093951

DeMorrow S, Francis H, Gaudio E, Venter J, Franchitto A, Kopriva S, et al. The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway. Am J Physiol Gastrointest Liver Physiol. 2008 Dec;295(6):G1150-8. doi: 10.1152/ajpgi.90455.2008. PMID: 18832445; PMC2604798

Lang M, Henson R, Braconi C, Patel T. Epigallocatechin-gallate modulates chemotherapy-induced apoptosis in human cholangiocarcinoma cells. Liver Int. 2009 May;29(5):670-7. doi: 10.1111/j.1478- 3231.2009.01984.x. PMID: 19226332; PMC3903791

Onori P, DeMorrow S, Gaudio E, Franchitto A, Mancinelli R, Venter J, et al. Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF-kappaB and induction of apoptosis. Int J Cancer. 2009 Aug 1;125(3):565-76. doi: 10.1002/ijc.24271. PMID: 19358267; PMC3051346

Kojima Y, Honda K, Hamada H, Kobayashi N. Oncolytic gene therapy combined with double suicide genes for human bile duct cancer in nude mouse models. J Surg Res. 2009 Nov;157(1):e63-70. doi: 10.1016/j. jss.2008.12.016. PMID: 19345377

Cao LQ, Xue P, Lu HW, Zheng Q, Wen ZL, Shao ZJ. Hematoporphyrin derivative-mediated photodynamic therapy inhibits tumor growth in human cholangiocarcinoma in vitro and in vivo. Hepatol Res. 2009 Dec;39(12):1190-7. doi: 10.1111/j.1872-034X.2009.00569.x. PMID: 19788692

Frampton GA, Lazcano EA, Li H, Mohamad A, DeMorrow S. Resveratrol enhances the sensitivity of cholangiocarcinoma to chemotherapeutic agents. Lab Invest. 2010 Sep;90(9):1325-38. doi: 10.1038/labinvest.2010.99. PMID: 20458282; PMC2921554

Marienfeld C, Tadlock L, Yamagiwa Y, Patel T. Inhibition of cholangiocarcinoma growth by tannic acid. Hepatology. 2003 May;37(5):1097-104. doi: 10.1053/jhep.2003.50192. PMID: 12717390

Braconi C, Swenson E, Kogure T, Huang N, Patel T. Targeting the IL-6 dependent phenotype can identify novel therapies for cholangiocarcinoma. PLoS One. 2010 Dec 16;5(12):e15195. doi: 10.1371/journal.pone.0015195. PMID: 21179572; PMC3002961

Han Y, Demorrow S, Invernizzi P, Jing Q, Glaser S, Renzi A, et al. Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma: Its synthesis is reduced favoring cholangiocarcinoma growth. Am J Physiol Gastrointest Liver Physiol. 2011 Oct;301(4):G623-33. doi: 10.1152/ajpgi.00118.2011. PMID: 21778461; PMCID: PMC3191557

Meng F, Han Y, Staloch D, Francis T, Stokes A, Francis H. The H4 histamine receptor agonist, clobenpropit, suppresses human cholangiocarcinoma progression by disruption of epithelial mesenchymal transition and tumor metastasis. Hepatology. 2011 Nov;54(5):1718-28. doi: 10.1002/hep.24573. PMID: 21793031

Zhang K, Chen D, Wang X, Zhang S, Wang J, Gao Y, et al. RNA interference targeting slug increases cholangiocarcinoma cell sensitivity to cisplatin via upregulating PUMA. Int J Mol Sci. 2011 Jan 14;12(1):385-400. doi: 10.3390/ijms12010385. Retraction in: Int J Mol Sci. 2017 Jul 10;18(7):E1483. doi: 10.3390/ijms18071483. PMID: 21339993; PMC3039959

Yokomuro S, Tsuji H, Lunz JG 3rd, Sakamoto T, Ezure T, Murase N, et al. 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. Hepatology. 2000 Jul;32(1):26-35. doi: 10.1053/jhep.2000.8535. PMID: 10869285

Yang H, Li TW, Peng J, Tang X, Ko KS, Xia M, et al. A mouse modelof cholestasis-associated cholangiocarcinoma and transcription factors involved in progression. Gastroenterology. 2011 Jul;141(1):378- 88, 388.e1-4. doi: 10.1053/j.gastro.2011.03.044. PMID: 21440549; PMC3129489

Marquardt JU, Raggi C, Andersen JB, Seo D, Avital I, Geller D, et al. Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways. Hepatology. 2011 Sep 2;54(3):1031-42. doi: 10.1002/hep.24454. PMID: 21618577; PMC3179780

de Jong M, Maina T. Of mice and humans: are they the same?--Implications in cancer translational research. J Nucl Med. 2010 Apr;51(4):501-4. doi: 10.2967/jnumed.109.065706. PMID: 20237033

Lee JS, Chu IS, Mikaelyan A, Calvisi DF, Heo J, Reddy JK, et al. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet. 2004 Dec;36(12):1306-11. doi: 10.1038/ng1481. PMID: 15565109

De Minicis S, Kisseleva T, Francis H, Baroni GS, Benedetti A, Brenner D, Alvaro D, et al. Liver carcinogenesis: rodent models of hepatocarcinoma and cholangiocarcinoma. Dig Liver Dis. 2013 Jun;45(6):450-9. doi: 10.1016/j.dld.2012.10.008. PMID: 23177172; PMC3716909

Published

07-05-2025

How to Cite

LOKESHVAR RAVIKUMAR, et al. “EXPERIMENTAL RODENT MODELS FOR HEPATOCELLULAR CARCINOMA AND CHOLANGIOCARCINOMA: A PRE-CLINICAL FRAMEWORK FOR LIVER CANCER RESEARCH”. Asian Journal of Pharmaceutical and Clinical Research, vol. 18, no. 5, May 2025, pp. 18-31, doi:10.22159/ajpcr.2025v18i5.54026.

Issue

Section

Review Article(s)

Most read articles by the same author(s)