Animal Models of Hepatocellular Carcinoma Prevention

Hepatocellular carcinoma (HCC) is a deadly disease and therapeutic efficacy in advanced HCC is limited. Since progression of chronic liver disease to HCC involves a long latency period of a few decades, a significant window of therapeutic opportunities exists for prevention of HCC and improve patient prognosis. Nonetheless, there has been no clinical advancement in instituting HCC chemopreventive strategies. Some of the major challenges are heterogenous genetic aberrations of HCC, significant modulation of tumor microenvironment and incomplete understanding of HCC tumorigenesis. To this end, animal models of HCC are valuable tools to evaluate biology of tumor initiation and progression with specific insight into molecular and genetic mechanisms involved. In this review, we describe various animal models of HCC that facilitate effective ways to study therapeutic prevention strategies that have translational potential to be evaluated in a clinical context.

[1]  Y. Aso,et al.  The SGLT2 Inhibitor Canagliflozin Prevents Carcinogenesis in a Mouse Model of Diabetes and Non-Alcoholic Steatohepatitis-Related Hepatocarcinogenesis: Association with SGLT2 Expression in Hepatocellular Carcinoma , 2019, International journal of molecular sciences.

[2]  S. Sabbioni,et al.  Metformin prevents liver tumourigenesis by attenuating fibrosis in a transgenic mouse model of hepatocellular carcinoma , 2019, Oncogene.

[3]  J. Meyerhardt,et al.  Association of Intake of Whole Grains and Dietary Fiber With Risk of Hepatocellular Carcinoma in US Adults. , 2019, JAMA oncology.

[4]  M. Manns,et al.  Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma , 2019, Liver international : official journal of the International Association for the Study of the Liver.

[5]  Hironori Yamamoto,et al.  Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high‐fat diet , 2019, Cancer science.

[6]  M. Ferracin,et al.  MicroRNA-Based Prophylaxis in a Mouse Model of Cirrhosis and Liver Cancer , 2018, Molecular therapy. Nucleic acids.

[7]  J. Meyerhardt,et al.  Association Between Aspirin Use and Risk of Hepatocellular Carcinoma , 2018, JAMA oncology.

[8]  V. Seewaldt.  Aspirin and Chemoprevention-Have We Arrived? , 2018, JAMA oncology.

[9]  Haojie Lu,et al.  Activated hepatic stellate cells promote epithelial-to-mesenchymal transition in hepatocellular carcinoma through transglutaminase 2-induced pseudohypoxia , 2018, Communications Biology.

[10]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[11]  Masayuki Yamamoto,et al.  Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis. , 2018, Journal of hepatology.

[12]  Jean-Michel Pawlotsky,et al.  EASL Recommendations on Treatment of Hepatitis C 2018. , 2018, Journal of hepatology.

[13]  A. Hung,et al.  Metformin use and incidence cancer risk: evidence for a selective protective effect against liver cancer , 2018, Cancer Causes & Control.

[14]  P. A. Futreal,et al.  Toll-like receptor 4: a target for chemoprevention of hepatocellular carcinoma in obesity and steatohepatitis , 2018, Oncotarget.

[15]  Mohammad Hossein Khosravi,et al.  Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016 , 2018, JAMA oncology.

[16]  B. McMahon,et al.  Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance , 2018, Hepatology.

[17]  D. Calvisi,et al.  Loss of Pten synergizes with c-Met to promote hepatocellular carcinoma development via mTORC2 pathway , 2018, Experimental & Molecular Medicine.

[18]  M. Buti,et al.  The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B , 2017, Hepatology.

[19]  Alan D. Lopez,et al.  The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level , 2017, JAMA oncology.

[20]  S. Friedman,et al.  Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. , 2017, Journal of hepatology.

[21]  E. Kang,et al.  Statin use and the risk of hepatocellular carcinoma in patients at high risk: A nationwide nested case-control study. , 2017, Journal of hepatology.

[22]  D. Hutton,et al.  Cost effectiveness of regorafenib as second‐line therapy for patients with advanced hepatocellular carcinoma , 2017, Cancer.

[23]  Vincent Wai-Sun Wong,et al.  New trends on obesity and NAFLD in Asia. , 2017, Journal of hepatology.

[24]  R. Darnell,et al.  Argonaute CLIP Defines a Deregulated miR-122-Bound Transcriptome that Correlates with Patient Survival in Human Liver Cancer. , 2017, Molecular cell.

[25]  Jack Cuzick,et al.  Preventive therapy for cancer. , 2017, The Lancet. Oncology.

[26]  Thomas Berg,et al.  EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. , 2017, Journal of hepatology.

[27]  A. Gasbarrini,et al.  Hepatic decompensation is the major driver of death in HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma. , 2017, Journal of hepatology.

[28]  Jie Luo,et al.  Inhibition of the sterol regulatory element‐binding protein pathway suppresses hepatocellular carcinoma by repressing inflammation in mice , 2017, Hepatology.

[29]  Jing Wang,et al.  Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice , 2017, Clinical Cancer Research.

[30]  Takuji Tanaka,et al.  Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice , 2017, Oncotarget.

[31]  R. Vilaichone,et al.  Epidemiology and treatment of hepatocellular carcinoma in Thailand , 2017, Japanese journal of clinical oncology.

[32]  Miaoyin Liang,et al.  International incidence and mortality trends of liver cancer: a global profile , 2017, Scientific Reports.

[33]  Takuji Tanaka,et al.  Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model , 2017, Oncotarget.

[34]  D. Leslie,et al.  Independent of Cirrhosis, Hepatocellular Carcinoma Risk Is Increased with Diabetes and Metabolic Syndrome. , 2017, The American journal of medicine.

[35]  A. Subramanian,et al.  Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition. , 2016, Cancer cell.

[36]  B. Graubard,et al.  Population attributable fractions of risk factors for hepatocellular carcinoma in the United States , 2016, Cancer.

[37]  G. Lauwers,et al.  Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis , 2016, Cancer.

[38]  T. Goto,et al.  Toll-like Receptor 4 on Macrophage Promotes the Development of Steatohepatitis-related Hepatocellular Carcinoma in Mice* , 2016, The Journal of Biological Chemistry.

[39]  A. Sood,et al.  Differentiation therapy for hepatocellular carcinoma: Multifaceted effects of miR‐148a on tumor growth and phenotype and liver fibrosis , 2016, Hepatology.

[40]  H. Reeves,et al.  Hepatocellular Carcinoma in Obesity, Type 2 Diabetes, and NAFLD , 2016, Digestive Diseases and Sciences.

[41]  P. Hertzog,et al.  Optimizing mouse models for precision cancer prevention , 2016, Nature Reviews Cancer.

[42]  Jae-Eun Ryu,et al.  Metformin inhibits early stage diethylnitrosamine-induced hepatocarcinogenesis in rats , 2015, Molecular medicine reports.

[43]  Amit G Singal,et al.  Hepatocellular Carcinoma From Epidemiology to Prevention: Translating Knowledge into Practice. , 2015, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[44]  Jing-quan Li,et al.  Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma , 2015, Gut.

[45]  Takuji Tanaka,et al.  Inhibition of microRNA-214 ameliorates hepatic fibrosis and tumor incidence in platelet-derived growth factor C transgenic mice , 2015, Cancer science.

[46]  A. Rashid,et al.  miR-21 Inhibition Reduces Liver Fibrosis and Prevents Tumor Development by Inducing Apoptosis of CD24+ Progenitor Cells. , 2015, Cancer research.

[47]  J. Trebicka,et al.  The carbon tetrachloride model in mice , 2015, Laboratory animals.

[48]  M. Schwarz,et al.  Diethylnitrosamine (DEN)-induced carcinogenic liver injury in mice , 2015, Laboratory animals.

[49]  J. Bruix,et al.  SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  A. Lok,et al.  Hepatitis B virus infection , 2014, The Lancet.

[51]  Ja Hyun Koo,et al.  microRNA-148a dysregulation discriminates poor prognosis of hepatocellular carcinoma in association with USP4 overexpression , 2014, Oncotarget.

[52]  Anthony D. Schmitt,et al.  Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma , 2014, Hepatology.

[53]  S. Sabbioni,et al.  Inhibiting the oncogenic mir-221 by microRNA sponge: toward microRNA-based therapeutics for hepatocellular carcinoma , 2014, Gastroenterology and hepatology from bed to bench.

[54]  S. Gabriel,et al.  Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. , 2013, Gastroenterology.

[55]  Kenji Suzuki,et al.  A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma , 2013, Medical Molecular Morphology.

[56]  Cheng Huang,et al.  The potential of microRNAs in liver fibrosis. , 2012, Cellular signalling.

[57]  Y. Hoshida,et al.  Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges. , 2012, Current cancer drug targets.

[58]  Derek LeRoith,et al.  Obesity, type 2 diabetes, and cancer: the insulin and IGF connection. , 2012, Endocrine-related cancer.

[59]  C. Croce,et al.  Liver tumorigenicity promoted by microRNA‐221 in a mouse transgenic model , 2012, Hepatology.

[60]  Takuji Tanaka,et al.  Acyclic retinoid targets platelet-derived growth factor signaling in the prevention of hepatic fibrosis and hepatocellular carcinoma development. , 2012, Cancer research.

[61]  M. Caligiuri,et al.  Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. , 2012, The Journal of clinical investigation.

[62]  M. Sivalingam,et al.  Resveratrol interferes with N-nitrosodiethylamine-induced hepatocellular carcinoma at early and advanced stages in male Wistar rats. , 2011, Molecular medicine reports.

[63]  C. Croce,et al.  microRNA involvement in hepatocellular carcinoma. , 2011, Anti-cancer agents in medicinal chemistry.

[64]  Y. Eishi,et al.  Autophagy-deficient mice develop multiple liver tumors. , 2011, Genes & development.

[65]  J. Bruix,et al.  Management of hepatocellular carcinoma: An update , 2011, Hepatology.

[66]  M. Inoue,et al.  Impact of viral load of hepatitis C on the incidence of hepatocellular carcinoma: A population-based cohort study (JPHC Study). , 2011, Cancer letters.

[67]  M. Birnbaum,et al.  Expansion of hepatic tumor progenitor cells in Pten-null mice requires liver injury and is reversed by loss of AKT2. , 2010, Gastroenterology.

[68]  M. Foti,et al.  PTEN in liver diseases and cancer. , 2010, World journal of gastroenterology.

[69]  W. Blonski,et al.  Non-viral causes of hepatocellular carcinoma. , 2010, World journal of gastroenterology.

[70]  Suguru Yamada,et al.  Mouse model of carbon tetrachloride induced liver fibrosis: Histopathological changes and expression of CD133 and epidermal growth factor , 2010, BMC gastroenterology.

[71]  H. El‐Serag,et al.  The changing pattern of epidemiology in hepatocellular carcinoma. , 2010, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[72]  Jeannie T. Lee,et al.  Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. , 2009, Cancer cell.

[73]  F. Heindryckx,et al.  Experimental mouse models for hepatocellular carcinoma research , 2009, International journal of experimental pathology.

[74]  A. Dennison,et al.  Phytochemicals as potential chemopreventive and chemotherapeutic agents in hepatocarcinogenesis , 2009, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[75]  Puneet Puri,et al.  Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression , 2008, Hepatology.

[76]  M. Binato,et al.  Mouse model of diethylnitrosamine-induced gastric cancer. , 2008, The Journal of surgical research.

[77]  D. Corley,et al.  Racial and ethnic variations in hepatocellular carcinoma incidence within the United States. , 2008, The American journal of medicine.

[78]  B. Daniele,et al.  Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma , 2008 .

[79]  Robin Mathew,et al.  Role of autophagy in cancer , 2007, Nature Reviews Cancer.

[80]  D. Prati.  Transmission of hepatitis C virus by blood transfusions and other medical procedures: a global review. , 2006, Journal of hepatology.

[81]  Guan-Tarn Huang,et al.  Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. , 2006, JAMA.

[82]  Yibang Chen,et al.  Toll-like receptors on tumor cells facilitate evasion of immune surveillance. , 2005, Cancer research.

[83]  M. Yeh,et al.  Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[84]  W. Cacheux,et al.  Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis , 2005, Hepatology.

[85]  Robert D Cardiff,et al.  Developmental Context Determines Latency of MYC-Induced Tumorigenesis , 2004, PLoS biology.

[86]  Jian-Min Yuan,et al.  Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S. , 2004, Cancer.

[87]  M. Thun,et al.  Obesity and cancer , 2004, Oncogene.

[88]  T. Mak,et al.  Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. , 2004, The Journal of clinical investigation.

[89]  G. Sanders,et al.  Cost‐effectiveness of screening for hepatocellular carcinoma in patients with cirrhosis due to chronic hepatitis C , 2004, Alimentary pharmacology & therapeutics.

[90]  H. El‐Serag,et al.  Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. , 2004, Gastroenterology.

[91]  G. Marchesini,et al.  Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. , 2003, Gastroenterology.

[92]  K. Kanki,et al.  Prevention of dual promoting effects of pentachlorophenol, an environmental pollutant, on diethylnitrosamine-induced hepato- and cholangiocarcinogenesis in mice by green tea infusion. , 2003, Carcinogenesis.

[93]  G. Maru,et al.  Inhibition of nitrosodiethylamine-induced hepatocarcinogenesis by dietary turmeric in rats. , 2003, Toxicology letters.

[94]  M. Moore,et al.  Platelet-derived Growth Factor C (PDGF-C), a Novel Growth Factor That Binds to PDGF α and β Receptor* , 2001, The Journal of Biological Chemistry.

[95]  J. Lin,et al.  Inhibition by curcumin of diethylnitrosamine-induced hepatic hyperplasia, inflammation, cellular gene products and cell-cycle-related proteins in rats. , 2000, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[96]  L. Kömüves,et al.  Expression of Epidermal Growth Factor and Its Receptor in Cirrhotic Liver Disease , 2000, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[97]  Jen-kun Lin,et al.  Curcumin-containing diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis. , 2000, Carcinogenesis.

[98]  W. Chan,et al.  Resistance to carbon tetrachloride-induced hepatotoxicity in mice which lack CYP2E1 expression. , 1998, Toxicology and applied pharmacology.

[99]  P. Rosenthal,et al.  American Association for the Study of Liver Diseases , 1993, IDrugs : the investigational drugs journal.

[100]  R. Peto,et al.  Chronic nitrosamine ingestion in 1040 rodents: the effect of the choice of nitrosamine, the species studied, and the age of starting exposure. , 1991, Cancer research.

[101]  G. Merlino,et al.  TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas , 1990, Cell.

[102]  R. Palmiter,et al.  Oncogene-induced liver neoplasia in transgenic mice. , 1989, Oncogene.

[103]  M. Dumont,et al.  European Association for the Study of the Liver , 1971 .

[104]  W. Filipowicz,et al.  The liver-specific microRNA miR-122: biology and therapeutic potential. , 2011, Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques.

[105]  M. Moore,et al.  Platelet-derived growth factor C (PDGF-C), a novel growth factor that binds to PDGF alpha and beta receptor. , 2001, The Journal of biological chemistry.

[106]  G. Evans,et al.  Reverse genetics using transgenic mice. , 1990, Annual review of physiology.