An orthotopic mouse model of hepatocellular carcinoma with underlying liver cirrhosis (original) (raw)

References

  1. Njei, B., Rotman, Y., Ditah, I. & Lim, J.K. Emerging trends in hepatocellular carcinoma incidence and mortality. Hepatology 61, 191–199 (2015).
    Article Google Scholar
  2. Forner, A. & Bruix, J. Biomarkers for early diagnosis of hepatocellular carcinoma. Lancet Oncol. 13, 750–751 (2012).
    Article Google Scholar
  3. Zhu, A.X., Duda, D.G., Sahani, D.V. & Jain, R.K. HCC and angiogenesis: possible targets and future directions. Nat. Rev. Clin. Oncol. 8, 292–301 (2011).
    Article CAS Google Scholar
  4. Hernandez-Gea, V., Toffanin, S., Friedman, S.L. & Llovet, J.M. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144, 512–527 (2013).
    Article Google Scholar
  5. Chauhan, V.P., Stylianopoulos, T., Boucher, Y. & Jain, R.K. Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Annu. Rev. Chem. Biomol. Eng. 2, 281–298 (2011).
    Article CAS Google Scholar
  6. Inghilesi, A.L. et al. Predictors of survival in patients with established cirrhosis and hepatocellular carcinoma treated with sorafenib. World J. Gastroenterol. 20, 786–794 (2014).
    Article Google Scholar
  7. Chen, Y. et al. Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 α/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology 59, 1435–1447 (2014).
    Article CAS Google Scholar
  8. Forner, A., Reig, M.E., de Lope, C.R. & Bruix, J. Current strategy for staging and treatment: the BCLC update and future prospects. Semin. Liver Dis. 30, 61–74 (2010).
    Article CAS Google Scholar
  9. European Association For The Study Of The Liver. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 56, 908–943 (2012).
  10. Fukumura, D. & Jain, R.K. Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J. Cell. Biochem. 101, 937–949 (2007).
    Article CAS Google Scholar
  11. Chen, Y. et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology 61, 1591–1602 (2015).
    Article CAS Google Scholar
  12. Newell, P., Villanueva, A., Friedman, S.L., Koike, K. & Llovet, J.M. Experimental models of hepatocellular carcinoma. J. Hepatol. 48, 858–879 (2008).
    Article CAS Google Scholar
  13. Huynh, H., Soo, K.C., Chow, P.K., Panasci, L. & Tran, E. Xenografts of human hepatocellular carcinoma: a useful model for testing drugs. Clin. Cancer Res. 12, 4306–4314 (2006).
    Article CAS Google Scholar
  14. Coulouarn, C. et al. Oncogene-specific gene expression signatures at preneoplastic stage in mice define distinct mechanisms of hepatocarcinogenesis. Hepatology 44, 1003–1011 (2006).
    Article CAS Google Scholar
  15. Srivastava, J. et al. Astrocyte elevated gene-1 promotes hepatocarcinogenesis: novel insights from a mouse model. Hepatology 56, 1782–1791 (2012).
    Article CAS Google Scholar
  16. Srivastava, J. et al. Astrocyte elevated gene-1 and c-Myc cooperate to promote hepatocarcinogenesis in mice. Hepatology 61, 915–929 (2015).
    Article CAS Google Scholar
  17. Stauffer, J.K. et al. Coactivation of AKT and β-catenin in mice rapidly induces formation of lipogenic liver tumors. Cancer Res. 71, 2718–2727 (2011).
    Article CAS Google Scholar
  18. Willimsky, G., Schmidt, K., Loddenkemper, C., Gellermann, J. & Blankenstein, T. Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance. J. Clin. Invest. 123, 1032–1043 (2013).
    Article CAS Google Scholar
  19. Wolf, M.J. et al. Metabolic activation of intrahepatic CD8+ T cells and NK T cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26, 549–564 (2014).
    Article CAS Google Scholar
  20. Zhou, D. et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16, 425–438 (2009).
    Article CAS Google Scholar
  21. Zender, L. et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253–1267 (2006).
    Article CAS Google Scholar
  22. Xu, M.Z. et al. AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma. Oncogene 30, 1229–1240 (2011).
    Article CAS Google Scholar
  23. Hato, T., Goyal, L., Greten, T.F., Duda, D.G. & Zhu, A.X. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology 60, 1776–1782 (2014).
    Article CAS Google Scholar
  24. Zhang, H.L. et al. Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J. Hepatol. 57, 803–812 (2012).
    Article Google Scholar
  25. Yin, H. et al. Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver. Gastroenterology 146, 801–811 (2014).
    Article CAS Google Scholar
  26. Lu, L. et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc. Natl. Acad. Sci. USA 107, 1437–1442 (2010).
    Article CAS Google Scholar
  27. Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals http://www.nap.edu/catalog/12910/guide-for-the-care-and-use-of-laboratory-animals-eighth (National Academies Press, 2011).
  28. The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 20, 15–20 (1994).
    Article Google Scholar
  29. Lee, K.H. et al. Percutaneous US-guided implantation of Vx-2 carcinoma into rabbit liver: a comparison with open surgical method. J. Surg. Res. 155, 94–99 (2009).
    Article Google Scholar
  30. Bissig, K.D., Le, T.T., Woods, N.B. & Verma, I.M. Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model. Proc. Natl. Acad. Sci. USA 104, 20507–20511 (2007).
    Article CAS Google Scholar
  31. Tannous, B.A. & Teng, J. Secreted blood reporters: insights and applications. Biotechnol. Adv. 29, 997–1003 (2011).
    Article CAS Google Scholar

Download references

Acknowledgements

The authors thank D. Nguyen, A. Pieters and C. Smith for their outstanding support in establishing this protocol. This study was supported by the NIH grant P01-CA080124, and in part by grants R01-CA159258, R21-CA139168, R01-CA126642 and National Cancer Institute/Proton Beam Federal Share Program awards (to D.G.D. and R.K.J.); by the American Cancer Society grant 120733-RSG-11-073-01-TBG (to D.G.D.); by a Max Kade Fellowship by the Austrian Academy of Science and a Erwin-Schroedinger Fellowship by the Austrian Science Funds (to T.R.); by a Howard Hughes Medical Institute Medical Research Fellowship (to C.F.); and by a Postdoctoral Fellowship from Astellas Foundation for Research on Metabolic Disorders (to T.H.).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Thomas Reiberger, Yunching Chen, Rakesh R Ramjiawan, Tai Hato, Christopher Fan, Rekha Samuel, Sylvie Roberge, Peigen Huang, Rakesh K Jain & Dan G Duda
  2. Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
    Thomas Reiberger
  3. Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan
    Yunching Chen
  4. Department of Medical Oncology, Angiogenesis Laboratory, Cancer Center Amsterdam, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands
    Rakesh R Ramjiawan
  5. Duke University School of Medicine, Durham, North Carolina, USA
    Christopher Fan
  6. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Gregory Y Lauwers
  7. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Andrew X Zhu & Nabeel Bardeesy

Authors

  1. Thomas Reiberger
  2. Yunching Chen
  3. Rakesh R Ramjiawan
  4. Tai Hato
  5. Christopher Fan
  6. Rekha Samuel
  7. Sylvie Roberge
  8. Peigen Huang
  9. Gregory Y Lauwers
  10. Andrew X Zhu
  11. Nabeel Bardeesy
  12. Rakesh K Jain
  13. Dan G Duda

Contributions

T.R., Y.C., A.X.Z., R.K.J. and D.G.D. contributed to the concept and design of the study. T.R., Y.C., R.R.R., T.H., P.H., S.R., C.F., R.S. and G.Y.L. were responsible for acquisition of the data. T.R., Y.C., R.R.R., T.H., R.S., P.H., G.Y.L., A.X.Z., N.B., R.K.J. and D.G.D. contributed to analysis and interpretation of the data. T.R., Y.C., R.R.R., T.H., C.F., R.S., S.R., P.H., G.Y.L., A.X.Z., N.B., R.K.J. and D.G.D. were involved in drafting of the article and revising it for important intellectual content.

Corresponding author

Correspondence toDan G Duda.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary information

Rights and permissions

About this article

Cite this article

Reiberger, T., Chen, Y., Ramjiawan, R. et al. An orthotopic mouse model of hepatocellular carcinoma with underlying liver cirrhosis.Nat Protoc 10, 1264–1274 (2015). https://doi.org/10.1038/nprot.2015.080

Download citation