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Establishment of Animal Models with Orthotopic Hepatocellular Carcinoma

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Abstract

Hepatocellular carcinoma (HCC) is one of the most serious health problems worldwide. Many researchers have investigated HCC at the level of genes, ribonucleic acid, proteins, cells, and animals. The resultant development of animal models and monitoring methods has improved the effectiveness of guidelines provided to researchers working with preclinical HCC models. HCC in animal models and clinical patients is monitored by various current imaging modalities such as ultrasound (US) imaging, computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET) and bioluminescence imaging (BLI). These techniques are currently used for both preclinical and clinical assessment, and provide valuable diagnostic information. In this article, we have mainly reviewed the established animal models and the assessment of orthotopic HCC using imaging modalities. Additionally, we have introduced a method of orthotopic HCC rat model developed in our laboratory. We have furthermore evaluated the occurrence of tumor mass using molecular imaging techniques.

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References

  1. World Health Organization. Liver Cancer Estimated Incidence, Mortality and Prevalence Worldwide in 2012. International Agency for Research on Cancer. 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed 13 Mar 2014.

  2. Siegel R, Naishadham D, Jemal A. Cancer Statistics, 2012. CA Cancer J Clin. 2012;62:10–29.

    Article  PubMed  Google Scholar 

  3. Siegel R, Naishadham D, Jemal A. Cancer Statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  4. Siegel R, Ma J, Zou Z, Jemal A. Cancer Statistics, 2014. CA Cancer J Clin. 2014;64:9–29.

    Article  PubMed  Google Scholar 

  5. Ruiz J, Mazzolini G, Sangro B, Qian C, Prieto J. Gene Therapy of Hepatocellular Carcinoma. Dig Dis. 2001;19:324–32.

    Article  CAS  PubMed  Google Scholar 

  6. Wong SY, Hann HW. Hepatitis B related hepatocellular carcinoma. OA Hepatology. 2013;1(1):7–22.

    Google Scholar 

  7. Xu C, Zhou W, Wang Y, Qiao L. Hepatitis B virus-induced hepatocellular carcinoma. Cancer Lett. 2014;345(2):216–22.

    Article  CAS  PubMed  Google Scholar 

  8. Anderson SC, Johnson DE, Harris MP, et al. p53 gene therapy in a rat model of hepatocellular carcinoma. Clin Cancer Res. 1998;4:1649–59.

    CAS  PubMed  Google Scholar 

  9. Tang ZY. Hepatocellular carcinoma-cause, treatment and metastasis. World J Gastroenterol. 2001;7(4):445–54.

    CAS  PubMed  Google Scholar 

  10. Kim KI, Lee YJ, Lee TS, Song I, Cheon GJ, Lim SM, et al. In vitro radionuclide therapy and in vivo scintigraphic imaging of alpha-fetoprotein-producing hepatocellular carcinoma by targeted sodium iodide symporter gene expression. Nucl Med Mol Imaging. 2013;47:1–8.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Quagliata L, Matter MS, Piscuoglio S, Arabi L, Ruiz C, Procino A, et al. Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients. Hepatology. 2014;59(3):911–23.

    Article  CAS  PubMed  Google Scholar 

  12. Tai WT, Shiau CW, Chen PJ, Chu PY, Huang HP, Liu CY, et al. Discovery of novel Src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma. Hepatology. 2014;59(1):190–201.

    Article  CAS  PubMed  Google Scholar 

  13. Peng YF, Shi YH, Ding ZB, Ke AW, Gu CY, Hui B, et al. Autophagy inhibition suppresses pulmonary metastasis of HCC in mice via impairing anoikis resistance and colonization of HCC cells. Autophagy. 2013;9(12):2056–68.

    Article  CAS  PubMed  Google Scholar 

  14. Huynh H, Ong R, Soo KC. Foretinib demonstrates anti-tumor activity and improves overall survival in preclinical models of hepatocellular carcinoma. Angiogenesis. 2012;15(1):59–70.

    Article  CAS  PubMed  Google Scholar 

  15. Chae MJ, Lee ST, Kim JY, Woo GS, Jung WS, Chun KS, et al. Small animal PET imaging with [124I]FIAU for herpes simplex virus type 1 thymidine kinase gene expression in a hepatoma model. Nucl Med Mol Imaging. 2008;42(3):235–45.

    Google Scholar 

  16. Lin CY, Chen JH, Liang JA, Lin CC, Jeng LB, Kao CH. 18F-FDG PET or PET/CT for detecting extrahepatic metastases or recurrent hepatocellular carcinoma: a systematic review and meta-analysis. Eur J Radiol. 2012;81(9):2417–22.

    Article  PubMed  Google Scholar 

  17. Addley HC, Griffin N, Shaw AS, Mannelli L, Parker RA, Aitken S, et al. Accuracy of hepatocellular carcinoma detection on multidetector CT in a transplant liver population with explant liver correlation. Clin Radiol. 2011;66(4):349–56.

    Article  CAS  PubMed  Google Scholar 

  18. Ma X, Liu Z, Yang X, Gao Q, Zhu S, Qin C, et al. Dual-modality monitoring of tumor response to cyclophosphamide therapy in mice with bioluminescence imaging and small-animal positron emission tomography. Mol Imaging. 2011;10(4):278–83.

    CAS  PubMed  Google Scholar 

  19. Thompson SM, Callstrom MR, Knudsen B, Anderson JL, Butters KA, Grande JP, et al. AS30D model of hepatocellular carcinoma: tumorigenicity and preliminary characterization by imaging, histopathology, and immunohistochemistry. Cardiovasc Intervent Radiol. 2013;36(1):198–203.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Schmitz V, Tirado-Ledo L, Tiemann K, Raskopf E, Heinicke T, Ziske C, et al. Establishment of an orthotopic tumour model for hepatocellular carcinoma and non-invasive in vivo tumour imaging by high resolution ultrasound in mice. J Hepatol. 2004;40(5):787–91.

    Article  PubMed  Google Scholar 

  21. Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, et al. Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol. 2001;7(5):630–6.

    CAS  PubMed  Google Scholar 

  22. Armengol C, Tarafa G, Boix L, Solé M, Queralt R, Costa D, et al. Orthotopic implantation of human hepatocellular carcinoma in mice: analysis of tumor progression and establishment of the BCLC-9 cell line. Clin Cancer Res. 2004;10(6):2150–7.

    Article  CAS  PubMed  Google Scholar 

  23. Lin HL, Lui WY, Liu TY, Chi CW. Reversal of Taxol resistance in hepatoma by cyclosporin A: involvement of the PI-3 kinase-AKT 1 pathway. Br J Cancer. 2003;88(6):973–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Lee TK, Lau TC, Ng IO. Doxorubicin-induced apoptosis and chemosensitivity in hepatoma cell lines. Cancer Chemother Pharmacol. 2002;49(1):78–86.

    Article  CAS  PubMed  Google Scholar 

  25. Yao X, Hu JF, Daniels M, et al. A novel orthotopic tumor model to study growth factors and oncogenes in hepatocarcinogenesis. Clin Cancer Res. 2003;9:2719–26.

    CAS  PubMed  Google Scholar 

  26. Ma SH, Chen GG, Yip J, Lai PB. Therapeutic effect of alpha-fetoprotein promoter-mediated tBid and chemotherapeutic agents on orthotopic liver tumor in mice. Gene Ther. 2010;17(7):905–12.

    Article  CAS  PubMed  Google Scholar 

  27. Vongchan P, Kothan S, Wutti-In Y, Linhardt RJ. Inhibition of human tumor xenograft growth in nude mice by a novel monoclonal anti-HSPG isolated from human liver. Anticancer Res. 2011;31(12):4067–74.

    CAS  PubMed  Google Scholar 

  28. Chandra PK, Kundu AK, Hazari S, Chandra S, Bao L, Ooms T, et al. Inhibition of hepatitis C virus replication by intracellular delivery of multiple siRNAs by nanosomes. Mol Ther. 2012;20(9):1724–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Cho HR, Choi JW, Kim HC, Song YS, Kim GM, Son KR, et al. Sprague-Dawley rats bearing McA-RH7777 cells for study of hepatoma and transarterial chemoembolization. Anticancer Res. 2013;33(1):223–30.

    PubMed  Google Scholar 

  30. Buijs M, Geschwind JF, Syed LH, Ganapathy-Kanniappan S, Kunjithapatham R, Wijlemans JW, et al. Spontaneous tumor regression in a syngeneic rat model of liver cancer: implications for survival studies. J Vasc Interv Radiol. 2012;23(12):1685–91.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Wu SD, Ma YS, Fang Y, Liu LL, Fu D, Shen XZ. Role of the microenvironment in hepatocellular carcinoma development and progression. Cancer Treat Rev. 2012;38(3):218–25.

    Article  CAS  PubMed  Google Scholar 

  32. Lee HJ, Choi HJ, Yang HM, Kim YM, Lee J, Chio D, et al. Establishment of primary xenograft model from newly characterized patient extrauterine carcinosarcoma. Int J Gynecol Cancer. 2013;23(9):1552–60.

    Article  PubMed  Google Scholar 

  33. Wang Q, Luan W, Goz V, Burakoff SJ, Hiotis SP. Non-invasive in vivo imaging for liver tumour progression using an orthotopic hepatocellular carcinoma model in immunocompetent mice. Liver Int. 2011;31(8):1200–8.

    Article  PubMed  Google Scholar 

  34. Walters DM, Stokes JB, Adair SJ. Stelow EB. Lowrey BT, et al. Clinical, molecular and genetic validation of a murine orthotopic xenograft model of pancreatic adenocarcinoma using fresh human specimens. PLoS ONE. 2013;8(10):e77065.

  35. Lu W, Melancon MP, Xiong C, Huang Q, Elliott A, Song S, et al. Effects of photoacoustic imaging and photothermal ablation therapy mediated by targeted hollow gold nanospheres in an orthotopic mouse xenograft model of glioma. Cancer Res. 2011;71(19):6116–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Oliva MR, Saini S. Liver cancer imaging: role of CT. US and PET. Cancer Imaging. 2004;4(Spec No A):S42-6.

  37. Cheung TT, Fan ST, Chan SC, Chok KS, Chu FS, Jenkins CR, et al. High-intensity focused ultrasound ablation: an effective bridging therapy for hepatocellular carcinoma patients. World J Gastroenterol. 2013;19(20):3083–9.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Wintermark M, Sesay M, Barbier E, Borbély K, Dillon WP, Eastwood JD, et al. Comparative overview of brain perfusion imaging techniques. J Neuroradiol. 2005;32(5):294–314.

    Article  CAS  PubMed  Google Scholar 

  39. Sarraf-Yazdi S, Mi J, Dewhirst MW, Clary BM. Use of in vivo bioluminescence imaging to predict hepatic tumor burden in mice. J Surg Res. 2004;120(2):249–55.

    Article  PubMed  Google Scholar 

  40. Zheng J, Xu L, Zhou H, Zhang W, Chen Z. Quantitative analysis of cell tracing by in vivo imaging system. J Huazhong Univ Sci Technol Med Sci. 2010;30(4):541–5.

    Article  CAS  PubMed  Google Scholar 

  41. Pino-Lagos K, Michea P, Sauma D, Alba A, Morales J, Bono MR, et al. Cyclosporin A-treated dendritic cells may affect the outcome of organ transplantation by decreasing CD4 + CD25+ regulatory T cell proliferation. Biol Res. 2010;43(3):333–7.

    Article  CAS  PubMed  Google Scholar 

  42. Rogosheske JR, Fargen AD, DeFor TE, Warlick E, Arora M, Blazar BR, et al. Higher therapeutic CsA levels early post transplantation reduce risk of acute GVHD and improves survival. Bone Marrow Transplant. 2014;49(1):122–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Hamdy S, Haddadi A, Shayeganpour A, Alshamsan A, Montazeri Aliabadi H, Lavasanifar A. The immunosuppressive activity of polymeric micellar formulation of cyclosporine A: in vitro and in vivo studies. AAPS J. 2011;13(2):159–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Hammond-McKibben D, Lake P, Zhang J, Tart-Risher N, Hugo R, Weetall M. A high-capacity quantitative mouse model of drug-mediated immunosuppression based on rejection of an allogeneic subcutaneous tumor. J Pharmacol Exp Ther. 2001;297(3):1144–51.

    CAS  PubMed  Google Scholar 

  45. Van de Vrie W, Marquet RL, Eggermont AM. Cyclosporin A enhances locoregional metastasis of the CC531 rat colon tumour. J Cancer Res Clin Oncol. 1997;123(1):21–4.

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported by Radiation Technology R&D programs through the National Research Foundation of Korea Grant (NRFG) funded by the Ministry of Education, Science and Technology (2012-M2A2A7014020, 2011-0028581).

Conflict of Interest

Tai Kyoung Lee, Kyung Sook Na, Jeonghun Kim and Hwan-Jeong Jeong declare that they have no conflict of interest.

Ethical Statement

This study was approved by the animal ethics committee in our hospital and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Research Institute of Clinical Medicine, Cyclotron Research Center, Institute for Medical Sciences, Molecular Imaging & Therapeutic Medicine Research Center, Chonbuk National University Medical School and Hospital, 634-18, Geumam-dong, Dukjin-gu, Jeonju, Republic of Korea

    Tai Kyoung Lee, Kyung Sook Na, Jeonghun Kim & Hwan-Jeong Jeong

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  1. Tai Kyoung Lee
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Lee, T.K., Na, K.S., Kim, J. et al. Establishment of Animal Models with Orthotopic Hepatocellular Carcinoma. Nucl Med Mol Imaging 48, 173–179 (2014). https://doi.org/10.1007/s13139-014-0288-y

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