Review Article | Published:

Mouse models of hepatocellular carcinoma: an overview and highlights for immunotherapy research

Nature Reviews Gastroenterology & Hepatologyvolume 15pages536554 (2018) | Download Citation


Mouse models are the basis of preclinical and translational research in hepatocellular carcinoma (HCC). Multiple methods exist to induce tumour formation in mice, including genetically engineered mouse models, chemotoxic agents, intrahepatic or intrasplenic injection of tumour cells and xenograft approaches. Additionally, as HCC generally develops in the context of diseased liver, methods exist to induce liver disease in mice to mimic viral hepatitis, fatty liver disease, fibrosis, alcohol-induced liver disease and cholestasis. Similar to HCC in humans, response to therapy in mouse models is monitored with imaging modalities such as CT or MRI, as well as additional techniques involving bioluminescence. As immunotherapy is increasingly applied to HCC, mouse models for these approaches are required for preclinical data. In studying cancer immunotherapy, it is important to consider aspects of antitumour immune responses and to produce a model that mimics the complexity of the immune system. This Review provides an overview of the different mouse models of HCC, presenting techniques to prepare an HCC mouse model and discussing different approaches to help researchers choose an appropriate model for a specific hypothesis. Specific aspects of immunotherapy research in HCC and the applied mouse models in this field are also highlighted.

Key points

  • Hepatocellular carcinoma (HCC) is a heterogeneous tumour and requires genetically engineered models to study different genetic mutations in detail; however, these models are limited to one specific driver mutation.

  • Liver-specific induction of HCC can be achieved by transgenic modification using liver-specific promoters, plasmid injection via liver-specific viruses, hydrodynamic injection or orthotopic implantation of tumour cells.

  • Comorbid liver disease must be considered and can be modelled by diets, injection of chemotoxic agents or expression of inflammation promoting genes.

  • Only syngeneic orthotopic and subcutaneous mouse models can be utilized to investigate immunotherapy for HCC, whereas orthotopic models in HCC mimic the tumour microenvironment more accurately.

  • Xenograft models in immunocompromised mice are useful to study specific treatment effects but lack a full immune response that includes all immune cell subsets, lymphangiogenesis and chemokine signalling.

  • Immunologically humanized mouse models might overcome the shortcomings of traditional xenograft models, but the techniques to create these models are challenging.

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The authors thank the Mouse Imaging Facility (MIF) at the NIH for preparing and providing pictures for imaging in hepatocellular carcinoma mouse models.

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  1. These authors contributed equally: Zachary J. Brown and Bernd Heinrich.


  1. Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    • Zachary J. Brown
    • , Bernd Heinrich
    •  & Tim F. Greten


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The authors declare no competing interests.

Corresponding author

Correspondence to Tim F. Greten.

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Having a fully functional immune system.


A mouse model with modifications to incorporate or mimic human cells or tissue.

Cre–Lox recombination

A method of site-specific recombination enabling investigators to manipulate genes at targeted locations in the DNA.


Enables RNA-guided cutting of DNA for targeting genes to be deleted or inserted.

Hydrodynamic injection

Injection of 10% volume per mouse weight and with high pressure to cause swelling of the liver to allow for better plasmid delivery.


Small DNA molecules distinct from the host DNA that can be induced as a vector for genetic engineering.

Latency period

The time between the exposure of a chemotoxic agent or the manipulation of a gene or genes to the development of tumour.


A procedure that occurs in the original place, such as inducing a tumour within its tissue of origin.


A procedure occurring outside the original place, such as inducing a tumour in a foreign tissue.


Genetically similar cells arising from the same species.


Tissue or cells from one species transplanted into a different species.


An organism in which certain immune subsets are absent or nonfunctional, rendering the organism unable to mount a full immune response.

Sleeping Beauty Transposon

A synthetic DNA transposon that enables incorporation of introduced genetic material into the host DNA.

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