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Page 2 of 16 Liu et al. Hepatoma Res 2020;6:7 I http://dx.doi.org/10.20517/2394-5079.2019.39

INTRODUCTION
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and ranks as the fifth
most common incident cancer and the fourth most common cause of cancer-related death worldwide.
Major causes for HCC include chronic liver disease such as infection with hepatitis B virus (HBV) or
[1]
hepatitis C virus (HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) .
Over 80% of the world’s HCCs are found in less developed countries due to the influence of chronic HBV
infection; however, the incidence and mortality are largely decreasing in these regions due to immunisation
[2]
and antiviral therapy . Instead, the burden of HCC is increasing in Western or developed countries due
[3,4]
to the rise of NAFLD-associated HCC . Indeed, NAFLD has either already become or is on the verge
[5-8]
of becoming the leading cause of HCC in most Western countries . Alarmingly, even in non-Western
countries where viral hepatitis-related HCC predominates, the proportion of patients with HCC due to
NAFLD is increasing at an exponential rate [9,10] . Moreover, with no effective pharmacologic agents to date,
the burden of NAFLD is expected to rise further in the future.

The epidemiology of HCC in the context of ALD is poorly captured with heterogeneous geographic
[11]
distribution . However, current data show alcohol accounts for 21% of HCC cases globally, making it the
[12]
third leading cause (behind HBV and HCV) and the leading cause in many regions . The age-specific
incidence rates for ALD-related HCC are also increasing.

Alongside NAFLD, hereditary haemochromatosis (HH) is another metabolic liver disease impacted by
HCC which deserves special mention. HCC accounts for up to 28%-45% of deaths in HH patients and
[13]
the relative risk of HCC development in those with cirrhosis is greater than 200 . HCC has also been
described in HH patients without cirrhosis. Furthermore, iron has been implicated as a cofactor for HCC
[14]
development in other liver diseases such as NAFLD .
Therefore, with continuing improvements in global HBV vaccination coverage and effective therapies to
control HBV and eradiate HCV, alcohol and metabolic liver diseases will take their place as the major
contributors of hepatocarcinogenesis in the coming decades.

WHY DO WE NEED ANIMAL MODELS?
The biology of HCC is complex and incompletely understood with no single dominant molecular
pathology. However, therapeutic approaches for primary intervention over the past ten years have resulted
in numerous negative randomised controlled trials [15,16] . The current approved therapies for advanced
[17]
disease prolong survival by only 2-3 months . Thus, new targets for therapies are urgently needed.
Unlike other cancers, HCC can be diagnosed by imaging criteria alone and few patients (< 30%) are eligible
for curative surgical resection or liver transplantation . This has limited the availability of human HCC
[18]
tissue samples for study. Indeed, the large number of human studies that have classified human HCC
at the molecular level have almost exclusively used tissue from relatively early HCC obtained at hepatic
resection or transplantation. Thus, animal models of more advanced HCC have proved to be crucial for
investigating the genetic alterations, signalling pathways and microenvironment interactions involved
in hepatocarcinogenesis. Importantly, they also allow for the evaluation of potential novel treatment
paradigms and drugs in preclinical trials.

Although many animal models of HCC exist, this review focuses on mouse (Mus musculus) models,
which are considered some of the best animal models for studying HCC owing to their compact size,
[19]
short lifespan, breeding capacity and physiologic and genetic similarities to human biology . After a brief
overview of HCC mouse models, the review concentrates on mouse models for HCC arising from ALD,
NAFLD and HH.