Mouse models for investigating the underlying mechanisms of nonalcoholic steatohepatitis-derived hepatocellular carcinoma

Abstract

As the incidence of hepatocellular carcinoma (HCC) caused by infection with the hepatotropic viruses hepatitis B and hepatitis C decreases, greater attention has become focused on HCC caused by nonalcoholic steatohepatitis (NASH), an advanced form of nonalcoholic fatty liver disease which has shown increasing prevalence in correspondence with the overall increase in metabolic syndrome over the recent decades. Several clinical population studies have shown a positive relationship between NASH and HCC, while also providing initial insights into the underlying mechanisms of HCC development from NASH. Research into the pathological progression of NASH to HCC has advanced by use of several beneficial rodent models. In this review, we summarize the established mouse models for preclinical research of NASH-associated HCC and discuss the underlying hepatic mechanisms of NASH-related tumorigenesis identified to date that could lead to new targets for treatment and prevention.

Predicting Clinical Efficacy of Vascular Disrupting Agents in Rodent Models of Primary and Secondary Liver Cancers: An Overview with Imaging-Histopathology Correlation

“…In terms of animal models, due to the fact that non-alcoholic steatohepatitis (NASH) has played an increasingly important role in the occurrence of HCCs due to the decreasing incidence of hepatitis and improved hepatitis management, animal models of NASH-associated HCCs may better mimic the clinical scenario nowadays [81,82]. Besides, the above-mentioned studies failed to incorporate the utilization of alpha-fetoprotein (AFP) into the multi-dimensional evaluation of tumor burden as we do in clinic for screening, diagnosis, surveillance and follow-up [83].…”

Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?

“…Our opinion is that any significant progress in these fronts depends on the availability of mouse models that closely mimic human NASH. Since mouse models of NASH have been recently reviewed (Haczeyni et al, 2018; Hansen et al, 2017; Takakura et al, 2018), we focus the following discussion on preclinical models for studying NASH-driven HCC, the most dangerous outcome of untreated NASH. In addition to replicating the human pathology and showing robust progression to HCC within a reasonable timeframe (less than 12 months) and without the use of chemical carcinogens, a suitable preclinical model of NASH-driven HCC should also be responsive to the only effective HCC treatment identified thus far, inhibitors of the PD-L1:PD-1 checkpoint (El-Khoueiry et al, 2017).…”

NAFLD Preclinical Models: More than a Handful, Less of a Concern?

“…Other studies have used the hepatocyte-specific phosphatase and tensin homolog (PTEN)-deficient mouse model as a model for NAFLD [83,84]. PTEN, which is a phosphatase with activities towards both protein and lipids, was first discovered as a tumor suppressor protein [85].…”

“…More recently, its function as a metabolic regulator, also in the liver, has received increasing attention [85]. Indeed, PTEN-deficient mice were shown to display human-like lipid accumulation followed by liver fibrosis and HCC [83,84]. Nevertheless, these mice do not exhibit obvious human-like NASH features, such as increased circulating fatty acid levels and obesity, thereby limiting its translational potential.…”