A method utilizing chemical carcinogens and a Western diet to reliably induce advanced hepatocellular carcinoma in male and female mice

Background A combination of chemical carcinogens and Western diet have been used to induce hepatocellular carcinoma (HCC) in mice, but these models show low incidence of HCC in female mice, while mice that do develop HCC show a wide range of HCC stage development. Therefore, a more reliable method that induces advanced stage HCC in both male and female mice is warranted. The purpose of this study was to create a simple, yet tolerable and reliable method that utilizes chemical carcinogens and a Western diet to induce advanced stage HCC in both male and female mice. Methods Mice were provided with a low-fat control diet or Western diet at weaning and for the remainder of their 30-week lifetime. To induce HCC, mice given the Western diet received the sequential administration of low dose diethylnitrosamine (DEN), thioacetamide (TAA), and sucrose water. Results This method produced stage 2–3 HCC by 30 weeks of age in 100% of male mice and 96% of female mice (4% had stage 1 HCC), with a low fatality rate. Spatial transcriptomics, proteomics, and western blotting revealed this method alters gene and protein markers of HCC in a similar fashion compared to human HCC. Conclusions This study introduces a new method that utilizes chemical carcinogens and a Western diet to reliably induce advanced HCC in both male and female mice. Importantly, the method was tolerable while the HCC model is translational as it induced protein and gene signatures comparable to human advanced HCC. This new method provides a valuable HCC model that can be used to better understand the pathogenesis of HCC or for preclinical testing of new therapeutic approaches to treat advanced HCC. Clinical trial number Not applicable.