Comparative Study of Liver Cancer Formation During DEN/CCL₄ and Hydrodynamic Injection- Induced Carcinogenesis

Abstract

The pronounced molecular and phenotypic heterogeneity in heapatocellular carcionoma (HCC) development poses significant challenges for developing effective therapies. Accordingly, Experimental animal models that accurately reflect HCC pathophysiology are essential. In this study, we compared two widely used murine models of HCC to evaluate their utility for investigating hepatocarcinogenesis: a chemically induced model based-diethylnitrosamine (DEN) and carbon tetrachloride (CCl₄), and a genetically driven model established by hydrodynamic tail vein injection of plasmids encoding myr-AKT and NRasV12D oncogenes. The DEN/CCl₄ model gradually induced tumors in a fibrotic and inflamed hepatic microenvironment, recapitulating the multistep carcinogenic process seen in human liver disease. In contrast, the AKT/Ras HDI model rapidly induced neoplastic lesions within weeks, providing a model to recapitulate molecular mechanisms driven by specific oncogenes or tumor suppressor genes that are regulated during hepatocarcinogenesis. Quantitative analysis revealed that the AKT/Ras model produced significantly earlier and more extensive hepatomegaly than the DEN/CCl₄ model. Histological and molecular characterization also confirmed upregulation of classical HCC markers, including AFP and GPC3, in both models. Our comparative analysis thus offers important insights into the strengths and limitations of each HCC models and highlights the critical importance of model selection in liver cancer research.