Characterization of HCC mouse models: Towards an etiology-oriented subtyping approach.

Murine liver tumors often fail to recapitulate the complexity of human hepatocellular carcinoma (HCC), which might explain the difficulty to translate preclinical mouse studies into clinical science. The aim of this study was to evaluate a subtyping approach for murine liver cancer models with regard to etiology-defined categories of human HCC, comparing genomic changes, histomorphology, and IHC profiles. Sequencing and analysis of gene copy-number changes [by comparative genomic hybridization (CGH)] in comparison with etiology-dependent subsets of HCC patients of The Cancer Genome Atlas (TCGA) database were conducted using specimens (75 tumors) of five different HCC mouse models: diethylnitrosamine (DEN) treated wild-type C57BL/6 mice, c-Myc and AlbLTab transgenic mice as well as TAK1(LPC-KO) and Mcl-1(Delta hep) mice. Digital microscopy was used for the assessment of morphology and IHC of liver cell markers (A6-CK7/19, glutamine synthetase) in mouse and n = 61 human liver tumors. Tumor CGH profiles of DEN-treated mice and c-Myc transgenic mice matched alcohol-induced HCC, including morphologic findings (abundant inclusion bodies, fatty change) in the DEN model. Tumors from AlbLT alpha beta transgenic mice and TAK1(LPC-KO) models revealed the highest overlap with NASH-HCC CGH profiles. Concordant morphology (steatosis, lymphocyte infiltration, intratumor heterogeneity) was found in AlbLT alpha beta murine livers. CGH profiles from the Mcl-1(Delta hep) model displayed similarities with hepatitis-induced HCC and characteristic human-like phenotypes (fatty change, intertumor and intratumor heterogeneity). Implications: Our findings demonstrate that stratifying preclinical mouse models along etiology-oriented genotypes and human-like phenotypes is feasible. This closer resemblance of preclinical models is expected to better recapitulate HCC subgroups and thus increase their informative value.