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

Abstract

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 TAK1LPC-KO and Mcl-1Dhep 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 AlbLTab transgenic mice and TAK1LPC-KO models revealed the highest overlap with NASH-HCC CGH profiles. Concordant morphology (steatosis, lymphocyte infiltration, intratumor heterogeneity) was found in AlbLTab murine livers. CGH profiles from the Mcl-1Dhep model displayed similarities with hepatitis-induced HCC and characteristic human-like phenotypes (fatty change, intertumor and intratumor heterogeneity).