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 AlbLTαβ transgenic mice as well as TAK1LPC-KO and Mcl-1Δhep 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 AlbLTαβ 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 AlbLTαβ murine livers. CGH profiles from the Mcl-1Δhep 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.
Highlights
Human hepatocellular carcinoma (HCC) is the most common primary liver cancer and has become the third leading cause of cancer related death worldwide [1, 2]
The size of cells and nuclei in individual tumors was higher in the TAK1LPC-KO and AlbLTαβ models compared to others (p < 0.01)
The challenge for future liver cancer models is to account for heterogeneity of disease, etiology-dependent pathogenesis and therapeutic targets
Summary
Human HCC is the most common primary liver cancer and has become the third leading cause of cancer related death worldwide [1, 2]. Strategies to improve the still poor survival of HCC patients rely on preclinical mouse models, such as cell-line derived models in immunocompromised mice (allo- and xenografts), genetically engineered mouse models (GEMM) and environmentally induced models. Besides the need for discovering new anti-HCC targets and compounds and testing them in vivo, it is of utmost importance to improve analyses and subtyping for preclinical mouse model research. Reporting of morphology, immunohistochemistry profiles, genetic landscapes, sequencing of the key tumor suppressors/oncogenes and growth monitoring of murine tumors is poorly standardized in mouse research [6]. Mutational profiles of murine liver tumors, with frequent CTNNB1 mutations and rare or absent TP53 alterations were characterized in earlier studies [13,14,15]
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