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 TAK1 LPC-KO and Mcl-1 Dhep 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 ¼ 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 TAK1 LPC-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-1 Dhep 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.

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…This blue light treatment followed by promotion of melatonin secretion at night inhibited tumor growth in xenograft rat models with Morris 7288CTC hepatoma although detailed mechanisms are undefined . Diethylnitrosamine (DEN) administration is utilized to induce HCC in rodents as an animal model of HCC . A previous study administered melatonin (5 or 10 mg/kg per day for 10, 20, 30, or 40 weeks via i.p.…”

“…83 Diethylnitrosamine (DEN) administration is utilized to induce HCC in rodents as an animal model of HCC. 84 A previous study administered melatonin (5 or 10 mg/kg per day for 10, 20, 30, or 40 weeks via i.p. injection) to DEN mice and demonstrated that melatonin inhibited HCC development and improved liver conditions during DEN-induced liver injury.…”

Hepatocyte apoptosis is tumor promoting in murine nonalcoholic steatohepatitis

“…6e, f), confirmed by histologic analyses. Interestingly, tumor lesions in FFC-fed Mcl1 Δhep mice differed from tumors in chow-fed Mcl1 Δhep mice 8,29 in respect to their growth pattern which frequently lacked distinct borders (Fig. 6g, left and middle image) but often showed nodule-in-nodule appearance (Fig.…”

Animal models for hepatocellular carcinoma arising from alcoholic and metabolic liver diseases

“…Therefore, a "second-hit" usually consisting of a chemical hepatotoxin is required for progression of ALD to cirrhosis and/or HCC. Indeed, of the hepatotoxins, DEN-induced C57BL/6 tumours have recently been matched to most resemble alcohol-induced HCC both morphologically and by comparative genomic hybridisation in a study comparing five different HCC models with human data [47] . Ambade et al [48] established a model of alcohol-driven HCC in adult C57BL/6 male mice.…”