Molecular characterization of hepatocarcinogenesis using mouse models

Abstract

Hepatocellular carcinoma (HCC) is a deadly disease, often unnoticed until the late stages, when treatment options become limited. Thus, there is a crucial need to identify biomarkers for early detection of developing HCC, as well as molecular pathways that would be amenable to therapeutic intervention. Although analysis of human HCC tissues and serum components may serve these purposes, inability of early detection also precludes possibilities of identification of biomarkers or pathways that are sequentially perturbed at earlier phases of disease progression. We have therefore explored the option of utilizing mouse models to understand in a systematic and longitudinal manner the molecular pathways that are progressively deregulated by various etiological factors in contributing to HCC formation, and we report the initial findings in characterizing their validity. Hepatitis B surface antigen transgenic mice, which had been exposed to aflatoxin B1 at various stages in life, were used as a hepatitis model. Our findings confirm a synergistic effect of both these etiological factors, with a gender bias towards males for HCC predisposition. Time-based aflatoxin B1 treatment also demonstrated the requirement of non-quiescent liver for effective transformation. Tumors from these models with various etiologies resemble human HCCs histologically and at the molecular level. Extensive molecular characterization revealed the presence of an 11-gene HCC-expression signature that was able to discern transformed human hepatocytes from primary cells, regardless of etiology, and from other cancer types. Moreover, distinct molecular pathways appear to be deregulated by various etiological agents en route to formation of HCCs, in which common pathways converge, highlighting the existence of etiology-specific as well as common HCC-specific molecular perturbations. This study therefore highlights the utility of these mouse models, which provide a rich resource for the longitudinal analysis of molecular changes and biomarkers associated with HCC that could be exploited further for therapeutic targeting.

Genome-scale mutational signatures of aflatoxin in cells, mice, and human tumors

“…Under this hypothesis, we speculate that, in the HBsAg mice, oncogenesis required few AFB1 mutations in addition to the HBsAg transgene, while for wild-type mice, oncogenesis occurred only in the most heavily mutated cells. This scenario would be consistent with the observation of smaller and (Teoh et al 2015).…”

Genome-scale mutational signatures of aflatoxin in cells, mice and human tumors

“…Under this hypothesis, we speculate that in the HBsAg mice, oncogenesis required few AFB1 mutations in addition to the HBsAg transgene, while for wild-type mice, oncogenesis occurred only in the most heavily mutated cells. This scenario would be consistent with the observation of smaller and far fewer tumors in AFB1-treated wild type mice than in AFB1-treated HBsAg mice (Teoh et al 2015).…”

“…Details of the mice, their treatment, and similarity of the mouse liver tumors to human HCCs are provided in (Teoh et al 2015). Briefly, we studied tumors from 6 C57BL/6J mice, 3 of which bore an hepatitis B surface antigen (HBsAg) transgene (Chisari et al 1985).…”

Longitudinal metabolic imaging of hepatocellular carcinoma in transgenic mouse models identifies acylcarnitine as a potential biomarker for early detection

“…Histology analysis of the tumors has been described in our earlier work 22 . Gp-I HCC showed more aggressive histological features corresponding to severe carcinoma compared with Gp-II and Gp-III.…”

“…Therefore, sensitive and specific biomarkers for the early (preneoplastic stage) detection of HCC might help in prevention and better management of HCC. In this study, we used four groups of mice (three HCC groups and one control group) models which closely resemble human HCC in their histopathological features and upstream regulators 22 . We investigated the early metabolic changes from normal liver to malignant stage involving independent and cumulative risk factors of hepatitis B, and AFB 1 exposure.…”