Biological Basis of Differential Susceptibility to Hepatocarcinogenesis among Mouse Strains

Abstract

There is a vast amount of literature related to mouse liver tumorigenesis generated over the past 60 years, not all of which has been captured here. The studies reported in this literature have generally been state of the art at the time they were carried out. A PubMed search on the topic “mouse liver tumors” covering the past 10 years yields over 7000 scientific papers. This review address several important topics related to the unresolved controversy regarding the relevance of mouse liver tumor responses observed in cancer bioassays. The inherent mouse strain differential sensitivities to hepatocarcinogenesis largely parallel the strain susceptibility to chemically induced liver neoplasia. The effects of phenobarbital and halogenated hydrocarbons in mouse hepatocarcinogenesis have been summarized because of recurring interest and numerous publications on these topics. No single simple paradigm fully explains differential mouse strain responses, which can vary more than 50-fold among inbred strains. In addition to inherent genetics, modifying factors including cell cycle balance, enzyme induction, DNA methylation, oncogenes and suppressor genes, diet, and intercellular communication influence susceptibility to spontaneous and induced mouse hepatocarcinogenesis. Comments are offered on the evaluation, interpretation, and relevance of mouse liver tumor responses in the context of cancer bioassays.

Role of CYP2B in Phenobarbital-Induced Hepatocyte Proliferation in Mice

“…The mechanistic basis for the sex difference in the extent of PB-induced hepatocyte proliferation and the apparent noninvolvement of CYP2B in the proliferative response in females are currently not understood, but they may be partly explained by the lower extent of hepatic CYP2B induction by PB in females than in males. In that regard, our present result was consistent with previous reports, that PB induced CYP2B10 to a larger extent in males than in females (Li-Masters and Morgan, 2001;Stamou et al, 2014) and that male mice were more susceptible to PB-induced hepatocarcinogenesis than female mice (Heindryckx et al, 2009;Maronpot, 2009). This sex difference in CYP2B inducibility by PB does not appear to be due to a difference in CAR expression, because cytosolic (Hernandez et al, 2009) or nuclear (Saito et al, 2013) CAR protein level was found to be similar between untreated male and female mice.…”

Hepatocellular Carcinoma: Epidemiology and Etiology

“…Interestingly, all these agents also induced cancer in other sites than the liver. These results confirm the finding that different strains of rats and mice present a different susceptibility to the development of HCC (Feo et al, 2009;Maronpot 2009). It should be noted that recent studies on genetic susceptibility and epigenetic regulation of the signaling pathways involved in hepatocarcinogenesis in rats have shown that most alterations responsible for a resistant or susceptible phenotype in rats also have a similar contribution to the prognosis of human HCC (Feo et al, 2009).…”

A review of the carcinogenic potential of bisphenol A

“…This represented a statistically significant increase compared to controls, even when preneoplastic lesions were excluded from the analysis. It is also noteworthy that hepatic tumors occurred in the absence of additional carcinogenic insult even though this study used the C56BL/6 mouse strain, a model that is considered “relatively resistant” to hepatocellular carcinoma [139]. It should be noted, however, that the doses of BPA used to achieve significant induction of liver pathologies were above the RfD, yet female offspring exhibited a significant linear dose-response for combined neoplastic and preneoplastic lesions [138].…”