Hepadnaviral hepatocarcinogenesis: in situ visualization of viral antigens, cytoplasmic compartmentation, enzymic patterns, and cellular proliferation in preneoplastic hepatocellular lineages in woodchucks.

BACKGROUND/AIMS: Hepadnaviral hepatocarcinogenesis induced in woodchucks with and without dietary aflatoxin B1 has been established as an appropriate animal model for studying the pathogenesis of human hepatocellular carcinoma in high-risk areas. Our aim in this study was the elucidation of phenotypic cellular changes in early stages of this process.

METHODS

Woodchucks were inoculated as newborns with woodchuck hepatitis virus (WHV), and partly also exposed to aflatoxin B1. Sequential hepatocellular changes in the expression of viral antigens, ultrastructural organization, cellular proliferation and apoptosis were studied in situ by electron microscopy, enzyme and immunohistochemistry.

RESULTS

A characteristic finding in WHV-infected animals (with and without aflatoxin B1) was proliferative areas of minimal structural deviation, which predominated periportally, comprised glycogen-rich, amphophilic, and ground-glass hepatocytes, and expressed the woodchuck hepatitis core and surface antigens. Two main types of proliferative foci emerged from minimal deviation areas, glycogenotic clear cell foci and amphophilic cell foci (being poor in glycogen but rich in mitochondria), giving rise to the glycogenotic-basophilic and the amphophilic preneoplastic hepatocellular lineages. A gradual loss in the expression of viral antigens appeared in both lineages, particularly early in the glycogenotic-basophilic cell lineage. Whereas glycogenosis was associated with an enzymic pattern suggesting an early activation of the insulin-signaling pathway, amphophilic cells showed changes in enzyme activities mimicking a response of the hepatocytes to thyroid hormone, which may also result from early changes in signal transduction.

CONCLUSION

Preneoplastic hepatocellular lineages in hepadnaviral and chemical hepatocarcinognesis show striking phenotypic similarities, indicating concordant and possibly synergistic early changes in signaling.