Strong, sustained hepatocellular proliferation precedes hepatocarcinogenesis in hepatitis B surface antigen transgenic mice

Authors

  • Shao-Nan Huang,

    1. Department of Pathology, Sunnybrook Health Science Centre, University of Toronto, Canada
    Search for more papers by this author
  • Francis V. Chisari MD

    Corresponding author
    1. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA
    • Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10666 North Torrey Pines Rd, La Jolla, CA 92037
    Search for more papers by this author

Abstract

Hepatocyte turnover rates were studied in two lineages of transgenic mice that overproduce the hepatitis B virus (HBV) large envelope protein and retain filamentous hepatitis B surface antigen (HBsAg) particles in the endoplasmic reticulum, resulting in the formation of ground glass hepatocytes. The high producer lineage (50-4) develops a necroinflammatory liver disease that progresses to hepatocellular carcinoma (HCC), whereas the low producer lineage (107-5) displays no histopathologic changes other than ground glass hepatocytes. Bromodeoxyuridine (BrdU)-labeling studies of S-phase hepatocytes provide quantitative evidence for a strong, sustained proliferative response in the hepatocytes in lineage 50-4 that occurs after the onset of hepatocellular injury but long before the development of liver cell tumors. In contrast, the level of hepatocellular proliferation in lineage 107-5 is the same as nontransgenic controls. The findings support the concept that sustained hepatocellular proliferation plays an important role in the development of hepatocellular carcinoma (HCC).

Ancillary