Strong, sustained hepatocellular proliferation precedes hepatocarcinogenesis in hepatitis B surface antigen transgenic mice.
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).
Huang
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Department of Pathology, Sunnybrook Health Science Centre, University of Toronto, Canada.
Chisari
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FV
D000818:Animals; D002455:Cell Division; D006514:Hepatitis B Surface Antigens / Q000235:genetics*; D006515:Hepatitis B virus / Q000378:metabolism; D006520:Hepatitis, Animal / Q000473:pathology; D008099:Liver / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D016196:S Phase; D014407:Tumor Cells, Cultured; D014759:Viral Envelope Proteins / Q000235:genetics
D006514:Hepatitis B Surface Antigens; D014759:Viral Envelope Proteins