Dunsford H A, Sell S, Chisari F V
Department of Pathology, University of Texas Medical Branch, Galveston 77550.
Cancer Res. 1990 Jun 1;50(11):3400-7.
Fifty-nine transgenic mice from a lineage that overproduces the hepatitis B virus large envelope polypeptide and accumulates high intrahepatic concentrations of hepatitis B surface antigen were followed for evidence of liver disease throughout their 24-month life span. By 4 months of age all mice displayed biochemical and histological evidence of moderately severe chronic hepatitis which was followed sequentially by the development of regenerative nodules and oval cell hyperplasia (by 6 months), liver cell adenomas (by 8 months), and hepatocellular carcinomas (by 12 months of age). One hundred % of mice in this lineage developed hepatocellular carcinoma by 20 months of age, whereas no histopathological changes were observed in age- and sex-matched nontransgenic littermate controls over the same period of observation. These results indicate that overproduction of the hepatitis B virus large envelope polypeptide initiates a process characterized by liver cell injury, inflammation, and regenerative hyperplasia, which places large numbers of hepatocytes at risk for the development of transforming mutations, and inexorably progresses to hepatocellular carcinoma. We suggest that this is a general mechanism of hepatocarcinogenesis that may be operative in human hepatitis B virus infection and other necroinflammatory liver diseases as well.
对来自一个品系的59只转基因小鼠进行了为期24个月的跟踪观察，该品系小鼠过度产生乙肝病毒大包膜多肽，并在肝脏中积累高浓度的乙肝表面抗原，以寻找肝脏疾病的证据。到4个月大时，所有小鼠均表现出中度严重慢性肝炎的生化和组织学证据，随后依次出现再生结节和卵圆细胞增生（6个月时）、肝细胞腺瘤（8个月时）和肝细胞癌（12个月时）。该品系100%的小鼠在20个月大时发生肝细胞癌，而在相同观察期内，年龄和性别匹配的非转基因同窝对照未观察到组织病理学变化。这些结果表明，乙肝病毒大包膜多肽的过度产生引发了一个以肝细胞损伤、炎症和再生性增生为特征的过程，这使大量肝细胞有发生转化突变的风险，并不可避免地发展为肝细胞癌。我们认为，这是肝癌发生的一种普遍机制，可能在人类乙肝病毒感染和其他坏死性炎症性肝病中也起作用。
