Viral versus chemical hepatocarcinogenesis

Almost all experimental studies on hepatocarcinogenesis have been performed on models induced by chemicals. The human hepatocellular carcinoma (HCC), a highly malignant tumor, particularly frequent in the Far East and in Africa, is overwhelmingly associated with hepatitis B virus (HBV) infections and only very rarely is it caused by chemicals. This raises the question as to what degree observations on the preferentially studied chemical carcinogenesis apply to human HCC. This question is timely, since a woodchuck model has been developed in which laboratory infection with a hepadna virus, biologically and genomically similar to HBV, regularly produces HCC in prolonged surface antigen carrier woodchucks. Permanent surface antigen carriage by itself may also be a risk factor. A comparison, based on available observations of chemical and hepadna viral carcinogenesis, was attempted on four aspects: (1) histologic features, (2) growth patterns, (3) growth factors, and (4) molecular biological observations. At this time, only few conclusions can be drawn, mainly on a morphological and molecular biological basis. In the initial stage, chemicals cause mutations of very few bases, while in hepadna viral infections long sequences are inserted into both strands of chromosomal DNA. Additional studies appear to be indicated, to the greatest degree with existing methods and primarily on hepadna viral carcinogenesis. A key question is whether the active necroinflammation, preceding or observed at the time the HCC is recognized, in woodchuck and also in human chronic HBV infections is a promoting event or a secondary reaction. Additional therapeutic strategies, specific for hepadna viral carcinogenesis, can be considered, particularly elimination of hepatocytes carrying integrated viral sequences and prevention or suppression of the promoting necroinflammation. Success in HCC may be applicable to cancers related to papilloma virus in other organs, for instance, the female genital tract.