Pathogenesis of experimental liver cancer: comparison with humans.

The multi-step nature of cancer development in the liver with chemical carcinogens is very well developed in the rat and is highly probable in humans and in mice. Since this step-by-step analysis of hepatocarcinogenesis is much more advanced in the rat than in the other two species, the pathogenesis in the rat will be briefly reviewed. Initiation steps I and II, promotion steps III and IV and progression steps V and VI will be highlighted together with further unknown steps in progression to cancer. The focal proliferation of hepatocytes, as represented by hepatocyte nodules, appears to play a central and critical role as a precursor for cancer. In the rat, nodules have a very characteristic phenotype biologically, histologically and biochemically. Some of the options available to nodules and their significance will be discussed. The possible analogy between rat on the one hand and mice and humans on the other will be presented. A critical assessment of the relevance of pathological changes seen in rats and mice to the possible carcinogenicity of agents in humans will be discussed. The urgent need for more step-by-step studies of hepatocarcinogenesis in mice is very obvious and must be stressed.