Abstract
A large body of evidence suggests that neoplasia is associated with a reversal towards a foetal type of cell in terms of morphology, behaviour, antigenic and biochemical properties. This evidence is largely based on the end-point of carcinogenesis, i. e. tumours, so that theories on the mechanisms by which the foetal state arises are speculative. The work reported in this thesis concerns the study of early, as well as late, biochemical and histological changes occurring during hepatocarcinogenesis in comparison with normal liver differentiation and liver regeneration after partial hepatectomy in rats. Enzymes which show phase-specific profiles of activity during development were studied during normal liver differentiation, during chronic and two-stage (phenobarbitone-promoted) diethylnitrosamine-induced hepatocarcinogenesis, in transplantable hepatomas, during liver regeneration and the host liver of tumour-bearing rats. During chronic hepatocarcinogenesis there were increased activities of characteristic foetal enzymes whereas adult enzyme activities, with the exception of malic enzyme, decreased. These enzyme changes were apparent before histological changes indicative of neoplasia could be detected. Histological similarities with foetal and neonatal hepatocytes also developed in the livers during hepatocarcinogenesis. Rank correlation analysis of the enzyme data reveals that the liver during carcinogenesis first assumes a neonatal enzymic pattern before attaining a foetal enzymic state. In two-stage carcinogenesis experiments enzymic dedifferentiation also occurred, but to a lesser extent, and the focal lesions that developed showed phenotypic heterogeneity. Two transplantable hepatomas studied also exhibited foetal-type enzymic patterns, but contrary to previously reported data no enzymic dedifferentiation was observed in the host liver of tumour-bearing rats. A similar sequence of enzymic dedifferentiation and histological changes to that during carcinogenesis was observed in regenerating liver after partial hepatectomy, but in contrast, the cells retained the capacity to undergo redifferentiation to a normal adult histological and biochemical pattern. The results are discussed in relation to the nature of cancer, the mechanisms of carcinogenesis, and their diagnostic potential.