[Sequential cellular and molecular changes during hepatocarcinogenesis].

Oncogenic agents may hit at least four different types of target cells in the liver, namely the hepatocytes, the cholangiolar cells, the sinusoidal endothelial and the perisinusoidal cells. All of these cell types may give rise to neoplasms which develop from phenotypically altered preneoplastic cell populations via various intermediate stages to benign and/or malignant neoplasms. The manifestation of hepatocellular neoplasms induced by chemicals, radiation or viruses in different species including primates is regularly preceded by focal metabolic and morphological alterations which emerge in the liver parenchyma long before the neoplasms appear. The predominant sequence of metabolic changes leads from a focal excessive storage of glycogen (glycogenosis) through intermediate stages, in which the glycogenosis is frequently replaced by a lipidosis, to glycogen-poor hepatocellular carcinomas. The early hepatocellular glycogenosis is due to a disturbance in glycogen breakdown, which is associated with a dysfunction of signal transduction and glucose transport. During progression from the preneoplastic hepatocellular glycogenosis to glycogen-poor hepatocellular neoplasms a fundamental shift in carbohydrate metabolism takes place, gradually redirecting metabolites such as glucose-6-phosphate toward alternative metabolic pathways such as the pentose phosphate pathway and glycolysis. Studies on about 70 resected or explanted livers from patients bearing hepatocellular carcinomas or suffering from cirrhosis provided evidence for focal changes in glycogen metabolism similar to those observed in laboratory animals. An alternative sequence of cellular changes involving oncocytes and amphophilic cell populations rich in mitochondria and sometimes also peroxisomes has been observed in rats after administration of non-genotoxic hepatocarcinogens, particularly peroxisomal proliferators, and in woodchucks during hepadnaviral hepatocarcinogenesis. Our observations suggest fundamental changes in the cellular energy metabolism during hepatocarcinogenesis, which are most probably due to a disturbance in signal transduction pathways and may be causally linked to neoplastic cell conversion.