APOPTOSIS IN THE LIVER AND ITS ROLE IN HEPATOCARCINOGENESIS

Apoptosis seems to be the predominant type of active cell death in the liver (type I), while in other tissues cells may die via biochemicall y and morphologically different pathways (type II, type III). Active c ell death is under the control of growth factors and death signals. In the liver, endogenous factors, such as transforming growth factor bet a(1) (TGF-beta(1)), activin A, CD95 ligand, and tumor necrosis factor (TNF) may be involved in induction of apoptosis. Release and action of these death factors seems to be triggered by exogenous signals such a s withdrawal of hepato-mitogens, food restriction, etc. During stages of hepatocarcinogenesis, not only DNA synthesis but also apoptosis gra dually increase from normal to preneoplastic to adenoma and carcinoma tissue. Also, in human carcinomas, birth and death rates of cells are several times higher than in surrounding liver. (Pre)neoplastic liver cells are more susceptible than normal hepatocytes to stimulation of c ell replication and of cell death. Consequently, tumor promoters may a ct as survival factors; i.e., inhibit apoptosis preferentially in pren eoplastic and even in malignant liver cells, thereby stimulating selec tive growth of (pre)neoplastic lesions. On the other hand, regimens fa voring apoptosis and lowering cell replication may result in selective elimination of (pre)neoplastic cell clones from the liver. Finally, w e have studied the first stage of carcinogenesis, namely the appearanc e of putatively initiated cells after a single dose of the genotoxic c arcinogen N-nitrosomorpholine (NNM). Most of these cells were found to be eliminated by apoptosis, suggesting that initiation, at the organ level, can be reversed at least partially by preferential elimination of initiated cells. These events may be regulated by autocrine or para crine actions of survival factors.