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 biochemically and morphologically different pathways (type II, type III). Active cell death is under the control of growth factors and death signals. In the liver, endogenous factors, such as transforming growth factor beta 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 as withdrawal of hepato-mitogens, food restriction, etc. During stages of hepatocarcinogenesis, not only DNA synthesis but also apoptosis gradually 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 cell replication and of cell death. Consequently, tumor promoters may act as survival factors, i.e., inhibit apoptosis preferentially in preneoplastic and even in malignant liver cells, thereby stimulating selective growth of (pre)neoplastic lesions. On the other hand, regimens favoring apoptosis and lowering cell replication may result in selective elimination of (pre)neoplastic cell clones from the liver. Finally, we have studied the first stage of carcinogenesis, namely the appearance of putatively initiated cells after a single dose of the genotoxic carcinogen 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 paracrine actions of survival factors.
Schulte-Hermann
R
R
Institut für Tumorbiologie-Krebsforschung, Wien, Austria.
Bursch
W
W
Löw-Baselli
A
A
Wagner
A
A
Grasl-Kraupp
B
B
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001685:Biological Factors / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D008099:Liver / Q000166:cytology / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D011230:Precancerous Conditions / Q000473:pathology
D001685:Biological Factors; D004247:DNA