Transforming growth factor beta 1-induced cell death in preneoplastic foci of rat liver and sensitization by the antiestrogen tamoxifen.
Previous studies have shown 5- to 10-fold higher rates of apoptosis in prestages of liver cancer (putative preneoplastic cell foci [PPF]) than in unaltered liver; fasting or withdrawal of tumor promoters enhanced apoptosis even further. We studied whether transforming growth factor beta 1 (TGF-beta 1), an inducer of apoptosis in normal liver, might be involved in induction of apoptosis in PPF. PPF were produced in 7-week-old female Sprague-Dawley rats with a single oral dose of the genotoxic carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). At 24 weeks of age, TGF-beta 1 was injected into animals (40 micro g/kg intravenously) either once and they were killed 4 hours later (single-dose experiment) or eight times at 24-hour intervals and they were killed 24 hours after the last administration (multiple-dose experiment). Further subgroups received daily subcutaneous injections of tamoxifen (TAM) (8 mg/kg) for 4 consecutive weeks before TGF-beta 1 treatment. In normal liver, the apoptosis incidence was low in solvent- and TAM-only-treated animals, in the single- as well as the multiple-dose experiment. TGF-beta 1, increased the apoptosis incidence severalfold, and the combined administration of TGF-beta 1 with TAM caused a further strong increase. The already-elevated basal apoptotic incidence in PPF was further increased by TGF-beta 1, and particularly by TGF-beta 1 plus TAM treatments, which resulted in a reduction of foci number and size. In summary, these results show that TGF-beta 1 can induce apoptosis in PPF. This apoptosis-inducing activity is strongly enhanced by the additional treatment with the antiestrogen TAM, which by itself does not have any cell death-inducing effect in the liver or PPF. The elevated apoptotic activity of PPF in response to TGF-beta 1 can lead to a selective reduction of the liver load with preneoplastic cells.
Müllauer
L
L
Institute for Tumor Biology-Cancer Research, University of Vienna, Austria.
Grasl-Kraupp
B
B
Bursch
W
W
Schulte-Hermann
R
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000627:therapeutic use
D004965:Estrogen Antagonists; D016212:Transforming Growth Factor beta; D013629:Tamoxifen