1: J Cancer Res Clin Oncol.  2003 Sep;129(9):536-42. Epub 2003 Aug 06. 

Induction of apoptosis in mouse liver adenoma and carcinoma in vivo by
transforming growth factor-beta1.

Chabicovsky M, Wastl U, Taper H, Grasl-Kraupp B, Schulte-Hermann R, Bursch W.

Institut fur Krebsforschung der Universitat Wien, Borschkegasse 8a, 1090, Wien,
Austria.

PURPOSE: In the liver, transforming growth factor beta-1 (TGF-beta1) constitutes
a major negative growth regulating factor involved in the control of cell
numbers; failure of this control mechanism has been associated with the
development of liver cancer. Since no reports on the in vivo effects of
exogenously administered TGF-beta1 on apoptosis in liver tumors have been
published yet, we studied hepatocyte sensitivity to the proapoptotic action of
TGF-beta1 in stages of chemically induced mouse liver carcinogenesis. METHODS:
Mouse liver carcinogenesis was initiated by a single dose of
N-nitrosodiethylamine (NDEA, 90 mg/kg b.w., i.p.) to 5-week-old B6C3F1 mice.
After 2 weeks, mice received either standard diet or a diet containing
phenobarbital (PB, 90 mg/kg b.w) for 85 weeks. Four hours before being killed
mice received a single dose of TGF-beta1 (56 microg or 200 microg TGF-beta1/kg
of b.w., injected into the tail vein). Quantitative histological analysis of
mitosis and apoptosis in normal liver tissue (NL), putative preneoplastic foci
(PPF), hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC) was
performed on H&E-stained liver sections. RESULTS: In NDEA and NDEA + PB-treated
mice, NL exhibited a very low incidence of apoptosis and mitosis, which
increased in HCA and HCC. In the lesions apoptoses ranged between 0.03 and 0.6%.
Two hundred micrograms of TGF-beta1/kg stimulated apoptoses in NL as well as in
neoplastic lesions (significant increase in NL, HCA, and HCC); the most
pronounced proapoptotic action of TGF-ss1 was observed in lesions of NDEA+PB
pretreated mice (about 1.7%). Fifty-six microg TGF-beta1/kg had no detectable
effect on apoptosis. CONCLUSION: These observations indicate that during
chemically induced liver carcinogenesis in B6C3F1 mice basal rates of apoptoses
in adenoma and carcinoma are higher than in normal liver and can be further
increased by a proapoptotic cytokine.

PMID: 12905009 [PubMed - indexed for MEDLINE]