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01.09.2003 | Original Paper | Ausgabe 9/2003

Journal of Cancer Research and Clinical Oncology 9/2003

Induction of apoptosis in mouse liver adenoma and carcinoma in vivo by transforming growth factor-β1

Zeitschrift:
Journal of Cancer Research and Clinical Oncology > Ausgabe 9/2003
Autoren:
Monika Chabicovsky, Ute Wastl, Henryk Taper, Bettina Grasl-Kraupp, Rolf Schulte-Hermann, Wilfried Bursch

Abstract

Purpose

In the liver, transforming growth factor beta-1 (TGF-β1) 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-β1 on apoptosis in liver tumors have been published yet, we studied hepatocyte sensitivity to the proapoptotic action of TGF-β1 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-β1 (56 μg or 200 μg TGF-β1/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-β1/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 μg TGF-β1/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.

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