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ToxSci Advance Access published online on February 23, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi129
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received July 20, 2004
Accepted February 14, 2005

Carcinogenicity

Apoptosis in stages of mouse hepatocarcinogenesis: failure to counterbalance cell proliferation and to account for strain differences in tumor susceptibility

Wilfried Bursch 1*, Monika Chabicovsky 2, Ute Wastl 1, Bettina Grasl-Kraupp 1, Krystina Bukowska 1, Henryk Taper 3, and Rolf Schulte-Hermann 1

1 Medizinische Universität Wien, Univ. Klinik für Innere Medizin I Abtl. Institut für Krebsforschung, Borschkegasse 8a, A-1090 Wien
2 Medizinische Universität Wien, Univ. Klinik für Innere Medizin I Abtl. Institut für Krebsforschung, Borschkegasse 8a, A-1090 Wien; Present address: Igeneon Immunotherapy of Cancer AG, Brunner Strasse 69, A-1230 Vienna
3 Unité de Biochemie Toxicologique et Cancérologique, Université Catholique Louvain, UCL 7369, B-1200 Bruxelles

* To whom correspondence should be addressed.
Wilfried Bursch, E-mail: wilfried.bursch{at}meduniwien.ac.at


  Abstract

C3H/He and B6C3F1 show a much higher liver cancer susceptibility as C57BL/6J mice. We studied the hypothesis that this difference might result from failure of apoptosis. Hepatocarcinogenesis was induced by a single dose of N-nitrosodiethylamine (NDEA), followed by phenobarbital (PB) for up to 90 weeks. We observed:

1.) Earlier appearance of putative preneoplastic foci (PPF), hepatocellular adenoma (HCA) and carcinoma (HCC) in C3H/He than in C57Bl/6J mice.

2.) An increase of hepatocellular DNA synthesis in C3H/He and C57Bl/6J mice from normal liver via PPF and HCA to HCC. PB enhanced DNA synthesis and growth of PPF in the C3H/He strain only, and of HCA and HCC of both strains.

3.) Apoptoses were rare in unaltered livers as well as in preneoplastic lesions but tended to increase in HCA and HCC of both strains. PB lowered apoptotic activity in PPF of C3H/He mice, but enhanced it in HCA and HCC of C57Bl/6J mice at late stages.

In conclusion, the strain difference in growth rates of PPF and tumors is largely determined by higher rates of cell proliferation in C3H/He mice, with and without promotion by PB. Moreover, in C57Bl/6J mice the promoting effect of PB was restricted to HCA and HCC and was not seen in PPF. Apoptosis was generally low and was not a major cause of the strain difference in tumor susceptibility. In contrast with rat liver inhibition of apoptosis appears to be a minor determinant of tumor promotion in mice.

Keywords: B6C3F1; C3H/He; C57BL/6J; hepatocarcinogenesis; tumor susceptibility; apoptosis; cell proliferation; phenobarbital.
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