1: Toxicol Lett. 2004 Apr 1;149(1-3):25-35. 

Role of apoptosis for mouse liver growth regulation and tumor promotion:
comparative analysis of mice with high (C3H/He) and low (C57Bl/6J) cancer
susceptibility.

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

Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a,
A-1090 Vienna, Austria. wilfried.bursch@univie.ac.at

Apoptosis constitutes one of the organisms defense lines against cancer. We
investigated whether failure of apoptosis may be concurrently causative for the
high cancer susceptibility in C3H/He as compared to C57BL/6J mice (low cancer
susceptibility). First, in short-term in vivo experiments (7-21 days), mouse
liver growth (C3H/He, C57BL/6J) was induced by administration of phenobarbital
(PB; 2 days 500 ppm + 5 days 750 ppm via the food) or nafenopin (NAF; 7 days 500
ppm via the food), cessation of PB or NAF treatment served to initiate liver
involution. Liver weight, DNA content, hepatocyte ploidy and apoptotic activity
were studied as endpoints. Secondly, in a long-term study liver carcinogenesis
was initiated by a single dose of N-nitrosodiethylamine (NDEA, 90 mg/kg b.w.) to
5-weeks-old C57Bl/6J and C3H/He mice. After 2 weeks, mice received either
standard diet or a diet containing phenobarbital (PB, 90 mg/kg b.w.) for up to
90 weeks. Cell proliferation and apoptosis in normal liver tissue and
(pre)neoplastic tissue was quantitatively analysed by histological means. The
short term studies revealed that PB and NAF-induced mouse liver growth is
essentially due to cell enlargement (hypertrophy). A moderate increase of liver
DNA content was brought about by hepatocellular polyploidization; C3H/He mice
exhibited the most pronounced ploidy shift, corresponding to their high cancer
susceptibility. Upon cessation of PB or NAF treatment, regression of liver mass
was neither associated with a loss of DNA nor an increase in apoptoses in the
liver of C3H/He and C57Bl/6J mice; food restriction did not enforce the
occurrence of apoptosis. Thus, the mouse strains did not differ with respect to
the occurrence of apoptosis. In the long-term study, PB promoted liver tumor
formation in all strains, exhibiting quantitative differences in growth kinetics
of preneoplasia rather than a specific biological quality. Quantitative analysis
of apoptosis in normal and (pre)neoplastic liver tissue of C3H/He and C57BL/6J
mice revealed no clue to explain their different cancer susceptibility. Rather,
cell proliferation seems to be the prevailing determinant of tumor promotion in
the liver of both mouse strains.

Publication Types:
    Review
    Review, Tutorial

PMID: 15093245 [PubMed - indexed for MEDLINE]