The aim of this study was to determine whether a dietary restriction, which significantly decreases body weight gain, also influences the development of diethylnitrosamine (DEN)-induced liver tumours in Swiss mice. At birth, mice were injected i.p. with a single dose of DEN (0.4 mumol/g body wt); negative control mice were sham injected. After weaning the animals received a stock diet either ad libitum (control group) or at 30% restriction (restricted group). A positive control group was fed ad libitum and received phenobarbital (500 p.p.m.) in their drinking water. At 12 weeks of age, glucose-6-phosphatase (G6Pase)-deficient foci were present in the liver of 80% of the control animals but only in 32% of the restricted group. Quantitatively, restricted animals had fewer foci per unit volume liver and these were smaller than in the control animals. By 36 weeks of age, hepatocarcinomas were seen in 100% of the control mice while in the restricted group there were no such malignant lesions and only 32% showed adenomas. The results clearly show that restriction of food intake inhibits promotion and progression of induced liver tumours. Amongst other uses, this model permits the study of the effect of dietary restriction on liver tumours, at an early stage.
Caloric restriction depresses the development of several types of tumours, yet the mechanisms involved are poorly understood. In the present experiment we investigated the development of diethylnitrosamine (DEN)-induced liver tumours in mice treated with caffeine. The latter was found to reduce body growth, possibly due to increased energy expenditure, without reducing food consumption. Newborn mice received an i.p. injection of DEN. At weaning they were either fed lab chow ad libitum, with the same diet containing 0.2% (w/w) of caffeine, or their access to food was restricted to 70% of that consumed by the ad libitum group. Diet caloric restriction starting at weaning in male Swiss mice decreased the rate of development of glucose-6-phosphatase-deficient (G6Pd) preneoplastic foci. At the age of 24 weeks, 10% of the surface of a standardized liver section of ad libitum fed mice was G6Pase negative, compared to only 1% in the restricted mice due to a reduction of the number and size of these preneoplastic foci. The number and size of G6Pd foci decreased to the same extent with the ingestion of a lab chow supplemented with 0.2% of caffeine as with the diet restriction. This finding suggests that restriction slows down hepatic tumour growth by modifying body growth rather than by limited nutrient supply. In parallel, somatomedin-C (Sm-C) and insulin secretion following glucose challenge were decreased in diet restricted mice and those treated with 0.2% caffeine. The serum Sm-C and insulin levels were respectively 480 and 4.6 ng/ml in the restricted mice, 519 and 16.6 ng/ml in the caffeine-fed mice and 664 and 25.7 ng/ml in the ad libitum fed mice. Our results suggest that the decrease of secretion of these two hormones that are known mitogens for hepatocytes in vitro may be responsible at least in part for the reduction in the growth of liver tumours.
The effects of alternating ad libitum feeding and 30% restriction of the dietary intake on the development of diethylnitrosamine (DEN)-induced hepatic neoplasia were investigated. Dietary restriction retarded the growth of glucose-6-phosphatase-deficient (G6Pd) preneoplastic foci and subsequently that of hepatocellular adenomas and adenocarcinomas. The number of foci in standardized liver sections increased from 4.44 foci/cm2 at 12 weeks to 9.65 foci/cm2 at 24 weeks in ad libitum fed animals but only from 2.35 foci/cm2 to 3.29 foci/cm2 in restricted animals. In animals fed first ad libitum for 12 weeks and then for 12 weeks on a restricted diet, the number of G6Pd foci dropped from 4.44 at 12 weeks to 3.54 at 24 weeks. This reduction appeared to be the result of a regression of the small sized G6Pd foci. Dietary restriction was most efficient in inhibiting the development of G6Pd foci when started early in life. Conversely, the growth of foci was stimulated when the mice first had restricted access to food and thereafter were fed ad libitum. The plasma insulin concentrations after a glucose challenge increased with age. Insulinaemia was much higher in ad libitum fed compared to the restricted mice. It was correlated to the number of G6Pd foci in the liver. This study suggests that insulin, which is a known mitogen for hepatocytes in vitro, may contribute to the promotion of DEN-induced liver tumours in mice.
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