Food restriction eliminates preneoplastic cells through apoptosis and antagonizes carcinogenesis in rat liver.

Abstract

Restriction of dietary calories reduces cancer formation in experimental animals and probably also in humans. This effect is generally attributed to the inhibitory effect of fasting on cell proliferation. Here we studied the effect of fasting on physiological cell death through apoptosis by using rat liver as a model. (i) In normal liver, involution of hyperplasia by apoptosis was reinforced by food withdrawal and suppressed by feeding. Complete food withdrawal for 8 days or food reduction by 40% for 3 months eliminated 20-30% of normal liver cells through apoptosis. (ii) Putative preneoplastic liver foci exhibited severalfold higher rates of DNA replication and apoptosis than unaltered liver. Food restriction lowered DNA replication but increased apoptosis, which reduced the number and volume of putative preneoplastic liver foci by 85% within 3 months. Subsequent return to ad libitum feeding normalized cell replication and apoptosis but clear differences in the volume and number of putative preneoplastic liver foci persisted throughout the following 17 months. Treatment of animals after food restriction with nafenopin, a peroxisome proliferator and potent tumor promoter, produced only half as many hepatocellular adenomas and rcinomas as in animals fed unr c throughout their lifetime. This indicates that food restriction had actually eliminated a part of the initiated cells. This study demonstrates that food restriction preferentiday enhances apoptosis of preneoplastic cells. This effect in combination with lowered cell replication provides protection from carcinogenesis.

Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes

“…Moreover, caloric restriction, which extends the life span and retards most if not all age-related pathology in these animals, increased both the basal and damage-induced levels of apoptosis, and the elimination of preneoplastic cells. in aged liver (Grasi-Kraupp et al, 1994). Thus, aging appears to suppress the apoptotic response, at least in the liver and in response to DNA damage, and suppression is retarded by regimens (caloric restriction) that retard aging.…”

Inherent growth advantage of (pre)malignant hepatocytes associated with nuclear translocation of pro-transforming growth factor α

“…At 3 weeks before treatment, animals were adapted to rhythmic feeding (from 0900 to 1400 h). This procedure synchronises DNA synthesis in the liver to a single peak per day (Grasl-Kraupp et al, 1994. After adaptation, animals were treated with a single dose of NNM (Sigma, St Louis, MO, USA; 250 mg per 10 ml phosphate-buffered saline per kg body weight).…”

“…Animals were killed by decapitation under CO 2 asphyxation. For further details, see Grasl-Kraupp et al (1994 and Löw-Baselli et al (2000a). All experiments were performed according to the 'Austrian Guidelines for Animal Care and Protection', which meet the standards required by the 'UKCCCR Guidelines for the Welfare of Animals in Experimental Neoplasia' (2nd edn.)…”

“…Human and rat liver samples, fixed in 10% buffered formaldehyde, were processed as described (Grasl-Kraupp et al, 1994 (Edmondson and Steiner, 1954). The TNM staging (tumour/node/metastasis) of the disease followed the UICC guidelines (Hermank et al, 1993).…”

“…Thus, initiation causes a change in the growth-regulatory network that becomes evident after the first replication cylce of GSTp þ cells. Treatment with tumour promoters, such as the progestin cyproterone acetate (CPA), or increased food intake further increases cell replication in preneoplasia, which is analogous to human hepatocarcinogenesis driven by anabolic steroids or overnutrition (Schulte-Hermann et al, 1990;Grasl-Kraupp et al, 1994;Fiel et al, 1996;Nair et al, 2002). This enhanced sensitivity of liver preneoplasia towards the various growth stimuli could result from an altered uptake, production and/or processing of endogeneous growth regulatory factors by the premalignant cell compartment.…”