RATES OF APOPTOSIS AND PROLIFERATION VARY WITH CALORIC-INTAKE AND MAYINFLUENCE INCIDENCE OF SPONTANEOUS HEPATOMA IN C57BL 6 X C3H F1-MICE/

Although the dysregulation of physiological signals and mechanisms con trolling cell proliferation has been a major focus in cancer research, recent evidence suggests that explicit evaluation of apoptosis or phy siological cell death may be equally important in understanding multis tage carcinogenesis. Dietary restriction of rodents is well known to r eproducibly retard development of spontaneous and chemically induced t umors. We reasoned that the decrease in metabolic and hormonal trophic factors induced with this intervention could promote selective cell d eletion via apoptosis. To pursue this possibility, we quantified the s pontaneous apoptotic rate in liver sections from diet-restricted (DR) and nd libitum-fed (AL) 12-month-old male C57BL/6 x C3H F-1 mice, a mu rine strain known to develop a high incidence of spontaneous liver tum ors by Ig months of age. The identification of hepatocyte apoptotic bo dies was facilitated by irt situ end-labeling immunohistochemistry. Th e basal rate of proliferation of hepatocytes was quantified utilizing proliferating cell nuclear antigen immunohistochemistry. The incidence of apoptotic bodies and total proliferating cell nuclear antigen-posi tive cells was enumerated in 14 mice/group by scoring 50,000 random he patocytes/liver and expressed as the mean incidence/100 cells. When th e comparison was made between diet groups, the apoptotic rate was sign ificantly higher in the DR mice relative to the AL mice, while the pro liferation rate was significantly lower (P < 0.01 and P < 0.05, respec tively). The increase in spontaneous level of apoptosis and the decrea se in proliferation rate in livers of DR mice were associated with a s ignificantly lower rate of spontaneous hepatoma over a 36-month period . In summary, the results suggest that caloric intake may modulate the basal turnover rates of cell death and proliferation in a direction c onsistent with a cancer-protective effect in the DR mice and a cancer- promoting effect in AL mice.