ROLE OF DIETARY RESTRICTION ON CELL TRANSFORMATION

超过三分之一的癌症死亡与饮食有关

Diet contributes to over one third of cancer deaths in the western world, yet the factors in the diet that influence cancer are not elucidated. A reduction in caloric intake dramatically slows cancer progression in rodents and this may be a major contributor to dietary effects on cancer. In humans as well as in rats, insulin-like growth factor-1 (IGF-1) is lowered during dietary restriction (DR). Because IGF-1 modulates cell proliferation, apoptosis, and tumorigenesis the mechanisms behind the protective effects of DR may depend upon reduction of this multifaceted growth factor. In our study, IGF-1 was restored during DR to ascertain if lowering of IGF-1 was central to slowing urinary bladder cancer progression during DR. Heterozygous p53 deficient mice received a urinary bladder carcinogen, p-cresidine, to induce preneoplasia. After confirmation of urinary bladder urothelial preneoplasia, the mice were divided into three groups: 1) ad libitum (AL), 2) 20% DR or 3) 20% DR plus IGF-1 (IGF-1/DR). Serum IGF-1 was lowered 24% by DR but was completely restored in the IGF-1/DR treated mice using recombinant IGF-1 administered via osmotic minipumps. While tumor progression was decreased by DR, restoration of IGF-1 serum levels in DR mice increased the stage of the cancers. Furthermore IGF-1 modulated tumor progression independent of changes in body weight. Rates of apoptosis in the preneoplastic lesions were ten times higher in DR mice compared to IGF/DR and AL treated mice. Administration of IGF-1 to DR mice also stimulated cell proliferation five fold in hyperplastic foci. In conclusion, DR lowered IGF-1, thereby favoring apoptosis over cell proliferation and ultimately slowing tumor progression. This is the first mechanistic study demonstrating that changes in diet influence cancer progression due to the modulation of IGF-1 levels. This will be the final year for this project.