ROLE OF DIETARY RESTRICTION ON CELL TRANSFORMATION

工作总结：饮食导致超过三分之一的癌症死亡， 西方世界，但影响癌症的饮食因素是 未阐明。 减少热量摄入可以显著减缓癌症 啮齿类动物的进展，这可能是饮食的主要贡献者 对癌症的影响。 在人类和大鼠中，胰岛素样生长 因子-1（IGF-1）在饮食限制（DR）期间降低。 因为 IGF-1调节细胞增殖、凋亡和肿瘤发生， DR保护作用背后的机制可能取决于减少 这个多方面的增长因素。 在我们的研究中， 在DR期间，以确定IGF-1的降低是否是减缓 DR杂合子p53缺陷期膀胱癌进展 小鼠接受膀胱致癌物p-cresidine， 瘤前病变膀胱尿路上皮确诊后 在肿瘤形成前，将小鼠分为三组：1）自由采食 (AL)2）20%DR或3）20%DR + IGF-1（IGF-1/DR）。 血清IGF-1 DR组降低24%，IGF-1/DR组完全恢复 小鼠使用重组IGF-1通过渗透微型泵给药。 而 DR、IGF-1血清水平的恢复降低了肿瘤进展 增加了癌症的分期。 IGF-1 不依赖于体重变化的调节肿瘤进展。 率 DR组癌前病变中的细胞凋亡率是DR组的10倍， 与IGF/DR和AL处理的小鼠相比。 将IGF-1施用至 DR小鼠也刺激细胞增殖5倍， 焦点 总之，DR降低IGF-1，从而有利于细胞凋亡，而不是 细胞增殖并最终减缓肿瘤进展。 这是 第一个机制研究表明，饮食的变化会影响 由于IGF-1水平的调节而导致的癌症进展。

Summary of Work: 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.