ROLE OF DIETARY RESTRICTION ON CELL TRANSFORMATION

饮食导致超过三分之一的癌症死亡 在西方世界，影响癌症的饮食因素 没有被阐明。热量摄入的减少大大减缓了 啮齿类动物的癌症进展，这可能是一个主要贡献者 饮食对癌症的影响。在人类和大鼠中， 生长因子-1（IGF-1）在饮食限制（DR）期间降低。 由于IGF-1调节细胞增殖、凋亡和 DR保护作用背后的机制 可能取决于这种多方面增长因素的减少。在 在我们的研究中，IGF-1在DR期间恢复，以确定 IGF-1是减缓膀胱癌进展的核心 在DR期间，杂合p53缺陷小鼠接受尿 膀胱致癌物，p-克立西定，以诱导癌前病变。后 证实膀胱尿路上皮癌前病变，小鼠 分为三组：1）自由（AL），2）20% DR或 3)20%DR + IGF-1（IGF-1/DR）。血清IGF-1降低 DR组为24%，而IGF-1/DR组完全恢复 使用重组IGF-1通过渗透压给药的小鼠 微型泵虽然DR减少了肿瘤进展， DR小鼠IGF-1血清水平的恢复增加了 癌症此外，IGF-1调节肿瘤进展 与体重变化无关。细胞凋亡率 在DR小鼠中，肿瘤前病变是对照组的十倍。 IGF/DR和AL治疗的小鼠。向DR小鼠施用IGF-1 还刺激增生灶中的细胞增殖5倍。在 结论，DR降低IGF-1，从而有利于细胞凋亡， 细胞增殖并最终减缓肿瘤进展。这是 第一个机械研究表明饮食的变化 由于IGF-1水平的调节而影响癌症进展。 今年将是该项目的最后一年。

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.