Dunn S E, Kari F W, French J, Leininger J R, Travlos G, Wilson R, Barrett J C
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA.
Cancer Res. 1997 Nov 1;57(21):4667-72.
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 contribution to dietary effects on cancer. Insulin-like growth factor I (IGF-I) is lowered during dietary restriction (DR) in both humans and rats. Because IGF-I modulates cell proliferation, apoptosis, and tumorigenesis, the mechanisms behind the protective effects of DR may depend on the reduction of this multifaceted growth factor. To test this hypothesis, IGF-I was restored during DR to ascertain if lowering of IGF-I was central to slowing bladder cancer progression during DR. Heterozygous p53-deficient mice received a bladder carcinogen, p-cresidine, to induce preneoplasia. After confirmation of bladder urothelial preneoplasia, the mice were divided into three groups: (a) ad libitum; (b) 20% DR; and (c) 20% DR plus IGF-I (IGF-I/DR). Serum IGF-I was lowered 24% by DR but was completely restored in the IGF-I/DR-treated mice using recombinant IGF-I administered via osmotic minipumps. Although tumor progression was decreased by DR, restoration of IGF-I serum levels in DR-treated mice increased the stage of the cancers. Furthermore, IGF-I modulated tumor progression independent of changes in body weight. Rates of apoptosis in the preneoplastic lesions were 10 times higher in DR-treated mice compared to those in IGF/DR- and ad libitum-treated mice. Administration of IGF-I to DR-treated mice also stimulated cell proliferation 6-fold in hyperplastic foci. In conclusion, DR lowered IGF-I levels, thereby favoring apoptosis over cell proliferation and ultimately slowing tumor progression. This is the first mechanistic study demonstrating that IGF-I supplementation abrogates the protective effect of DR on neoplastic progression.
在西方世界，饮食导致超过三分之一的癌症死亡，但饮食中影响癌症的因素尚未阐明。热量摄入的减少会显著减缓啮齿动物的癌症进展，这可能是饮食对癌症产生影响的主要原因。在人类和大鼠的饮食限制（DR）期间，胰岛素样生长因子I（IGF-I）水平会降低。由于IGF-I调节细胞增殖、凋亡和肿瘤发生，DR的保护作用背后的机制可能取决于这种多方面生长因子的减少。为了验证这一假设，在DR期间恢复IGF-I水平，以确定降低IGF-I是否是DR期间减缓膀胱癌进展的关键。杂合子p53缺陷小鼠接受膀胱致癌物对甲酚idine，以诱导癌前病变。在确认膀胱尿路上皮癌前病变后，将小鼠分为三组：（a）自由采食组；（b）20%饮食限制组；（c）20%饮食限制加IGF-I组（IGF-I/DR组）。饮食限制使血清IGF-I降低了24%，但通过渗透微型泵给予重组IGF-I，在接受IGF-I/DR治疗的小鼠中血清IGF-I完全恢复。虽然饮食限制降低了肿瘤进展，但在接受DR治疗的小鼠中恢复IGF-I血清水平会增加癌症分期。此外，IGF-I调节肿瘤进展与体重变化无关。与IGF/DR组和自由采食组小鼠相比，接受DR治疗的小鼠癌前病变中的凋亡率高出10倍。给接受DR治疗的小鼠注射IGF-I也会使增生灶中的细胞增殖增加6倍。总之，饮食限制降低了IGF-I水平，从而有利于细胞凋亡而非细胞增殖，最终减缓肿瘤进展。这是第一项表明补充IGF-I会消除饮食限制对肿瘤进展的保护作用的机制研究。
