Food restriction eliminates preneoplastic cells through apoptosis and antagonizes carcinogenesis in rat liver.

Restriction of dietary calories reduces cancer formation in experimental animals and probably also in humans. This effect is generally attributed to the inhibitory effect of fasting on cell proliferation. Here we studied the effect of fasting on physiological cell death through apoptosis by using rat liver as a model. (i) In normal liver, involution of hyperplasia by apoptosis was reinforced by food withdrawal and suppressed by feeding. Complete food withdrawal for 8 days or food reduction by 40% for 3 months eliminated 20-30% of normal liver cells through apoptosis. (ii) Putative preneoplastic liver foci exhibited severalfold higher rates of DNA replication and apoptosis than unaltered liver. Food restriction lowered DNA replication but increased apoptosis, which reduced the number and volume of putative preneoplastic liver foci by 85% within 3 months. Subsequent return to ad libitum feeding normalized cell replication and apoptosis but clear differences in the volume and number of putative preneoplastic liver foci persisted throughout the following 17 months. Treatment of animals after food restriction with nafenopin, a peroxisome proliferator and potent tumor promoter, produced only half as many hepatocellular adenomas and carcinomas as in animals fed unrestrictedly throughout their lifetime. This indicates that food restriction had actually eliminated a part of the initiated cells. This study demonstrates that food restriction preferentially enhances apoptosis of preneoplastic cells. This effect in combination with lowered cell replication provides protection from carcinogenesis.

膳食热量限制可降低实验动物的癌症发生风险，对人类而言该效应大概率同样成立。该保护作用通常被归因于禁食对细胞增殖的抑制效应。本研究以大鼠肝脏为模型，探究了禁食通过细胞凋亡（apoptosis）介导的生理性细胞死亡所产生的影响。(1) 在正常肝脏中，食物撤除可强化凋亡介导的增生退缩过程，而进食则会抑制该过程。连续8天完全禁食，或3个月内将食物摄入量减少40%，均可通过细胞凋亡清除20%~30%的正常肝细胞。(2) 与未发生异常改变的肝脏组织相比，潜在癌前肝脏病灶（putative preneoplastic liver foci）的DNA复制速率与细胞凋亡水平均高出数倍。膳食限制会降低DNA复制速率，同时提升细胞凋亡水平，这一联合作用可在3个月内使潜在癌前肝脏病灶的数量与体积减少85%。后续恢复自由进食后，细胞复制与凋亡水平恢复至正常状态，但潜在癌前肝脏病灶的体积与数量差异在随后的17个月中仍持续存在。对膳食限制后的动物给予那芬诺平（nafenopin，一种过氧化物酶体增殖剂与强效肿瘤启动促进剂）干预，其肝细胞腺瘤与肝细胞癌的发生数量仅为终身自由进食对照组的一半。该结果表明，膳食限制实际上已清除了部分肿瘤起始细胞。本研究证实，膳食限制可优先增强癌前细胞的凋亡。该效应与细胞增殖水平降低相结合，可为机体提供抗癌变保护。