The intrinsic risk of cancer increases with body size and longevity; however, big long‐lived species do not exhibit this increase, a contradiction named Peto's paradox. Five hypotheses potentially resolving this paradox were modeled using the multistage model of carcinogenesis. The five hypotheses were based on (1) intrinsic changes in metabolic rate with body size; adaptive increase in immune policing of (2) cancer cells or (3) cells with driver mutations; or adaptive increase in cancer suppression via (4) decreased somatic mutation rate, or (5) increased genetic control. Parameter changes needed to stabilize cancer risk in three types of cancer were estimated for tissues scaled from mouse size and longevity to human and blue whale levels. The metabolic rate hypothesis alone was rejected due to a conflict between the required interspecific effect with the observed intraspecific effect of size on cancer risk, but some metabolic change was optionally incorporated in the other models. Necessary parameter changes in immune policing and somatic mutation rate far exceeded values observed; however, natural selection increasing the genetic suppression of cancer was generally consistent with data. Such adaptive increases in genetic control of cancers in large and/or long‐lived animals raise the possibility that nonmodel animals will reveal novel anticancer mechanisms.

中文翻译：

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解决皮托悖论：模拟与体型相关的代谢变化以及免疫警务和癌症抑制进化的潜在影响。


患癌症的内在风险随着体型的增大和寿命的延长而增加；然而，大型长寿物种却没有表现出这种增长，这一矛盾被称为佩托悖论。使用致癌作用的多阶段模型对可能解决这一悖论的五种假设进行了建模。这五个假设基于（1）代谢率随体型的内在变化； (2) 癌细胞或 (3) 具有驱动突变的细胞的免疫监管适应性增强；或通过（4）降低体细胞突变率，或（5）增加遗传控制来适应性增强癌症抑制。针对从小鼠大小和寿命到人类和蓝鲸水平的组织，估计了稳定三种类型癌症的癌症风险所需的参数变化。由于所需的种间效应与观察到的种内大小对癌症风险的影响之间的冲突，单独的代谢率假设被拒绝，但一些代谢变化可选地纳入其他模型中。免疫警务和体细胞突变率的必要参数变化远远超过观察到的值；然而，自然选择增加了癌症的基因抑制，这与数据基本一致。大型和/或长寿动物中癌症遗传控制的这种适应性增强提高了非模型动物揭示新的抗癌机制的可能性。