Abstract
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.
Highlights
The multistage model of carcinogenesis was proposed by Nordling (1953) and, despite a variety of suggested modifications, remains the model that underpins our understanding of how cancer initiates
This adaptive strategy was formalized in an evolutionary model of multistage carcinogenesis (EMMC) (Nunney, 1999a, 2003)
The MR hypothesis was tested using a size-related exponent of −0.3 to define the drop in the accumulation of somatic mutations per unit time (=uk; see Equation 4), based on the assumption that the change in the rate at which somatic mutations accumulate over time is proportional to the change in cellular metabolic rate with body size (Equation 3)
Summary
The multistage model of carcinogenesis was proposed by Nordling (1953) and, despite a variety of suggested modifications (see Hornsby, Page, & Tomlinson, 2007), remains the model that underpins our understanding of how cancer initiates. The first general solution proposed to resolve Peto's paradox was via the adaptive evolution of cancer suppression through the recruitment of additional genes in the control of specific cancers This adaptive strategy was formalized in an evolutionary model of multistage carcinogenesis (EMMC) (Nunney, 1999a, 2003). | 1583 responsible for resolving Peto's paradox by keeping cancer risk relatively constant regardless of body size or longevity: nonadaptive scaling effects; adaptive cancer suppression; and adaptive immune policing (Table 1). The second goal is to test the plausibility of four evolutionary hypotheses for controlling cancer risk, either with or without some level of metabolic rate effect These evolutionary hypotheses involve adaptive changes either in cancer suppression via changes in (a) the somatic mutation rate, or (b) the number of driver mutations required to initiate a cancer, or in the policing of cancer cells via changes in (c) the immune surveillance of cancer cells, or (d) the immune surveillance of individual driver mutations. The multistage model (Equation 1) was used to quantify the potential effects of these various hypotheses on three different cancers during the theoretical transition from an organism with the size and longevity of a mouse, to one with the characteristics of a human, and of a blue whale
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