2014
DOI: 10.18632/aging.100707
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Abstract: Age-dependent tissue decline and increased cancer incidence are widely accepted to be rate-limited by the accumulation of somatic mutations over time. Current models of carcinogenesis are dominated by the assumption that oncogenic mutations have defined advantageous fitness effects on recipient stem and progenitor cells, promoting and rate-limiting somatic evolution. However, this assumption is markedly discrepant with evolutionary theory, whereby fitness is a dynamic property of a phenotype imposed upon and w… Show more

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Cited by 53 publications
(61 citation statements)
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References 71 publications
(77 reference statements)
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“…However, in the BM microenvironment of antiinflammatory aged mice, selection for NRAS V12 was completely suppressed. We propose that the maintenance of hematopoietic progenitor fitness in both young and antiinflammatory, aged backgrounds can prevent oncogenic adaptation via stabilizing selection (35,83). While oncogenic NRAS can restore fitness parameters (such as for signaling) in B progenitors (whether young or old) in an old hematopoietic background, it does not do so for progenitors in either young microenvironments or old but antiinflammatory microenvironments, as there appears to be little room for improvement.…”
Section: Edu Analysis Of B Progenitor Populationsmentioning
confidence: 98%
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“…However, in the BM microenvironment of antiinflammatory aged mice, selection for NRAS V12 was completely suppressed. We propose that the maintenance of hematopoietic progenitor fitness in both young and antiinflammatory, aged backgrounds can prevent oncogenic adaptation via stabilizing selection (35,83). While oncogenic NRAS can restore fitness parameters (such as for signaling) in B progenitors (whether young or old) in an old hematopoietic background, it does not do so for progenitors in either young microenvironments or old but antiinflammatory microenvironments, as there appears to be little room for improvement.…”
Section: Edu Analysis Of B Progenitor Populationsmentioning
confidence: 98%
“…Using transgenic expression of two different proteins, α-1-antitrypsin (AAT) and IL-37, in order to reduce inflammation in old mice, we show that preventing aging-associated reductions in B progenitor fitness abrogates selection for oncogene-initiated progenitors. dicts evolutionary theory, which holds that fitness is dictated by the interaction of a genotype-defined phenotype with the environment (35). Similarly, the somatic mutation theory of aging largely attributes age-dependent tissue decline to the accumulation of somatic mutations throughout life (2,32,33,36).…”
Section: Introductionmentioning
confidence: 99%
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“…Such approaches are applicable to the interpretation of many other complex phenomena in cancer (e.g., phenomena discussed in refs. [9][10][11][12]. iii) Another use of mathematical models is the estimation of crucial kinetic parameters by applying those models to experimental and clinical data.…”
mentioning
confidence: 99%
“…In the Moran process, the fitness of WT cells is set equal to 1 and the fitness of mutants is set to r, where r < 1, r = 1, and r > 1 correspond to disadvantageous, neutral, and advantageous mutations, respectively. Although mutant fitness can be context-dependent and can change over time in some settings (10), there are currently no data that show such effects for the mutants under consideration; hence, this possibility is not included in the model. At each time step, we select two random cells: one for reproduction and one for elimination.…”
mentioning
confidence: 99%