Trends in Cancer
OpinionThe Evolution of Lifespan and Age-Dependent Cancer Risk
Section snippets
The Armitage–Doll Multistage Paradigm of Carcinogenesis in the Light of Current Evidence
Over half a century ago, Carl Nordling postulated that carcinogenesis is driven by mutations that occur in cells [1]. Peter Armitage and Richard Doll generalized these ideas and proposed the multistage theory of carcinogenesis in a seminal paper [2] stating that carcinogenesis typically requires six or seven mutations and/or other cell alterations to malignantly transform a cell, based on the evidence that the age-dependent exponential increase in cancer incidence follows mathematically the
The Evolution of Lifespan as Key to Understanding Aging-Related Cancer Risk
To understand how and why physiological aging, not just chronological timing, can be directly implicated in cancer and other disease risk, it is key to consider how lifespans evolve. A substantial emphasis in medical and cancer-related literature is placed on time-dependent accumulation of cellular damage as a major driver of aging, thus positing aging as rate limited by a certain mutation/damage ‘clock’ 26, 27. However, as mentioned previously, roughly half of all somatic mutations occur early
Understanding Carcinogenesis as Rate Limited by Physiological Aging-Dependent Processes
Carcinogenesis is currently understood as a series of oncogenic mutations that increase the relative fitness of the cells in which they occur and lead to a series of clonal expansions of these oncogenically initiated cells [5]. Stem and progenitor cells have been shown to compete for niche space [40], so fitness can be considered as the ability of dividing cells to remain in the competitive stem and progenitor pool and expand their progeny instead of differentiating, dying, or senescing. If a
Concluding Remarks
The fate of somatic mutations (including oncogenic ones) should be governed by the same basic evolutionary principles that govern natural populations, whereby adaptation leads to higher fitness and increased stabilizing and purifying selection while positive selection is driven by environmental change and lower population fitness 20, 46. From this perspective carcinogenesis should be viewed as a function of physiological aging whereby aging and altered tissue microenvironments lead to selection
Acknowledgments
The authors thank Hannah Scarborough, Roberta Pelanda, Eric Pietras, and Richard Davis of the University of Colorado for critical review of the manuscript. These studies were supported by National Cancer Institute grants (R01CA180175 and R21CA179501) to J.D.
Glossary
- Adaptive
- increases fitness (e.g., a mutation that increases fitness is adaptive).
- Allele
- a variant of a gene. Different alleles for the same gene will be largely homologous but can differ modestly in sequence and can encode proteins with different activities.
- Drift
- random assortment of genetic alleles. The influence of drift becomes greater as population size decreases.
- Fitness
- a measure of reproductive success; classically, the ability of an organism to pass its genes on to future generations of that
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