Declining cellular fitness with age promotes cancer initiation by selecting for adaptive oncogenic mutations

Abstract

SummaryAge is the single most important prognostic factor in the development of many cancers. The major reason for this age-dependence is thought to be the progressive accumulation of oncogenic mutations and epigenetic changes. Similarly, mutagens are thought to be carcinogenic primarily by engendering oncogenic mutations. Yet while the accumulation of heritable somatic changes is expected to augment the incidence of oncogenic mutations, a major effect of increased mutation load is reduced fitness. We propose that the fitness of progenitor cell compartments substantially impacts on the selective advantage conferred by particular mutations. We hypothesize that reduced cellular fitness within aged stem cell pools can select for adaptive oncogenic events and thereby promote the initiation of cancer. Thus, certain oncogenic mutations may be adaptive within aged but not young stem cell pools. We further argue that accumulating genetic alterations with age or mutagen exposure might promote cancer not only by causing oncogenic hits within cells but also by leading to eventual reduction in stem cell fitness, which then selects for oncogenic events. Therefore, initial stages of cancer development may not be limited by the incidence of initiating oncogenic changes, but instead by contexts of reduced cellular fitness that select for these changes.

Ionizing radiation and hematopoietic malignancies: Altering the adaptive landscape

“…Cytotoxicity associated with carcinogenic treatments has been proposed to increase selection for oncogenic mutations that confer resistance to the insult, thereby initiating tumorigenesis. 21,[31][32][33][34] Despite the persuasive logic of this idea, its validity has had limited experimental support in vivo.…”

“…29 An analogy mutations. 21 However, when cellular fitness is reduced as a result of damage accumulating in both the stem cells themselves and in their microenvironment, a WT (epi)genotype will no longer possess optimal fitness and certain oncogenic (epi)mutations will have an increased chance of being adaptive and hence advantageous (Fig. 1B).…”

“…We have argued that long-lived multicellular organisms (like us) have evolved stem cell populations with high fitness, not only as a means of efficiently maintaining a tissue, but also because high fitness in a cell population will oppose somatic evolution. 21 Like animal populations well adapted to their environments, Stabilizing Selection should limit changes that improve fitness in a population of stem cells with high fitness. Highly effective competition in a young healthy stem cell population should serve to maintain the status quo, preventing somatic evolution.…”

Declining lymphoid progenitor fitness promotes aging-associated leukemogenesis

“…We have previously proposed that stem and progenitor cells are highly adapted to their niches in a young healthy individual, minimizing selective pressure for adaptive changes (12). Cellular competition in young healthy progenitor pools appears to be tumor-suppressive, and the competitive elimination (at least partially genetically determined) of less fit cells appears to be important for the culling of damaged cells (34)(35)(36).…”

“…The effects of mutations on fitness are highly context dependent, however (11). We have proposed that age-related reductions in the fitness of stem and progenitor pools, attributable both to cell-intrinsic accumulation of genomic damage as well as to alterations in the microenvironment, should increase selection for adaptive oncogenic mutations (12).…”