Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors

The Evolution of Lifespan and Age-Dependent Cancer Risk

“…In fact, evidence from the hematopoietic system corroborates the idea that positive selection in tissue for mutant cellular phenotypes is stronger late in life, as selection for particular oncogenic events has been shown to be substantially stronger in old murine hematopoietic microenvironments than in young [11, 12]. Increased oncogenic clonal expansions and clonal hematopoiesis have also been demonstrated in old mice [13, 14].…”

Aging, Clonality, and Rejuvenation of Hematopoietic Stem Cells

“…This aging-associated impairment in immunity was initially anticipated to be a consequence of reduced numbers of HSCs. Evolutionary theories on hematopoietic aging support a model in which an early peak in lymphocyte production in life is a program favored by natural selection and a decline over time is inevitable, whereas an additional decline in HSCs and lymphoid progenitor fitness further contributes to aging-associated immune remodeling [16]. Interestingly, HSC numbers are 2-3 fold times increased in C57Bl/6 aged mice (>20 months old) relative to young and are only slightly decreased in other aged mouse strains, DBA/2 and Balb/c [9, 17-20].…”

“…In these studies, ex vivo treatment of HSCs with RANTES resulted in fewer T-cell progeny, and Rantes knockout mice rescued the aging-associated myeloid-biased lineage differentiation. Moreover, computational modeling approaches, in combination with transplantation experiments, have established a critical link between niche aging and an indirect induction of HSC aging [16, 36, 37]. Combined, these studies imply that both HSC cell intrinsic and extrinsic aging-associated changes contribute to the altered HSC lineage potential and function with age.…”

Connecting Cancer to Its Causes Requires Incorporation of Effects on Tissue Microenvironments

“…2) (e.g. (5)). In addition to the role for tissue changes in altering selective pressures for oncogenic events, the microenvironment can directly influence the phenotype of malignant cells without altering their genetic makeup (6).…”

“…A more effective strategy for cancer prevention could be to alter tissue landscapes in order to limit selection for the inevitable oncogenic mutations. Therapeutic strategies could be used to alter the selective value of cancer phenotypes by increasing the fitness of more benign phenotypes and/or disfavoring malignant genotypes through modulating tissue parameters, as has been shown for pH (27), oxygen levels (28), cytokines (5,29), and the presence of senescent cells (30). In each case, treatments engendering a tissue microenvironment that better approached that of a young healthy individual, such as by ameliorating inflammation, reduced the selective value of malignant or aggressive genotypes and thus impaired cancer initiation and progression.…”