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

Henry, Curtis J.; Casás‐Selves, Matias; Kim, Jihye; Zaberezhnyy, Vadym; Aghili, Leila; Daniel, Ashley E.; Jimenez, Linda; Azam, Tania; McNamee, Eóin N.; Clambey, Eric T.; Klawitter, Jost; Serkova, Natalie J.; Tan, Aik Choon; Dinarello, Charles A.; DeGregori, James

doi:10.1172/jci83024

Cited by 124 publications

(131 citation statements)

References 83 publications

Supporting

Mentioning

126

Contrasting

Order By: Relevance

“…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].…”

Section: The Armitage-doll Multi-stage Paradigm Of Carcinogenesis Inmentioning

confidence: 75%

The Evolution of Lifespan and Age-Dependent Cancer Risk

Rozhok

DeGregori

2016

Trends in Cancer

Self Cite

View full text Add to dashboard Cite

The Armitage-Doll multi-stage model of carcinogenesis tremendously refocused cancer science by postulating that carcinogenesis is driven by a sequence of genetic changes in cells. Age-dependent cancer incidence thus has been explained in terms of the time necessary for oncogenic mutations to occur. While the multi-step nature of cancer evolution is well-supported by evidence, the mutation-centric theory is unable to explain a number of phenomena, such as the disproportion between cancer frequency and animal body size or the scaling of cancer incidence to animal lifespan. In this paper, we present a theoretical review of the current paradigm and discuss some fundamental evolutionary theory postulates that explain why cancer incidence is a function of lifespan and physiological, not chronological, aging.

show abstract

Section: The Armitage-doll Multi-stage Paradigm Of Carcinogenesis Inmentioning

confidence: 75%

The Evolution of Lifespan and Age-Dependent Cancer Risk

Rozhok

DeGregori

2016

Trends in Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…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].…”

Section: Aging Of Hematopoietic Stem Cellsmentioning

confidence: 99%

“…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.…”

Section: Aging Of Hematopoietic Stem Cellsmentioning

confidence: 99%

Aging, Clonality, and Rejuvenation of Hematopoietic Stem Cells

Akunuru

Geiger

2016

Trends in Molecular Medicine

148

120

View full text Add to dashboard Cite

Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and increased production of reactive oxygen species have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts such as global epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as clonal selection of HSCs upon aging provide new insights into HSC aging mechanisms. Rejuvenating agents that can reprogram the epigenetic status of aged HSCs or senolytic drugs that selectively deplete senescent cells provide promising translational avenues for attenuating hematopoietic aging and potentially, alleviating aging-associated immune remodeling and myeloid malignancies.

show abstract

“…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).…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

DeGregori

2017

Cancer Research

Self Cite

View full text Add to dashboard Cite

In a recent paper in Science, Tomasetti et al. present an expanded model for cancer risk, which they claim demonstrates the relative contribution of mutations caused by replication errors, environment and heredity. The foundation of this model is the theory that the overwhelming driver of cancer risk is mutations. This perspective will present experimental evidence and evolutionary theory to challenge the basis of this underlying theory. An argument will be presented that the mutation-centric model of cancer suggests unrealistic solutions to cancer and distracts the research community from more promising approaches that consider tissue context.

show abstract

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

Cited by 124 publications

References 83 publications

The Evolution of Lifespan and Age-Dependent Cancer Risk

The Evolution of Lifespan and Age-Dependent Cancer Risk

Aging, Clonality, and Rejuvenation of Hematopoietic Stem Cells

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

Contact Info

Product

Resources

About