Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations

Rozhok, Andrii I.; DeGregori, James

doi:10.1073/pnas.1501713112

Cited by 105 publications

(113 citation statements)

References 71 publications

Supporting

Mentioning

104

Contrasting

Order By: Relevance

“…Additionally, enhanced inflammatory chemokine/cytokine expression has been shown to be a prominent phenotype in senescent fibroblasts that serve to directly and indirectly (in part through recruitment of tumor promoting immune cells) promote cancer cell growth and survival (Coppe et al ., 2010; Lopez‐Otin et al ., 2013). Other recent studies have emphasized the influence of contexts such as altered tissue microenvironment on age‐dependent incidence of cancers (Lasry & Ben‐Neriah, 2015; Rozhok & DeGregori, 2015). …”

Section: Discussionmentioning

confidence: 99%

“…Different cancer types arise at similar rates even though their stem cell pools may have very different sizes, division rates, and mutational spectra. As proposed by Rozhok & DeGregori (2015), noncell autonomous processes such as age‐dependent tissue microenvironmental changes may play an important role in accelerating cancer development. The aged tissue microenvironment may provide a selective advantage in enhancing the oncogenic effects of mutated cancer driver genes compared to the youthful tissue microenvironment.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene‐induced lung tumors in aged mice

et al. 2017

View full text Add to dashboard Cite

SummaryAging is often accompanied by a dramatic increase in cancer susceptibility. To gain insights into how aging affects tumor susceptibility, we generated a conditional mouse model in which oncogenic Kras G12D was activated specifically in lungs of young (3–5 months) and old (19–24 months) mice. Activation of Kras G12D in old mice resulted in shorter survival and development of higher‐grade lung tumors. Six weeks after Kras G12D activation, old lung tissues contained higher numbers of adenomas than their young tissue counterparts. Lung tumors in old mice displayed higher proliferation rates, as well as attenuated DNA damage and p53 tumor suppressor responses. Gene expression comparison of lung tumors from young and old mice revealed upregulation of extracellular matrix‐related genes in young tumors, indicative of a robust cancer‐associated fibroblast response. In old tumors, numerous inflammation‐related genes such as Ccl7,IL‐1β, Cxcr6, and IL‐15ra were consistently upregulated. Increased numbers of immune cells were localized around the periphery of lung adenomas from old mice. Our experiments indicate that more aggressive lung tumor formation in older Kras G12D mice may be in part the result of subdued tumor suppressor and DNA damage responses, an enhanced inflammatory milieu, and a more accommodating tissue microenvironment.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene‐induced lung tumors in aged mice

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The explanation for such a discrepancy may be in the difference of SC pool organization between epithelia and such systems as HSCs and perhaps other SCs. SCs in epithelial tissues are often clustered into small effective populations, which should expose their clonal dynamics to a high influence of drift throughout the entire life span (38). In fact, clonal dynamics of gut epithelia have been shown to be heavily drift-driven (10,14,15).…”

Section: Discussionmentioning

confidence: 99%

Stochastic modeling reveals an evolutionary mechanism underlying elevated rates of childhood leukemia

Rozhok

Salstrom

DeGregori

2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Young children have higher rates of leukemia than young adults. This fact represents a fundamental conundrum, because hematopoietic cells in young children should have fewer mutations (including oncogenic ones) than such cells in adults. Here, we present the results of stochastic modeling of hematopoietic stem cell (HSC) clonal dynamics, which demonstrated that early HSC pools were permissive to clonal evolution driven by drift. We show that drift-driven clonal expansions cooperate with faster HSC cycling in young children to produce conditions that are permissive for accumulation of multiple driver mutations in a single cell. Later in life, clonal evolution was suppressed by stabilizing selection in the larger young adult pools, and it was driven by positive selection at advanced ages in the presence of microenvironmental decline. Overall, our results indicate that leukemogenesis is driven by distinct evolutionary forces in children and adults.childhood leukemia | somatic evolution | cancer | stochastic modeling | aging T he incidence of leukemia, like most cancers in humans, increases exponentially with age. However, most types of leukemia have an early peak of incidence (at 0-7 y of age), which subsequently decreases before rising again later in life (Fig. S1). Cancer development is generally thought to result from a sequence of cancer driver mutations that promote selection for recipient cells by conferring a positive fitness advantage within competing stem cell (SC) and progenitor cell pools (1-4). The acquisition of oncogenic mutations is thus thought to be rate-limiting for cancer development, leading to increased cancer incidence with age. Within this paradigm, the higher incidence of leukemia in young children compared with young adults is puzzling, because younger tissues should have accumulated fewer mutations.Evolution is driven by multiple forces, including mutation, selection, and drift. Although mutation is necessary for cancer development, a large body of evidence has accumulated indicating that the ability of oncogenic mutations to drive clonal evolution is not universal and depends on external factors (5-12). Carcinogenesis may therefore be driven or suppressed by non-cell-autonomous processes. One factor capable of limiting the ability of selection to influence population dynamics is drift. In evolutionary biology, the power of drift is known to be inversely related to population size (13). This relationship also holds true for mammalian tissues, as shown for intestinal SC pools, which are segregated into small groups within intestinal crypts (10,14,15). The number of hematopoietic stem cells (HSCs) per individual has been reported to be conserved across mammals at 11,000-22,000 cells in adults (16,17), with an initial pool size of ∼300 HSCs at birth (17) (Fig. S2A). Although higher estimates of the pool size exist (18), it is clear that during prenatal development, and perhaps the early postnatal period of life, the number of HSCs is substantially smaller than the number in the adult pool. Be...

show abstract

“…The decreased life span and early aging phenotypes exhibited by Bub1b H/H mice could be due to the exhaustion of adult stem cell pools that must proliferate more than wild-type stem cells to produce euploid cells. It is also possible that the strength of purifying selection in adult regenerative tissues is relaxed as organisms age and stem cell fitness declines (Rozhok and DeGregori 2015). Such decreased purifying selection would cause tissue function decline due to the accumulation of aneuploid and hence less-fit cells with time.…”

Section: Bub1bmentioning

confidence: 99%

Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

et al. 2016

View full text Add to dashboard Cite

Aneuploidy, an imbalanced karyotype, is a widely observed feature of cancer cells that has long been hypothesized to promote tumorigenesis. Here we evaluate the fitness of cells with constitutional trisomy or chromosomal instability (CIN) in vivo using hematopoietic reconstitution experiments. We did not observe cancer but instead found that aneuploid hematopoietic stem cells (HSCs) exhibit decreased fitness. This reduced fitness is due at least in part to the decreased proliferative potential of aneuploid hematopoietic cells. Analyses of mice with CIN caused by a hypomorphic mutation in the gene Bub1b further support the finding that aneuploidy impairs cell proliferation in vivo. Whereas nonregenerating adult tissues are highly aneuploid in these mice, HSCs and other regenerative adult tissues are largely euploid. These findings indicate that, in vivo, mechanisms exist to select against aneuploid cells.

show abstract

Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations

Cited by 105 publications

References 71 publications

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene‐induced lung tumors in aged mice

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene‐induced lung tumors in aged mice

Stochastic modeling reveals an evolutionary mechanism underlying elevated rates of childhood leukemia

Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

Contact Info

Product

Resources

About