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Review
. 2023 Oct 5;389(14):1310-1319.
doi: 10.1056/NEJMra2304431.

Stem-Cell Aging and Pathways to Precancer Evolution

Catriona H M Jamieson  1 , Irving L Weissman  1
Affiliations
Review

Stem-Cell Aging and Pathways to Precancer Evolution

Catriona H M Jamieson et al. N Engl J Med. .
No abstract available

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Figures

Figure 1.
Figure 1.. Pre-Cancer Stem Cell Progression to Cancer Stem Cell Propagation.
Pre-cancer stem cells in the tissue-specific stem cell compartment give rise to an expanded progenitor population and can undergo malignant regeneration and immune evasion, which promotes propagation of cancer stem cells.
Figure 2.
Figure 2.. Pre-cancer stem cell clonal architecture is determined by type and temporal sequence of mutations, epigenetic alterations, and epitranscriptomic changes.
,,,, The schematic shows a model for the proposed clonal evolution of secondary acute myeloid leukemia (sAML). Multipotent progenitors derived from HSCs display decreased self-renewal potential and an increased propensity for differentiation into progenitor cells. However, as HSCs age, epigenomic deregulation and activation of oncogenes leads to a cascade of events that generates pre-leukemic HSCs, clonal expansion of progenitor populations, and ultimately LSCs with deregulated self-renewal potential. The single-cell analysis identifies an example of sequential acquisition of mutations in pre-leukemic HSCs.
Figure 3.
Figure 3.. DNA and RNA Processing in Normal, Pre-Cancer, and Cancer Stem Cells.
During healthy human aging, normal stem cells undergo differentiation and experience a decrease in pro-survival splicing. As people age, there is an increased risk that epigenetic reprogramming and RNA and DNA editing may induce pre-malignant changes to these stem cells. If a significant proportion of the pre-malignant cancer stem cells undergo further malignant reprogramming and acquire the ability to self-renew and survive, this newly formed microenvironment may drive the evolution of cancer.
Figure 4.
Figure 4.. Factors that Contribute to Stem Cell Aging.
Stem cell aging is driven by both microenvironmental and macroenvironmental stressors. While intrinsic exposures have been linked to age-related decline in stem cell function and regulation, extrinsic factors are emerging as major drivers of stem cell aging and pre-cancer development. Inflammaging refers to an increase in pro-inflammatory markers in tissues during aging, is systemic, and is interconnected with other hallmarks of aging. In stem cells, the genomic instability that results from age-related intrinsic and extrinsic factors can drive pre-cancer and cancer evolution.
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References

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