Evolutionary Stem Cell Poker and Cancer Risks: the Paradox of the Large and Small Intestines
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Purpose of review
Recent studies demonstrate that normal human tissues accumulate substantial numbers of somatic mutations with aging, to levels comparable to their corresponding cancers. If mutations cause cancer, how do tissues avoid cancer when mutations are unavoidable?
The small intestines (SI) and colon accumulate similar numbers of replication errors, but SI adenocarcinoma is much rarer than colorectal cancer. Both the small and large intestines are subdivided into millions of small neighborhoods (crypts) that are maintained by small numbers of stem cells. To explain the SI cancer paradox, four fundamental evolution parameters (mutation, drift, selection, and population size) are translated to crypts.
The accumulations of driver mutations in a single stem cell may be analogous to an evolutionary poker game. The rarity of SI cancer may reflect that SI crypts are smaller and have fewer stem cells than the colon, which reduces the numbers of cells at risk for mutation and perhaps selection efficiency. Tissue microarchitecture may physically modulate cancer evolution by controlling the numbers of directly competing neighboring cells. A better understanding of the SI cancer paradox may illuminate how tissues naturally avoid cancers when mutations are unavoidable.
KeywordsStem cell niche Somatic mutation Replication errors Neutral evolution Small intestinal adenocarcinoma Selection efficiency
This work was supported by NIH Grant U54CA217376.
Compliance with Ethical Standards
Conflict of Interest
Darryl Shibata declares no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by the author.
Papers of particular interest, published recently, have been highlighted as: •• Of major Importance
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