Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 1, Pages 270-275Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0909738107
Keywords
cancer; stem cells; stochastic fate
Categories
Funding
- EPSRC
- EPSRC [EP/F032773/1, EP/F043325/1] Funding Source: UKRI
- MRC [G0601740, MC_U105370181, G0800784] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/F043325/1, EP/F032773/1] Funding Source: researchfish
- Medical Research Council [G0800784B, G0601740, MC_U105370181, G0800784] Funding Source: researchfish
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UVB (UVB) radiation induces clones of cells mutant for the p53 tumor suppressor gene inhuman and murine epidermis. Here were analyze large datasets that report the fate of clones in mice subjected to a course of UVB radiation, to uncover how p53 mutation affects epidermal progenitor cell behavior. We show that p53 mutation leads to exponential growth of clones in UV-irradiated epidermis; this finding is also consistent with the size distribution of p53 mutant clones in human epidermis. Analysis of the tail of the size distribution further reveals that the fate of individual mutant cells is stochastic. Finally, the data suggest that ending UVB exposure results in the p53 mutant cells adopting the balanced fate of wild-type cells: the loss of mutant cells is balanced by proliferation so that the population of preneoplastic cells remains constant. We conclude that preneoplastic clones do not derive from long-lived, self-renewing mutant stem cells but rather from mutant progenitors with random cell fate. It follows that ongoing, low-intensity UVB radiation will increase the number of precancerous cells dramatically compared with sporadic, higher-intensity exposure at the same cumulative dose, which may explain why nonmelanoma skin cancer incidence depends more strongly on age than on radiation dosage. Our approach may be applied to determine cell growth rates in clonally labeled material from a wide range of tissues including human samples.
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