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Escaping the stem cell compartment: sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent
W Zhang1, E Remenyik, D Zelterman
1Department of Therapeutic Radiology Yale School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040, USA.
Abstract:
Once mutated, a single cell must expand into a clone before becoming significant for carcinogenesis. The forces driving clonal expansion and the obstacles that must be overcome are poorly understood. In a genetic mechanism, acquiring a second mutation conferring a proliferative advantage would enable the cell to expand autonomously. If carcinogen exposure instead induced a physiological change, clonal expansion would require the carcinogen's continued presence. To determine which is the case, we studied microscopic clones of keratinocytes mutated in the p53 tumor suppressor gene. Carcinogen exposure was controlled by irradiating mice with 280-320 nm UV radiation (UVB), sunlight's principal carcinogenic component; expansion of mutant clones was observed in epidermal sheets. p53-mutant clones grew only during chronic UVB exposure. Therefore, clonal expansion was not triggered by a proliferative mutation but was instead continually driven by UVB. Unexpectedly, the clone size distribution showed periodicity with maxima at estimated intervals of 16 +/- 6 cells, the size of the epidermal proliferating unit in murine dorsal skin. In the absence of UVB, rare "imprisoned clones" increased in cell number without increasing in area. We conclude that: stem cell compartments act as physical barriers to clonal expansion of a p53-mutant keratinocyte; a rate-limiting step in clonal expansion is the colonization of an adjacent compartment; and sustained UVB enables the p53-mutant keratinocyte to colonize without incurring an additional mutation.
Insights
UVB radiation drives the expansion of p53-mutant keratinocyte clones, not a secondary mutation. Clonal expansion is limited by physical barriers and requires sustained UVB for colonization, revealing key factors in skin carcinogenesis.
Area of Science:
- Dermatology
- Cancer Biology
- Genetics
Background:
- Carcinogenesis involves the expansion of mutated cells into significant clones.
- The drivers and barriers of clonal expansion remain poorly understood.
- Two models exist: autonomous expansion via secondary mutation or continued carcinogen dependence.
Purpose of the Study:
- To investigate the mechanism driving clonal expansion of p53-mutant keratinocytes.
- To determine if UVB radiation or a secondary mutation fuels expansion.
- To understand the role of stem cell compartments and UVB in skin carcinogenesis.
Main Methods:
- Studied microscopic p53-mutant keratinocyte clones in murine dorsal skin.
- Controlled carcinogen exposure using chronic UVB irradiation (280-320 nm).
- Observed clonal expansion in epidermal sheets and analyzed clone size distribution.
Main Results:
- p53-mutant clones expanded only during chronic UVB exposure, indicating UVB dependence.
- Clone size distribution exhibited periodicity related to the epidermal proliferating unit size.
- In the absence of UVB, clones increased in cell number but not area ('imprisoned clones').
Conclusions:
- Stem cell compartments act as physical barriers to p53-mutant keratinocyte clonal expansion.
- Colonization of adjacent compartments is a rate-limiting step in clonal expansion.
- Sustained UVB exposure enables p53-mutant keratinocytes to colonize without additional mutations.