Low-dose ionizing radiation (LDIR) induces proliferation of Trp53-mutant, but not wild-type, cells.
Major Finding: Low-dose ionizing radiation (LDIR) induces proliferation of Trp53-mutant, but not wild-type, cells.
Concept: Antioxidant treatment in the context of LDIR provided a fitness advantage to Trp53–wild-type cells.
Impact: Interventions that provide a selective advantage to wild-type cells in aged tissue may be of interest.
With age, the human esophageal epithelium (EE) accumulates TP53-mutant cells, which may go on to develop into esophageal squamous cell carcinoma cells. Whether it's possible to shift the equilibrium toward healthy cells is not clear. Using mouse EE as a model tissue, Fernandez-Antoran and colleagues found, via genetic lineage tracing, that exposure to 50 mGy of low-dose ionizing radiation (LDIR)—equivalent to 3 to 4 CT scans—promoted differentiation of wild-type esophageal progenitor cells. In mouse primary EE cultures, LDIR increased mitochondrial oxidation, suggesting a mechanism for LDIR-induced cell differentiation. In vivo, immunostaining of a protein abundant in the nucleus after oxidative challenges (phosphoserine40 NRF) revealed that LDIR induced oxidative stress, but treatment with the antioxidant N-acetyl cysteine (NAC) abolished the differentiation of basal cells caused by LDIR exposure. In mice with some EE cells expressing a mutant Trp53 allele corresponding to a human p53 variant often found in keratinocyte-derived cancers, the Trp53-mutant clones expanded after one or multiple doses of ionizing radiation. Suggesting a reason for the Trp53-mutant cells’ advantage over wild-type cells after LDIR exposure, the Trp53-mutant cells had little mitochondrial oxidation compared to wild-type cells and were insensitive to irradiation. Importantly, NAC treatment in the absence of LDIR did not affect the Trp53-mutant clones’ fitness; this aligns with findings that antioxidants are not effective for cancer prevention in humans and may even increase mortality. However, with NAC treatment in the setting of LDIR, the p53-mutant cells lost their competitive advantage because they were less likely to produce proliferating daughter cells, diminishing their population and enabling wild-type cells to recolonize the basal layer. These results show that external interventions can have an impact on the fitness of wild-type versus mutant cells in some contexts and suggest that therapies that increase the competitive fitness of wild-type cells above that of dangerous mutant cells may be worth investigating.
Fernandez-Antoran D, Piedrafita G, Murai K, Ong SH, Herms A, Frezza C, et al. Outcompeting p53-mutant cells in the normal esophagus by redox manipulation. Cell Stem Cell 2019 July 9 [Epub ahead of print].
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