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Persistent Genetic Instability in Cancer Cells Induced by Non-DNA-damaging Stress Exposures¹

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710 [C-Y. L., K. H., W. Z., L. Z., M. W. D., Q. H.], and Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts 02115 [J. B. L.]

A hallmark of cancer cells is their pronounced genetic instability, which has been implicated in both tumor development and negative treatment outcomes. Recently, it has been reported that ionizing radiation may induce a persistent state of hypermutability in mammalian cells that lasts for many (>30) cell divisions. In this study, we examined whether other stress signals (both DNA-damaging non-DNA-damaging) can initiate a similar process. We show that persistent genetic instability was induced by nongenotoxic stress exposures such as heat treatment, serum starvation, or the tumor microenvironment, as well as genotoxic stresses such as ionizing radiation and exposure to hydrogen peroxide. Progeny of 10–20% of surviving cells exhibited persistent and pronounced genetic instability at both an artificially transfected gene and a genomic minisatellite locus 23 cell divisions after the initial exposure. Stress-induced persistent genetic instability may be a general response of tumor cells to a wide range of genotoxic or nongenotoxic stress conditions.

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