Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells

Cultured cells subjected to oxygen deprivation have been shown to undergo anomalous DNA synthesis, which can result in DNA overreplication and the generation of cellular variants [Rice, G. C., Hoy, C. & Schimke, R. T. (1986) Proc. Natl. Acad. Sci. USA 83, 5978-5982]. In the present study, murine tumor cells were exposed to severe hypoxia and then tested for their ability to form experimental metastases. Upon reoxygenation, cells transiently, yet dramatically, increased their metastatic potential. Flow cytometric analysis confirmed that hypoxia and reoxygenation induced cell cycle perturbations and DNA overreplication in these tumor cell lines. Fibrosarcoma cells with overreplicated DNA isolated by fluorescence-activated cell sorting proved to be highly metastatic, although cells with 2-4 times the haploid DNA content in populations treated with hypoxia were also markedly more metastatic than oxic populations. These results support the hypothesis that hypoxic conditions existing in regions of solid tumors promote cellular heterogeneity and tumor progression.