Cycling hypoxia selects for constitutive HIF stabilization

Abstract

AbstractTumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) in tumor cells are stabilized in response to low levels of oxygen and induce angiogenesis to re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, however, HIF-α stabilization becomes constitutive even under normoxia, a condition known aspseudohypoxia. Herein, we develop a mathematical model that predicts the effects of fluctuating levels of oxygen availability on stabilization of HIF-α and its client proteins based on fitness. The model shows that facultative regulation of HIF-α always promotes greater cell fitness than constitutive regulation. However, cell fitness is nearly identical regardless of HIF-α regulation strategy when there are rapid periodic fluctuations in oxygenation. Furthermore, the model predicts that stochastic changes in oxygenation favor facultative HIF-α regulation. We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia.