Phenotypic plasticity, i.e. the production of alternative phenotypes in response to variable environments, is ubiquitous in nature. An important abiotic threat is intermittent hypoxia, a reduction in oxygen availability. Hypoxia may be either acute or chronic, and it may be experienced at the organismal, tissue, or cellular levels. Nucleated cells of all metazoans respond to hypoxia via stabilization of the Hypoxia-inducible Factor (HIF), an inducible defense against both acute and chronic hypoxia within the cellular environment. HIF is a heterodimeric transcription factor that induces expression of genes that increase angiogenesis, glucose metabolism, and the re-supply of oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. However, in some cancers, HIF-α stabilization becomes constitutive and remains high even under normal levels of oxygen; a condition known as pseudohypoxia. We developed a mathematical model that calculates a cell’s payoff given the proliferation cost of producing HIF-α and the mortality of not producing HIF-α when in a hypoxic environment. The model assessed three scenarios: 1) constitutive expression of HIF-α regardless of oxygenation levels; 2) facultative regulation of HIF-α when oxygenation levels fluctuate regularly; 3) facultative HIF-α regulation when oxygenation levels fluctuate stochastically.
Results/Conclusions
The model indicates that facultative expression of HIF-α always promotes a greater payoff than constitutive expression. Importantly, however, the difference in payoffs between facultative and constitutive HIF-α expression varies depending upon the nature of the fluctuations between normoxia and hypoxia. With short cycling times, the difference between facultative and constitutive HIF-α stabilization is marginal, and the payoffs between constitutive and facultative expression are practically indistinguishable. In contrast, stochastic fluctuations strongly favor facultative HIF-α regulation. We conclude that the highly predictable occurrence of hypoxia in tumors provides a selective environment leading some cancer cells to evolve constitutive regulation of HIF-α (known as the Warburg phenotype). Our results are relevant to Optimal Defense Theory (ODT) in plants. ODT predicts that inducible defenses will be favored when probability of attack is low, and constitutive defenses will be favored when probability of attack is high. With regular fluctuations in oxygen, hypoxia is assured, which should favor constitutive expression of HIF-α, as seen in Warburg cells. Our model of the conditions that select for the Warburg phenotype in cancer thus support expectations of optimal defenses deployed by plants against herbivores. The results illustrate that dynamic tumor ecosystems provide excellent opportunities to test ecological and evolutionary theory.