Acute vs. Chronic vs. Cyclic Hypoxia: Their Differential Dynamics, Molecular Mechanisms, and Effects on Tumor Progression

Abstract

Hypoxia has been shown to increase the aggressiveness and severity of tumor progression. Along with chronic and acute hypoxic regions, solid tumors contain regions of cycling hypoxia (also called intermittent hypoxia or IH). Cyclic hypoxia is mimicked in vitro and in vivo by periodic exposure to cycles of hypoxia and reoxygenation (H-R cycles). Compared to chronic hypoxia, cyclic hypoxia has been shown to augment various hallmarks of cancer to a greater extent: angiogenesis, immune evasion, metastasis, survival etc. Cycling hypoxia has also been shown to be the major contributing factor in increasing the risk of cancer in obstructive sleep apnea (OSA) patients. Here, we first compare and contrast the effects of acute, chronic and intermittent hypoxia in terms of molecular pathways activated and the cellular processes affected. We highlight the underlying complexity of these differential effects and emphasize the need to investigate various combinations of factors impacting cellular adaptation to hypoxia: total duration of hypoxia, concentration of oxygen (O₂), and the presence of and frequency of H-R cycles. Finally, we summarize the effects of cycling hypoxia on various hallmarks of cancer highlighting their dependence on the abovementioned factors. We conclude with a call for an integrative and rigorous analysis of the effects of varying extents and durations of hypoxia on cells, including tools such as mechanism-based mathematical modelling and microfluidic setups.

Keywords: HIF-1α signaling; acute hypoxia; chronic hypoxia; cyclic hypoxia; intermittent hypoxia; mathematical modeling; obstructive sleep apnea.

Figure 1

Oxygen-dependent regulation of hypoxia inducible factors HIF-1α and HIF-2α. (A) In presence of oxygen, HIF-1α and HIF-2α are hydroxylated by prolyl hydroxylase domains (PHDs) and FIH (Factor Inhibiting HIF-1), and then targeted for proteasomal degradation mediated by VHL protein. (B) Under acute hypoxia, both HIF-1α and HIF-2α are stabilized. Under chronic hypoxia, HIF-2α is stabilized while HIF-1α is downregulated.

Figure 2

Dynamics of HIF-1α/HIF-2α stabilization under different O₂ levels and acute, chronic and cyclic hypoxia. (A) Stabilization of HIF-2α over a wider range of oxygen concentration than HIF-1α. (B) Stabilization of HIF-1α under acute hypoxia and HIF-2α under chronic hypoxia. (C) Effect of H–R periods on HIF-1α levels under cyclic hypoxia. (D) Variables involved in HIF-1α stabilization during cyclic hypoxia.

Figure 3

Effect of cycling hypoxia on various hallmarks of cancer.