Models of intermittent hypoxia and obstructive sleep apnea: Molecular pathways and their contribution to cancer

Abstract

Obstructive sleep apnea (OSA) is common and linked to a variety of poor health outcomes. A key modulator of this disease is nocturnal intermittent hypoxia. There is striking epidemiological evidence that patients with OSA have higher rates of cancer and cancer mortality. Small-animal models demonstrate an important role for systemic intermittent hypoxia in tumor growth and metastasis, yet the underlying mechanisms are poorly understood. Emerging data indicate that intermittent hypoxia activates the hypoxic response and inflammatory pathways in a manner distinct from chronic hypoxia. However, there is significant heterogeneity in published methods for modeling hypoxic conditions, which are often lacking in physiological relevance. This is particularly important for studying key transcriptional mediators of the hypoxic and inflammatory responses such as hypoxia-inducible factor (HIF) and NF-κB. The relationship between HIF, the molecular clock, and circadian rhythm may also contribute to cancer risk in OSA. Building accurate in vitro models of intermittent hypoxia reflective of OSA is challenging but necessary to better elucidate underlying molecular pathways.