Potential Pathophysiological Pathways in the Complex Relationships between OSA and Cancer

Abstract

Several epidemiological and clinical studies have suggested a relationship between obstructive sleep apnea (OSA) and a higher incidence or severity of cancer. This relationship appears to be dependent on a myriad of factors. These include non-modifiable factors, such as age and gender; and modifiable or preventable factors, such as specific comorbidities (especially obesity), the use of particular treatments, and, above all, the histological type or location of the cancer. Heterogeneity in the relationship between OSA and cancer is also related to the influences of intermittent hypoxemia (a hallmark feature of OSA), among others, on metabolism and the microenvironment of different types of tumoral cells. The hypoxia inducible transcription factor (HIF-1α), a molecule activated and expressed in situations of hypoxemia, seems to be key to enabling a variety of pathophysiological mechanisms that are becoming increasingly better recognized. These mechanisms appear to be operationally involved via alterations in different cellular functions (mainly involving the immune system) and molecular functions, and by inducing modifications in the microbiome. This, in turn, may individually or collectively increase the risk of cancer, which is then, further modulated by the genetic susceptibility of the individual. Here, we provide an updated and brief review of the different pathophysiological pathways that have been identified and could explain the relationship between OSA and cancer. We also identify future challenges that need to be overcome in this intriguing field of research.

Chronic intermittent hypoxia reveals role of the Postinspiratory Complex in the mediation of normal swallow production

“…CIH increases the gain of the carotid body response to hypoxia, which seems to be a major cause for the multiple comorbidities of OSA ( Iturriaga, 2023 ; Prabhakar et al, 2023 ). These OSA-related comorbidities ( Pack, 2023 ) include an increase in mortality ( Vgontzas et al, 2023 ) and cancer risk ( Sánchez-de-la-Torre et al, 2023 ), increased arousal and sleep fragmentation ( Horner, 2023 ), increased sympathetic drive leading to cardiovascular disease, metabolic syndromes such as obesity and diabetes ( Kurnool et al, 2023 ), renal disease, asthma ( Bonsignore et al, 2019 ), and decreased cognition ( Brockmann and Gozal, 2022 ). OSA is also commonly associated with altered and disordered swallow function, clinically known as dysphagia ( Pizzorni et al, 2021 ; Schindler et al, 2014 ).…”

Differential Impact of Intermittent vs. Sustained Hypoxia on HIF-1, VEGF and Proliferation of HepG2 Cells

“…These studies have addressed the impact of IH on breast [ 12 ], colorectal [ 13 ], lung [ 14 , 15 , 16 ], melanoma [ 17 , 18 , 19 , 20 ] and kidney [ 21 ] cancer, mainly demonstrating enhanced cell proliferation and tumor growth, along with enhanced metastasis. A recent review on the various pathophysiological pathways behind the association between cancer and OSA has revealed a heterogeneity of this relationship across cancer types [ 22 ]. It is therefore necessary to explore which tumor types are most affected by OSA as well as the specific pathways involved.…”

“…While the chronic intermittent hypoxia induced by OSA is systemic and thus perceived by almost all organs, it induces organ-specific and complex pathophysiological alterations. One of the main signaling pathways involved in both OSA patients and animal models in response to hypoxemia is an increase in oxidative stress, which in turn enhances the activity of the hypoxia-inducible factor 1 (HIF-1) transcription factor [ 22 , 27 , 28 ], as well as the expression of its target genes, including vascular endothelial growth factor (VEGF) [ 18 , 29 , 30 ] and endothelin-1 (ET-1) [ 28 , 31 ]. Experimental data also show that IH activates NF-kB, HIF-1, VEGF and endothelin-1 in tumor cells and promotes tumor cell proliferation and metastasis [ 12 , 18 , 19 , 20 , 32 ].…”

Chronic Intermittent Hypoxia reveals role of the Postinspiratory Complex in the mediation of normal swallow production

“…CIH increases the gain of the carotid body (CB) response to hypoxia which seems to be a major cause for the multiple comorbidities of OSA (Iturriaga, 2023;Prabhakar et al, 2023). These OSA-related comorbidities (Pack, 2023) include an increase in mortality (Vgontzas et al, 2023) and cancer risk (Sánchez-de-la-Torre et al, 2023), increased arousal and sleep fragmentation (Horner, 2023), increased sympathetic drive leading to cardiovascular disease; metabolic syndromes such as obesity and diabetes (Kurnool et al, 2023), renal disease, asthma, (Bonsignore et al, 2019), and decreased cognition (Brockmann & Gozal, 2022). OSA is also commonly associated with dysphagia, disordered swallow function (Pizzorni et al, 2021;Schindler et al, 2014).…”