Relación entre apnea del sueño y cáncer

doi:10.1016/j.arbres.2015.02.002

Archivos de Bronconeumología

Volume 51, Issue 9, September 2015, Pages 456-461

https://doi.org/10.1016/j.arbres.2015.02.002 Get rights and content

Resumen

En 2008, Abrams et al. publicaron que, habida cuenta de las anteriores relaciones encontradas entre la hipoxemia (hipoxia tisular) y el cáncer, el síndrome de apneas e hipopneas del sueño (SAHS) y su principal consecuencia, la hipoxia intermitente, podrían relacionarse con una mayor propensión a padecer cáncer o a un peor pronóstico de un tumor preexistente. Con esta base fisiopatológica y tras algunos estudios en animales que confirmaron esta asociación, 2 grupos independientes de investigación observaron en sendos estudios clínicos amplios de cohortes históricas que el grado de hipoxia nocturna aparecida en pacientes con SAHS se asociaba a una mayor incidencia y mortalidad por cáncer. Este dato ha sido confirmado por casi todos los estudios posteriores, si bien el carácter retrospectivo de todos ellos obliga a considerarlos tan solo como trabajos generadores de hipótesis. Un estudio puesto en marcha actualmente sobre un amplio grupo de pacientes con melanoma posiblemente arroje más luz en un futuro cercano sobre la existencia o no de esta relación y de los mecanismos fisiopatológicos que la gobiernan.

Abstract

In the light of relationships reported between hypoxemia (tissue hypoxia) and cancer, Abrams et al. concluded in 2008 that sleep apnea-hypopnea syndrome (SAHS) and its main consequence, intermittent hypoxia, could be related with increased susceptibility to cancer or poorer prognosis of a pre-existing tumor. This pathophysiological association was confirmed in animal studies. Two large independent historical cohort studies subsequently found that the degree of nocturnal hypoxia in patients with SAHS was associated with higher cancer incidence and mortality. This finding has been confirmed in almost all subsequent studies, although the retrospective nature of some requires that they be considered as hypothesis-generating only. The relationship between sleep apnea and cancer, and the pathophysiological mechanisms governing it, could be clarified in the near future in a currently on-going study in a large group of melanoma patients.

Section snippets

Introducción

La relación entre la apnea obstructiva del sueño (SAHS) y el cáncer abre un apasionante panorama de investigación para los próximos años, aunque de momento se sustenta clínicamente sobre arenas movedizas. Sin embargo, tanto los estudios fisiopatológicos como los estudios en animales realizados hasta la fecha parecen coincidir en otorgar credibilidad a esta relación. Desde un punto de vista clínico, varios estudios han observado que existe una asociación entre el SAHS (especialmente valorado por

Aspectos fisiopatológicos

Se han descubierto diversos mecanismos fisiopatológicos que podrían dar plausibilidad biológica a una posible relación entre el SAHS y la transformación de células sanas en malignas o la diseminación y el crecimiento tumoral. Entre los mecanismos implicados destacan: el estrés oxidativo1, 2, la existencia de un mayor grado de inflamación sistémica3, 4 (ambas amplificadas por la habitual coexistencia de obesidad en estos pacientes) y, por último y posiblemente más importante, la presencia de

Efectos de la hipoxia intermitente en cáncer

En un primer estudio²² se observó que la HI que simula a la acontecida en el SAHS era capaz de duplicar la tasa de crecimiento del tumor en un modelo de melanoma (fig. 2). Estos resultados se confirmaron en un segundo trabajo²³, donde se cuestionó si la obesidad en el SAHS podría enmascarar en cierta medida los efectos de la HI en la evolución del tumor. En ausencia de HI, los autores observaron un mayor crecimiento tumoral en los animales obesos respecto a los controles, tal y como se ha

Datos indirectos

Desafortunadamente, a día de hoy existen muy pocos estudios que hayan analizado la posible asociación entre el SAHS y cáncer en humanos (tabla 1), pero se dispone de algunos datos indirectos. En estudios de mortalidad en pacientes con SAHS, el cáncer suele ser la segunda causa de muerte, después de las enfermedades cardiovasculares45, 46, 47. Incluso, en alguno de estos estudios, se ha encontrado una asociación entre la presencia de un SAHS y mortalidad por cáncer⁴⁸. Sin embargo, un reciente

Conclusiones

A pesar del creciente interés en la posible asociación entre SAHS y cáncer, los escasos datos disponibles hasta la fecha, unidos a las limitaciones que presentan los estudios, inherentes a su diseño, los erigen más bien en estudios generadores de hipótesis que suscitan más preguntas de las que responden, y que animan a la realización de nuevos estudios, mejor diseñados, que aclaren esta posible relación (tabla 2)57, 58, 59.

Financiación

Fondo de Investigación Sanitaria (FIS) PI12/01363, Beca SEPAR 058/2011 y Programa Beatriu de Pinós de la Generalitat de Catalunya (2010 BP_00238).

Conflicto de intereses

Los autores declaran no tener ningún conflicto de intereses.

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Cited by (22)

Present, past, and future of the connection between SAHS and cancer
2021, Open Respiratory Archives
Up-regulation of selenoprotein P and HIP/PAP mRNAs in hepatocytes by intermittent hypoxia via down-regulation of miR-203
2017, Biochemistry and Biophysics Reports
Citation Excerpt :
In fact, the knockdown experiment using siRNA against HIP/PAP mRNA showed that HIP/PAP acts as an autocrine/paracrine growth factor for hepatocytes stimulated by IH (Fig. 5). Recently, putative links between SAS and increased cancer incidence were reported [45,46], suggesting possible involvement of up-regulation of HIP/PAP as a growth factor for cancer cells. In addition, HIP/PAP has recently been recognized as an obesogenic factor [47] in addition to a growth factor.
Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/type 2 diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human hepatocytes (JHH5, JHH7, and HepG2) to experimental IH or normoxia for 24 h, measured mRNA levels by real-time reverse transcription polymerase chain reaction (RT-PCR), and found that IH significantly increased the mRNA levels of selenoprotein P (SELENOP) — a hepatokine — and hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) — one of REG (Regenerating gene) family. We next investigated promoter activities of both genes and discovered that they were not increased by IH. On the other hand, a target mRNA search of micro RNA (miRNA) revealed that both mRNAs have a potential target sequence for miR-203. The miR-203 level of IH-treated cells was significantly lower than that of normoxia-treated cells. Thus, we introduced miR-203 inhibitor and a non-specific control RNA (miR-203 inhibitor NC) into HepG2 cells and measured the mRNA levels of SELENOP and HIP/PAP. The IH-induced expression of SELENOP and HIP/PAP was abolished by the introduction of miR-203 inhibitor but not by miR-203 inhibitor NC. These results demonstrate that IH stress up-regulates the levels of SELENOP in human hepatocytes to accelerate insulin resistance and up-regulates the levels of HIP/PAP mRNAs to proliferate such hepatocytes, via the miR-203 mediated mechanism.
Reflexology and polysomnography: Changes in cerebral wave activity induced by reflexology promote N1 and N2 sleep stages
2017, Complementary Therapies in Clinical Practice
Citation Excerpt :
It occupies more than one third of our life and it is basic in its proper development. Sleep deprivation entails important physiological and cognitive consequences [35–37,52]. Sleep can be defined as a conscious physiological and reversible state with associated characteristics such as a partial and temporary disconnection of the environment with an increase of the threshold of response to external stimuli, a decrease in activity, motor capacity and reaction to external stimuli, which are accompanied by a state of relaxation and decrease of muscular tone.
Several studies have shown the effectiveness of reflexology in different health problems as well as obtaining a high degree of relaxation during its application. A previous study suggested a possible relation between the relaxation obtained during the reflexology session and the sleep. However, the design of the study did not provide evidence for this hypothesis. In this study, we use a polysomnogram to investigate the effects during its application.
Prospective experimental study conducted in a sleep laboratory. Twelve healthy adults were enrolled. Two groups were created based on whether or not they had knowledge of reflexology. Reflexology was applied for 35 min and their sleep effects were measured by means of polysomnography. A descriptive and bivariate analysis was performed. A bivariate analysis conducted through chi-square test or ANOVA was considered appropriate.
After controlling for baseline data, nine of the participants did move toward N1 (p = 0.833) and N2 (p = 0.227) stages, remaining in these states between 4 min and 25.5 min. No significant differences were found between the two groups.
The application of reflexology induces changes in the activity of brain waves in correspondence with the appearance of a high degree of sleepiness and sleep (N1 and N2 NREM sleep). There is a gradual transition and an orderly progression from wakefulness to sleep, which could explain the effects of relaxation and well being obtained with this method, as well as many other benefits.
Ageing and chronic intermittent hypoxia mimicking sleep apnea do not modify local brain tissue stiffness in healthy mice
2017, Journal of the Mechanical Behavior of Biomedical Materials
Citation Excerpt :
OSA reduces the quality of life and labor productivity of patients because of the abnormal diurnal somnolence, the latter being mediated by neuronal cell injury along with disruption of sleep architecture caused by the episodic arousals associated with each apneic event (Punjabi, 2008; Zhan et al., 2005). Moreover, OSA imposes mid-term and long-term adverse health consequences, including increased risk for cardiovascular, metabolic, neurocognitive and malignant diseases (Punjabi, 2008; Arnardottir et al., 2009; Mokhlesi et al., 2016; Martinez-Garcia et al., 2015; Gozal et al., 2016). In addition to OSA representing nowadays a considerable public health problem, the forecast for OSA prevalence is expected to see marked increases over the next several years, mainly for two reasons: (i) as a consequence of the current obesity epidemics since OSA risk is directly linked to overweight and obesity (Punjabi, 2008; Schwartz et al., 2008); (ii) the secular trends of ageing in the population, since elder subjects are particularly susceptible to develop OSA (Punjabi, 2008).
Recent evidence suggests that obstructive sleep apnea (OSA) may increase the risk of Alzheimer´s disease (AD), with the latter promoting alterations in brain tissue stiffness, a feature of ageing. Here, we assessed the effects of age and intermittent hypoxia (IH) on brain tissue stiffness in a mouse model of OSA. Two-month-old and 18-month-old mice (N=10 each) were subjected to IH (20% O₂ 40 s – 6% O₂ 20 s) for 8 weeks (6 h/day). Corresponding control groups for each age were kept under normoxic conditions in room air (RA). After sacrifice, the brain was excised and 200-micron coronal slices were cut with a vibratome. Local stiffness of the cortex and hippocampus were assessed in brain slices placed in an Atomic Force Microscope. For both brain regions, the Young's modulus (E) in each animal was computed as the average values from 9 force-indentation curves. Cortex E mean (±SE) values were 442±122 Pa (RA) and 455±120 (IH) for young mice and 433±44 (RA) and 405±101 (IH) for old mice. Hippocampal E values were 376±62 (RA) and 474±94 (IH) for young mice and 486±93 (RA) and 521±210 (IH) for old mice. For both cortex and hippocampus, 2-way ANOVA indicated no statistically significant effects of age or challenge (IH vs. RA) on E values. Thus, neither chronic IH mimicking OSA nor ageing up to late middle age appear to modify local brain tissue stiffness in otherwise healthy mice.
Sleep and Cancer
2017, Archivos de Bronconeumologia
Obstructive sleep apnea and dermatologic disorders
2017, Clinics in Dermatology
Citation Excerpt :
The authors propose the possible role of intermittent hypoxemia in the formation or spread of the malignancy, via intermediate molecules such as hypoxia-inducible factor 1, a carcinogenesis-related molecule, and vascular endothelial growth factor, which promotes neovascularization of the cancer and therefore its expansion.33 Other factors implicated include oxidative stress and a high degree of systemic inflammation in OSA.34 A single case of mycosis fungoides (MF) associated with severe OSA has been reported.35
Obstructive sleep apnea (OSA) is present in at least 2% of women and 4% of men, and its prevalence is increasing, because a major predisposing factor for OSA is a high body mass index. Psoriasis has the most strongly substantiated link with OSA, where the relationship may be bidirectional. Dermatologic disorders may be comorbid with OSA due to several factors: (i) the heightened proinflammatory state in OSA, which can occur independent of body mass index, and may exacerbate inflammatory dermatoses; (ii) intermittent hypoxemia may promote neovascularization and tumor growth in certain cancers, such as melanoma; (iii) obesity, present in majority of OSA patients, can be associated with a heightened proinflammatory state; (iv) upper airway obstruction due to local tumors or soft tissue swelling due to physical urticaria or angioedema; (v) acute nasal congestion in the atopic patient with allergic rhinitis; (vi) dermatologic disorders associated with other OSA risk factors (eg, acanthosis nigricans and metabolic syndrome); and (vii) a high sympathetic tone (eg, in atopic dermatitis) and resultant sleep fragmentation contributing to upper airway instability during sleep. In many instances, the dermatology patient with OSA may have other medical and psychiatric comorbidities that are also associated with increased OSA risk.

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RevisiónRelación entre apnea del sueño y cáncerRelationship Between Sleep Apnea and Cancer

Resumen

Abstract

Section snippets

Introducción

Aspectos fisiopatológicos

Efectos de la hipoxia intermitente en cáncer

Datos indirectos

Conclusiones

Financiación

Conflicto de intereses

Estrés oxidativo y síndrome de apneas-hipopneas del sueño

Arch Bronconeumol

Oxidative stress in obstructive sleep apnea

Chest

Obstructive sleep apnea and inflammation

Prog Cardiovasc Dis

Sleep apnea, sleepiness, inflammation and insulin resistance in middle-aged men and women

Eur Respir J

Intermittent hypoxia and sleep-disordered breathing: Current concepts and perspectives

Eur Respir J

Multifaceted link between cancer and inflammation

Biosci Rep

Oxygen sensing, homeostasis, and disease

N Engl J Med

The role of hypoxia-induced factors in tumor progression

The Oncologist

Hypoxia-inducible factors: Mediators of cancer progression and targets for cancer therapy

Trends Pharmacol Sci

Molecular pathways: Hypoxia response in immune cells fighting or promoting cancer

Clin Cancer Res

Intermittent hypoxia is a key regulator of cancer cell and endothelial cell interplay in tumours

FEBS J

Tumors exposed to acute cyclic hypoxic stress show enhanced angiogenesis, perfusion and metastatic dissemination

Int J Cancer

Preconditioning of the tumor vasculature and tumor cells by intermittent hypoxia: Implications for anticancer therapies

Cancer Res

Intermittent hypoxia augments melanoma tumor metastases in a mouse model of sleep apnea

Am J Respir Crit Care Med

Diurnal variability of C-reactive protein in obstructive sleep apnea

Sleep Breath

Effects of continuous positive airway pressure therapy on systemic inflammation in obstructive sleep apnea: A meta-analysis

Sleep Med

The epidemiology of adult obstructive sleep apnea

Proc Am Thorac Soc

Obesity promotes melanoma tumor growth. Role of leptin

Cancer Biol Ther

Obesity and cancer risk: Recent review and evidence

Curr Oncol Rep

Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults

N Engl J Med

Association of all-cause mortality with overweight and obesity using standard body mass index categories: A systematic review and meta-analysis

JAMA

Intermittent hypoxia enhances cancer progression in a mouse model of sleep apnoea

Eur Respir J

Obesity and intermittent hypoxia increase tumor growth in a mouse model of sleep apnea

Sleep Med

Biology of obesity: Lessons from animal models of obesity

J Biomed Biotechnol

Obesity and cancer: The role of dysfunctional adipose tissue

Cancer Epidemiol Biomarkers Prev

Serum vascular endothelial growth factor levels in patients with medullary thyroid carcinoma

Eur J Endocrinol

Serum vascular endothelial growth factor: A prognostic factor in cervical cancer

J Cancer Res Clin Oncol

Inflammation and cancer: How friendly is the relationship for cancer patients?

Curr Opin Pharmacol

Circulating vascular endothelial growth factor levels in patients with obstructive sleep apnea

Sleep

Revisión
Relación entre apnea del sueño y cáncerRelationship Between Sleep Apnea and Cancer