Editorial
Sleep Apnea and Tumor Aggressivity
Apnea del sueño y agresividad tumoral
Miguel Ángel Martínez-Garcíaa,d,
, Francisco Campos-Rodríguezb, Isaac Almendrosc,d
Corresponding author
a Servicio de Neumología, Hospital Universitario y Politécnico La Fe, Valencia, Spain
b Servicio de Neumología, Hospital Universitario Valme, Sevilla, Spain
c Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
d CIBER de Enfermedades Respiratorias (CIBERes), Spain
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"correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Apnea del sueño y agresividad tumoral" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Both cancer and obstructive sleep apnea (OSA) constitute 2 serious public health problems, due to their high prevalence among the general population and their negative impact on health.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">1,2</span></a> OSA has been associated with various cardiovascular, neuropsychiatric and metabolic diseases, and most studies have focused on intermittent hypoxemia and sleep fragmentation as the mechanisms potentially underlying this association.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">2</span></a> With respect to cancer, many research groups continue to look for clinical or genetic causes, particularly those that are potentially preventable or treatable.</p><p id="par0010" class="elsevierStylePara elsevierViewall">For some time, intermittent hypoxia (IH), rapid cycles of hypoxia/tissue reoxygenation, an almost pathognomonic feature of OSA, has been known to be capable of activating pathogenic mechanisms associated with carcinogenesis and promoting increased aggressivity in an existing tumor.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">3</span></a> The primary mechanism by which IH achieves this effect is paradoxically related with a compensatory system to avoid tissue death in situations of hypoxia, namely, increased vascularization to ensure sufficient supply of oxygen to the cells.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">4</span></a> This mechanism, which may have saved many lives from a cardiovascular point of view, does not seem to be of benefit in tumor tissue (very hypoxic), since it can promote the development of metastasis and growth of the primary tumor, and thus increase its aggressivity. Two molecules appear to be particularly involved in this pathogenic mechanism: hypoxia-induced factor (HIF-1α), which is overexpressed in hypoxic tissues, and vascular endothelial growth factor (VEGF), the concentration of which increases as a direct consequence of HIF-1α overexpression.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">3,4</span></a> The mechanism is not, however, as simple as it seems, since both molecules can alter their expression as a result of the action of different pathogenic pathways, and produce effects that may occasionally even be paradoxical, depending on the cell environment under consideration.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">3,4</span></a> In recent years, attention has also been focused on alternative pathogenic mechanisms possibly associated with another of the characteristics of OSA, sleep fragmentation, via the activation of the Sympathetic overactivity or activation system changes.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">3</span></a> Experimental animal studies have shown that in IH conditions, tumor-associated macrophages (TAM) differentiate to a more protumoral phenotype (M2) instead of acting as tumor cell phagocytes (macrophages with anti-tumor phenotype or M1).<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">5</span></a> Finally, a promising line of research involves exosomes, microvesicles generated by multiple cells that promote intracellular communication, by way of increased tumor adhesion, formation, invasion and metastastization (aggressivity); these molecules increase in concentration in situations of hypoxia, mediated by HIF-1α concentrations, and even by sleep fragmentation.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">But looking beyond biological plausibility, what conclusions have been drawn from studies in humans? Although some studies, both clinical and populational,<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">7–9</span></a> have shown increases in the incidence of cancer or cancer mortality in individuals with OSA, very few studies have been performed in patients with a specific type of cancer.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a> Gozal et al. recently published a retrospective study of 1.7 million OSA patients and 1.7 million controls adjusted for different variables, and concluded that while OSA was associated with an increase in the incidence of some tumors, such as melanoma, or renal or pancreatic cancer, it was also paradoxically associated with a reduced incidence of other gastrointestinal, prostate and breast tumors, and in no case was it associated with an increase of any type of cancer death.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">11</span></a> Perhaps the research that throws more light on the possibility of a relationship between OSA and increased tumor aggressivity is the recently completed study of the SEPAR Spanish Sleep Group (GES). This study of 443 melanoma patients appears to support the physiopathological hypothesis of an association between OSA and increased tumor aggressivity. The authors found that several polygraphic variables, such as the apnea-hypopnea index, and, moreover, different desaturation indices were associated with well-validated markers of aggressivity in melanoma, such as the Breslow index or the Clark index, among others.</p><p id="par0020" class="elsevierStylePara elsevierViewall">A collateral finding of this study was also of enormous interest: the association appeared to occur in younger patients only.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">12</span></a> This observation had already been made in previous studies that analyzed the association of OSA with both cancer<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">7</span></a> and cardiovascular disease.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">13</span></a> This finding has still not been clearly explained. The cardiovascular community speculates that it may be due to what is called “hypoxic preconditioning”, that is to say, the very protection generated by IH by inducing the genesis of neovascularization in ischemic regions.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">14</span></a> However, this explanation is unconvincing in the case of cancer. It might be speculated, perhaps, that in cancer patients these hypoxia compensation mechanisms somehow deteriorate over time, and this is why tumor aggressivity is greater in younger patients with OSA. An alternative explanation may be that, as tumors are more common in elderly patients, the appearance of a new predisposing factor, in this case OSA, might have a relatively lower impact than in younger individuals.</p><p id="par0025" class="elsevierStylePara elsevierViewall">There is still much to explore in this exciting field of research in terms of confirming the nature of this association, assessing the role of confounding variables (particularly obesity), analyzing which subgroups of individuals are most affected and what types of cancer are more likely to be affected, or determining the potential role of treatment with CPAP, among other issues. Although studies published by GES and other research groups point to an association between both diseases, we should still take a prudent approach. As Confucius said, “The cautious seldom err”, and this is particularly important in a disease with the repercussions of cancer. However, prudence does not have to be an adversary of aspiration and hard work, and our task as investigators must be to persevere with this line of research. We must endeavor to substantiate this hitherto underexplored association, in the belief that such a confirmation might constitute one of the great findings in current respiratory medicine.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Martínez-García MÁ, Campos-Rodríguez F, Almendros I. Apnea del sueño y agresividad tumoral. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 1 | 8 |
| 2024 October | 44 | 21 | 65 |
| 2024 September | 38 | 13 | 51 |
| 2024 August | 52 | 41 | 93 |
| 2024 July | 41 | 18 | 59 |
| 2024 June | 67 | 37 | 104 |
| 2024 May | 89 | 30 | 119 |
| 2024 April | 42 | 26 | 68 |
| 2024 March | 41 | 13 | 54 |
| 2024 February | 48 | 23 | 71 |
| 2023 March | 16 | 7 | 23 |
| 2023 February | 48 | 22 | 70 |
| 2023 January | 24 | 44 | 68 |
| 2022 December | 45 | 33 | 78 |
| 2022 November | 64 | 36 | 100 |
| 2022 October | 77 | 42 | 119 |
| 2022 September | 35 | 49 | 84 |
| 2022 August | 38 | 43 | 81 |
| 2022 July | 31 | 51 | 82 |
| 2022 June | 20 | 35 | 55 |
| 2022 May | 34 | 38 | 72 |
| 2022 April | 25 | 32 | 57 |
| 2022 March | 46 | 38 | 84 |
| 2022 February | 33 | 36 | 69 |
| 2022 January | 37 | 52 | 89 |
| 2021 December | 46 | 39 | 85 |
| 2021 November | 34 | 49 | 83 |
| 2021 October | 56 | 47 | 103 |
| 2021 September | 33 | 38 | 71 |
| 2021 August | 28 | 51 | 79 |
| 2021 July | 25 | 39 | 64 |
| 2021 June | 35 | 45 | 80 |
| 2021 May | 38 | 53 | 91 |
| 2021 April | 97 | 89 | 186 |
| 2021 March | 33 | 29 | 62 |
| 2021 February | 21 | 28 | 49 |
| 2021 January | 39 | 24 | 63 |
| 2020 December | 25 | 21 | 46 |
| 2020 November | 18 | 17 | 35 |
| 2020 October | 25 | 12 | 37 |
| 2020 September | 24 | 22 | 46 |
| 2020 August | 24 | 18 | 42 |
| 2020 July | 36 | 31 | 67 |
| 2020 June | 26 | 14 | 40 |
| 2020 May | 23 | 15 | 38 |
| 2020 April | 28 | 13 | 41 |
| 2020 March | 12 | 14 | 26 |
| 2020 February | 24 | 15 | 39 |
| 2020 January | 27 | 16 | 43 |
| 2019 December | 36 | 15 | 51 |
| 2019 November | 29 | 21 | 50 |
| 2019 October | 13 | 9 | 22 |
| 2019 September | 14 | 11 | 25 |
| 2019 August | 21 | 17 | 38 |
| 2019 July | 23 | 23 | 46 |
| 2019 June | 20 | 7 | 27 |
| 2019 May | 74 | 21 | 95 |
| 2019 April | 60 | 40 | 100 |
| 2019 March | 51 | 34 | 85 |
| 2019 February | 27 | 18 | 45 |
| 2019 January | 27 | 20 | 47 |
| 2018 December | 26 | 16 | 42 |
| 2018 November | 71 | 20 | 91 |
| 2018 October | 90 | 17 | 107 |
| 2018 September | 57 | 11 | 68 |
| 2018 May | 17 | 0 | 17 |
| 2018 April | 27 | 5 | 32 |
| 2018 March | 41 | 5 | 46 |
| 2018 February | 31 | 8 | 39 |
| 2018 January | 127 | 7 | 134 |
| 2017 December | 114 | 11 | 125 |
| 2017 November | 19 | 10 | 29 |
| 2017 October | 32 | 6 | 38 |
| 2017 September | 42 | 15 | 57 |
| 2017 August | 1 | 2 | 3 |
| 2017 June | 1 | 0 | 1 |
| 2017 May | 1 | 0 | 1 |
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