Envejecimiento y efectos de la hipoxia intermitente crónica sobre tumorigénesis espontánea en ratón

Abstract

Association between sleep disturbances and frequency of cancer has long been suspected. However, how cancer may take advantage of sleep disturbances is a field of many hypothesis and few facts. Recent studies have evidenced that the constitutive elements of obstructive sleep apnea (OSA), short term chronic intermittent hypoxia (CIH) and sleep disruption, augment growth and metastasis rate of implanted tumors in mice (Almendros et al, 2012a; 2012b; 2013; 2014a; Hakim et al., 2014). These studies stimulated retrospective studies in OSA patients which, with some discrepancies, have reported an association between severity of OSA and cancer incidence/mortality (Nieto et al., 2012; Campos-Rodriguez et al. 2013; Christensen et al. 2013; Chang et al., 2014; Chen & Hwang, 2014; Martinez-Garcia et al., 2014; Martinez-Garcia et al., 2014). These discrepancies could be due to the large number of OSA-linked comorbidities and uncontrolled variables among patients, as it is lifestyle. Trying to simplify this complex pathological human situation, male Swiss CD1 mice were used in this study. As single variable chronic intermittent hypoxia (CIH), the main consequence of OSA, was used to evaluate its effects on spontaneous tumorigenesis. The exposure of mice to CIH lasted 3 months, equivalent to 8-10 human years of OSA illness. Outbred mice, to mimic the human genetic diversity, with 15-18 months equivalent to 50-60 human years, when OSA incidence and spontaneous tumorigenesis rate are higher, were used. Two intensities of CIH were applied, moderated (12% O2) and severe (7.5% O2), to study two stages of the illness; as a control group, mice remained in normoxic atmosphere (air). The main results obtained in this study were the following ones. CIH tends to augment multi-organ spontaneous tumorigenesis in a O2 desaturation-related manner. Tumor masses were found in 36.7% of control mice, in 38.8% of moderated CIH animals and in 62.3% severe CIH mice. Lung masses increased in number specially in animals exposed to severe CIH, doubling the incidence compared to control and moderated CIH mice. These spontaneous lung tumors appeared to be typical carcinoids (a neuroendocrine type tumor), with similar size in any of the groups. Plasmatic levels of several tumor markers were measured. Carcinoembryonic antigen and neuron specific enolase plasmatic concentrations, two lung cancer specific biomarkers, were similar in healthy mice of the three groups, but the increase of these tumor markers that occurred in control mice with neoplastic processes was attenuated in CIH mice with tumors, especially with severe CIH. Plasmatic levels of alfa-fetoprotein seemed to have similar behavior, but much less evident because it was only possible to appreciate a difference in severe CIH. These data could help to interpret cancer incidence/mortality in OSA patients. It seems that CIH as principal immediate consequence of OSA increases spontaneous tumorigenesis in a manner related to the intensity of the hypoxia, at least in certain types of cancer, as lung cancer. One of the tools commonly used to check the stage and which inform about the prognosis of the patients with cancer are the tumor markers. If the attenuated increase of several plasmatic tumor markers in aged mice with neoplastic conditions happens to occur in OSA patients, this fact could mislead the severity/staging of tumor situation. This should be interpreted as a warning sign.