Original ArticleObesity and intermittent hypoxia increase tumor growth in a mouse model of sleep apnea
Introduction
Obstructive sleep apnea (OSA) is characterized by recurrent disruptions of ventilation caused by an abnormal increase in upper airway collapsibility [1]. These repetitive obstructive apneas induce intermittent hypoxia, increased inspiratory efforts and sleep disruption which have been widely associated with several neurological and cardiovascular consequences [2], [3]. Interestingly, it is well known that hypoxia (a hallmark challenge in OSA) enhances tumor growth [4], [5], [6], [7]. More specifically, a recent report has indicated that intermittent hypoxia potentiates cancer progression in an animal model of OSA [8]. Similarly, data from some epidemiological studies also suggested a possible relationship between cancer death and severity of OSA [9], [10]. Moreover, a very recent analysis of a 22-year follow-up of a population-based sample cohort has provided evidence of an association between cancer mortality and OSA [11]. Obesity, a common finding associated with OSA, is known to increase the risk of several types of neoplasia [12] and enhances tumor growth [13], [14], [15]. As for the potential mechanism(s) involved, both intermittent hypoxia and obesity can contribute to increase the vascular endothelial growth factor (VEGF) [13], [16], [17], [18], [19], [20], which promotes angiogenesis and plays an important role in tumor growth [13], [21], [22].
To better understand the potential mechanisms involved in cancer growth in OSA, the aim of this work was to investigate the contribution of intermittent hypoxia and obesity to the enhancement of tumor progression in an animal model. To this end, we implanted melanoma tumor cells subcutaneously in both lean and obese mice and subjected them to a chronic pattern of intermittent hypoxia mimicking OSA. Given that intermittent hypoxia could induce some degree of sleep loss [23], we carried out an independent set of experiments to assess whether sleep deprivation could affect tumor growth, as this could be a potential confounding factor. Besides assessing tumor growth and necrosis, we also investigated the potential mechanisms involved by determining the levels of circulating VEGF and the expression of VEGF and CD-31 in the tumor tissue as markers of angiogenesis and vascularization, respectively.
Section snippets
Animals
This study, which was approved by the Ethical Committee for Animal Research of the University of Barcelona, was conducted on 60 pathogen-free, 10-week-old male mice. To assess the effects of IH and obesity, we used 40 mice from a recently established metabolic syndrome mouse model (The Pound Mouse; Charles River Laboratories, Saint Germain sur L’arbresle, France; http://www.criver.com/en-US/ProdServ/ByType/ResModOver/ResMod/Pages/PoundMouse.aspx) characterized by a deletion of the exon 2 in
Tumor growth
Seventeen days after the injection of melanoma cells, the tumor weight of control non-obese animals was enhanced in a similar manner by intermittent hypoxia (p = 0.006, F = 8.51) and by obesity (p = 0.003, F = 10.02). Specifically, the tumor weight was 0.81 ± 0.17 g in normoxic lean mice, 1.95 ± 0.32 g (p < 0.001) in lean mice subjected to intermittent hypoxia and 1.94 ± 0.18 g (p < 0.001) in normoxic obese animals. In obese mice, however, tumor growth was not affected by intermittent hypoxia (1.69 ± 0.23 g) (Fig. 2).
Discussion
The application of intermittent hypoxia with a frequency and relative duration that mimic OSA increased the growth of melanoma tumors in lean mice, but not in obese ones. In fact, the increased tumor growth induced by obesity was not enhanced by adding the intermittent hypoxia stimulus. The effect of intermittent hypoxia on tumoral necrosis and vascular density was smaller than the effect of obesity. Plasma levels of VEGF presented a similar behavior to that of tumor weight, resulting in a
Conflict of interest
The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2012.08.012.
Acknowledgments
The authors thank Esteve-Teijin for kindly providing the oxygen concentrators used to prepare the gas mixtures. The authors wish to thank Rocio Nieto and Miguel A. Rodríguez for their technical assistance. Sources of support: This work was supported in part by Ministerio de Economía y Competitividad (SAF2011-22576, FIS-PI11/00089, FIS-PI11/01892), SEPAR and FUCAP.
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