Abstract
We investigate the effects of intermittent hypoxia (IH), a characteristic feature of obstructive sleep apnea (OSA), on renal cancer progression in an animal and cell model. An in vivo mouse model (Balb/c, n = 50) of kidney cancer was used to assess the effect of IH on tumor growth, metastatic capacity, angiogenesis and tumor immune response. An in vitro model tested the effect of IH on RENCA cells, macrophages and endothelial cells. Tumor growth, metastatic capacity, circulating vascular endothelial growth factor (VEGF) and content of endothelial cells, tumor associated macrophages and their phenotype were assessed in the tumor. In vitro, VEGF cell expression was quantified.Although IH did not boost tumor growth, it significantly increased endothelial cells (p = 0.001) and circulating VEGF (p<0.001) in the in vivo model. Macrophages exposed to IH in vitro increased VEGF expression, whereas RENCA cells and endothelial cells did not. These findings are in keeping with previous clinical data suggesting that OSA has no effect on kidney cancer size and that the association observed between OSA and higher Fuhrman grade of renal cell carcinoma may be mediated though a proangiogenic process, with a key role of macrophages.
Highlights
Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder among adult population and is characterized by recurrent occlusions of the upper airway during sleep hours leading to intermittent hypoxia (IH) [1]
Plasma vascular endothelial growth factor (VEGF) was significantly overexpressed in the IH group, with a mean concentration of 306±93 pg/mL compared to 194±10 pg/mL in the normoxic control group (p
We did not observe any change in the expression of the M1 (Fig 1G) and M2 (Fig 1H) surface markers of tumor associated macrophages (TAMs) evaluated from IH-exposed RENCA tumors
Summary
Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder among adult population and is characterized by recurrent occlusions of the upper airway during sleep hours leading to intermittent hypoxia (IH) [1]. The most common risk factors of OSA are age, male gender and obesity [2]. Patients suffering from OSA present increased levels of oxidative stress, systemic inflammation and hypoxia-inducible factors (HIF) including their downstream gene products. IH and vascularization of RCC funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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