Abstract
Epidemiological associations linking between obstructive sleep apnea and poorer solid malignant tumor outcomes have recently emerged. Putative pathways proposed to explain that these associations have included enhanced hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) cell expression in the tumor and altered immune functions via intermittent hypoxia (IH). Here, we examined relationships between HIF-1α and VEGF expression and nocturnal IH in cutaneous melanoma (CM) tumor samples. Prospectively recruited patients with CM tumor samples were included and underwent overnight polygraphy. General clinical features, apnea–hypopnea index (AHI), desaturation index (DI4%), and CM characteristics were recorded. Histochemical assessments of VEGF and HIF-1α were performed, and the percentage of positive cells (0, <25, 25–50, 51–75, >75%) was blindly tabulated for VEGF expression, and as 0, 0–5.9, 6.0–10.0, >10.0% for HIF-1α expression, respectively. Cases with HIF-1α expression >6% (high expression) were compared with those <6%, and VEGF expression >75% of cells was compared with those with <75%. 376 patients were included. High expression of VEGF and HIF-1α were seen in 88.8 and 4.2% of samples, respectively. High expression of VEGF was only associated with increasing age. However, high expression of HIF-1α was significantly associated with age, Breslow index, AHI, and DI4%. Logistic regression showed that DI4% [OR 1.03 (95% CI: 1.01–1.06)] and Breslow index [OR 1.28 (95% CI: 1.18–1.46)], but not AHI, remained independently associated with the presence of high HIF-1α expression. Thus, IH emerges as an independent risk factor for higher HIF-1α expression in CM tumors and is inferentially linked to worse clinical CM prognostic indicators.
Highlights
Cutaneous melanoma (CM) is a very aggressive type of skin cancer that is fraught with a high mortality rate, but is a cancer type whose incidence has continued to increase over the last several decades [1]
This study shows that levels of hypoxia inducible factor-1α (HIF-1α) expression in CM are independently associated with indicators of episodic hypoxia as derived from nocturnal polygraphic recordings in a large prospectively recruited cohort of CM patients
Contrary to the significant associations between the patterns of HIF-1α expression and the severity of sleep-disordered breathing, vascular endothelial growth factor (VEGF) expression was high in the vast majority of CM lesions, and did not manifest any significant relationship with polygraphically derived measurements, suggesting the absence of co-linearity between HIF-1α and VEGF expression in CM
Summary
Cutaneous melanoma (CM) is a very aggressive type of skin cancer that is fraught with a high mortality rate, but is a cancer type whose incidence has continued to increase over the last several decades [1]. Potential associations between OSA and cancer have been reported and primarily ascribed to the effects of IH on tumor biology [28,29,30,31]. Both experimental and clinical evidence has indicated that CM is one of the more susceptible tumors to the IH patterns that characterize OSA [32,33,34]
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