Intermittent Hypoxia Is Associated With High Hypoxia Inducible Factor-1α but Not High Vascular Endothelial Growth Factor Cell Expression in Tumors of Cutaneous Melanoma Patients

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.

Obstructive sleep apnea and comorbidities: a dangerous liaison

“…A series of studies focused on the association of OSA and cutaneous malignant melanoma (CMM), to verify whether data from the mouse model could be confirmed in humans. Tumor aggressiveness was increased in CMM patients with OSA and long time spent at low oxygen saturation (CT90%) or high oxygen desaturation index (ODI 4%) [158, 170–173]. Interestingly, tumor aggressiveness was positively associated with expression of the adhesion molecule VCAM-1 [171], HIF-1alpha [173], but not with expression of vascular endothelial growth factor (VEGF) [173].…”

Targeting intermittent hypoxia downstream pathways for biomarker discovery and new treatment perspectives in cutaneous melanoma

“…In view of these results, the study by CUBILLOS-ZAPATA et al [16] does indeed allow proposal of sPD-L1 as a potential biomarker of cutaneous melanoma aggressiveness and metastasis in OSA patients. This is also reinforced by the fact that PD-L1 expression is upregulated by intermittent hypoxia, a major hallmark of OSA, as previously demonstrated by the same group [20] and by others [22,30]. In fact, PD-L1 has been formally identified as a target gene of HIF-1 [22], a transcription factor known to be involved in the deleterious cardiometabolic outcome of intermittent hypoxia/OSA [23] but also to worsen cutaneous melanoma prognosis [21,30].…”

A review of the “OMICS” for management of patients with obstructive sleep apnoea

“…Almendros et al 23 examined the correlation between HIF-1α factor and vascular endothelial growth factor (VEGF) expression in patients with cutaneous melanoma. Interestingly, they found in a large prospective study that the expression of HIF-1α was an independent factor associated with nocturnal IH measures of respiratory disturbance during sleep in patients affected by cutaneous melanoma 23 , meaning that it has a significant contribution to the disease. Notably, the risk of melanoma was significantly higher in patients with OSA (HR = 1.14, 95% CI 1.10-1.18), along with pancreatic and kidney cancer 24 .…”