Obstructive sleep apnoea is related to melanoma aggressiveness through paraspeckle protein-1 upregulation.

BACKGROUND: In patients with obstructive sleep apnoea (OSA), intermittent hypoxia induces overexpression of paraspeckle component (PSPC)1, a master modulator of transforming growth factor (TGF)-ß signalling, which promotes cell cancer progression through epithelial-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. However, the persistence of intermittent hypoxia-induced effects on PSPC1, and their consequences in cancer patients are not known. To this effect, circulating PSPC1 levels were compared in patients with cutaneous melanoma with or without OSA, and their relationship with tumour aggressiveness along with the in vitro effects of soluble PSPC1 and intermittent hypoxia on melanoma cell aggressiveness mechanisms were assessed. METHODS: In 292 cutaneous melanoma patients, sleep studies and serum levels of PSPC1 and TGF-ß were evaluated. The effect of PSPC1 on expression of EMT and CSC transcription factors was assessed using melanoma cell lines with patient sera under both normoxia and intermittent hypoxia conditions. RESULTS: PSPC1 levels were higher in patients with moderate-severe OSA compared with mild OSA or non-OSA patients. Serum levels of PSPC1 were associated with several cutaneous melanoma clinical aggressiveness indicators. Both intermittent hypoxia exposures and serum from OSA patients upregulated TGF-ß expression and amplified the expression of transcription factors associated with EMT activation and acquisition of CSC characteristics. CONCLUSION: In cutaneous melanoma patients, OSA severity is associated with higher PSPC1 serum levels, which jointly with intermittent hypoxia would enhance the self-reprogramming capabilities of EMT and CSC feature acquisition of melanoma cells, promoting their intrinsic aggressiveness.

Proangiogenic factor midkine is increased in melanoma patients with sleep apnea and induces tumor cell proliferation.

Midkine (MDK) might mediate the proangiogenic effect of intermittent hypoxia (IH) in patients with obstructive sleep apnea (OSA) and cutaneous melanoma (CM). We compare circulating MDK in CM patients with and without OSA, and their relationship with tumor aggressiveness, while exploring in vitro effects of soluble MDK on human lymphatic endothelial (HLEC) and melanoma cell proliferation. In 360 CM patients, sleep studies and MDK serum level measurements were performed. The effect of MDK on cell proliferation was assessed using HLEC and melanoma cell lines with patient sera under both normoxia and IH. MDK levels were higher in severe OSA compared to mild OSA or non-OSA patients, whereas no differences in VEGF levels emerged. In OSA patients, MDK levels correlated with nocturnal hypoxemia and CM mitotic rate. In vitro, MDK promotes HLEC proliferation under IH conditions. Moreover, cultures of the human melanoma cell line C81-61 with sera from patients with the highest MDK levels promoted tumor cell proliferation, which was attenuated after the addition of MDK antibody. These responses were enhanced by IH exposures. In conclusion, in CM patients, OSA severity is associated with higher MDK levels, which, appear to enhance both the lymphangiogenesis as the intrinsic aggressiveness of CM tumor cells.

Obesity attenuates the effect of sleep apnea on active TGF-ß1 levels and tumor aggressiveness in patients with melanoma.

Active transforming growth factor-ß1 (TGF-ß1), a cytokine partially regulated by hypoxia and obesity, has been related with poor prognosis in several tumors. We determine whether obstructive sleep apnea (OSA) increases serum levels of active TGF-ß1 in patients with cutaneous melanoma (CM), assess their relationship with melanoma aggressiveness and analyze the factors related to TGF-ß1 levels in obese and non-obese OSA patients. In a multicenter observational study, 290 patients with CM were underwent sleep studies. TGF-ß1 was increased in moderate-severe OSA patients vs. non-OSA or mild OSA patients with CM. In OSA patients, TGF-ß1 levels correlated with mitotic index, Breslow index and melanoma growth rate, and were increased in presence of ulceration or higher Clark levels. In CM patients, OSA was associated with higher TGF-ß1 levels and greater melanoma aggressiveness only in non-obese subjects. An in vitro model showed that IH-induced increases of TGF-ß1 expression in melanoma cells is attenuated in the presence of high leptin levels. In conclusion, TGF-ß1 levels are associated with melanoma aggressiveness in CM patients and increased in moderate-severe OSA. Moreover, in non-obese patients with OSA, TGF-ß1 levels correlate with OSA severity and leptin levels, whereas only associate with leptin levels in obese OSA patients.

Soluble PD-L1 is a potential biomarker of cutaneous melanoma aggressiveness and metastasis in obstructive sleep apnoea patients.

Obstructive sleep apnoea (OSA) upregulates the programmed cell death-1 receptor and its ligand (PD-L1) pathway, potentially compromising immunosurveillance. We compared circulating levels of soluble PD-L1 (sPD-L1) in patients with cutaneous melanoma according to the presence and severity of OSA, and evaluated relationships with tumour aggressiveness and invasiveness.In a multicentre observational study, 360 patients with cutaneous melanoma underwent sleep studies, and serum sPD-L1 levels were assayed using ELISA. Cutaneous melanoma aggressiveness indices included mitotic rate, Breslow index, tumour ulceration, Clark level and tumour stage, and sentinel lymph node (SLN) metastasis was recorded as a marker of invasiveness.sPD-L1 levels were higher in severe OSA compared to mild OSA or non-OSA patients. In OSA patients, sPD-L1 levels correlated with Breslow index and were higher in patients with tumour ulceration, advanced primary tumour stages or with locoregional disease. The incorporation of sPD-L1 to the classic risk factors to SLN metastasis led to net improvements in the classification of 27.3%.Thus, sPD-L1 levels are increased in melanoma patients with severe OSA, and, in addition, might serve as a potential biomarker of cutaneous melanoma aggressiveness and invasiveness in this group of subjects.

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.

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.

A prospective multicenter cohort study of cutaneous melanoma: clinical staging and potential associations with HIF-1α and VEGF expressions.

Melanoma is a highly prevalent cancer that is associated with substantial mortality. Although clinical staging procedures can serve as relatively robust prognostic indicators, we aimed to determine whether assessments of the abundance of hypoxia inducible factor-1α (HIF-1α) or vascular endothelial growth factor (VEGF) in postexcisional melanoma tumor tissues may enable more accurate determination of tumor aggressiveness. We carried out a multicenter prospective study, in which we systematically evaluated 376 consecutive patients diagnosed with melanoma, and performed histochemical assessments for both HIF-1α and VEGF immunoreactivity in the tumor biopsies. Multivariate analyses showed that higher HIF-1α expression, but not high VEGF, were associated significantly and independently with increased tumor aggressiveness as derived from several well-established aggressiveness criteria. A limitation of this study was that this was a descriptive prospective study lacking a post-hoc verification arm. Thus, the presence of increased numbers of positively labeled HIF-1α cells in melanoma tumors may potentially serve as an indicator of tumor phenotype and prognosis, and accordingly guide therapy.