Abstract
Active transforming growth factor-β1 (TGF-β1), 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-β1 in patients with cutaneous melanoma (CM), assess their relationship with melanoma aggressiveness and analyze the factors related to TGF-β1 levels in obese and non-obese OSA patients. In a multicenter observational study, 290 patients with CM were underwent sleep studies. TGF-β1 was increased in moderate-severe OSA patients vs. non-OSA or mild OSA patients with CM. In OSA patients, TGF-β1 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-β1 levels and greater melanoma aggressiveness only in non-obese subjects. An in vitro model showed that IH-induced increases of TGF-β1 expression in melanoma cells is attenuated in the presence of high leptin levels. In conclusion, TGF-β1 levels are associated with melanoma aggressiveness in CM patients and increased in moderate-severe OSA. Moreover, in non-obese patients with OSA, TGF-β1 levels correlate with OSA severity and leptin levels, whereas only associate with leptin levels in obese OSA patients.
Highlights
Active transforming growth factor-β1 (TGF-β1), a cytokine partially regulated by hypoxia and obesity, has been related with poor prognosis in several tumors
There is increasing evidence that the aggressiveness of cutaneous melanoma (CM) is largely due to the intrinsic plasticity of melanoma cells, which is regulated by a variety of mechanisms that prominently include the transforming growth factor-β (TGF-β) p athway[6,7]
A previous study did not identify a relationship between serum TGF-ß1 concentration and melanoma s tage[13], probably because circulating bioactive TGF-β1 levels were not measured, it has been demonstrated that overall canonical TGF-β/SMAD signaling is a potent promoter of melanoma progression, even at early stages of the d isease[14], and that soluble active TGF-β1 is directly related to the risk of melanoma metastasis[15,16]
Summary
Active transforming growth factor-β1 (TGF-β1), 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-β1 in patients with cutaneous melanoma (CM), assess their relationship with melanoma aggressiveness and analyze the factors related to TGF-β1 levels in obese and non-obese OSA patients. In CM patients, OSA was associated with higher TGF-β1 levels and greater melanoma aggressiveness only in non-obese subjects. TGF-β1 levels are associated with melanoma aggressiveness in CM patients and increased in Precision Medicine in Chronic Diseases, Hospital Universitari Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain. There is increasing evidence that the aggressiveness of CM is largely due to the intrinsic plasticity of melanoma cells, which is regulated by a variety of mechanisms that prominently include the transforming growth factor-β (TGF-β) p athway[6,7]. A previous study did not identify a relationship between serum TGF-ß1 concentration and melanoma s tage[13], probably because circulating bioactive TGF-β1 levels were not measured, it has been demonstrated that overall canonical TGF-β/SMAD signaling is a potent promoter of melanoma progression, even at early stages of the d isease[14], and that soluble active TGF-β1 is directly related to the risk of melanoma metastasis[15,16]
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