Article
β-adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines

https://doi.org/10.1038/labinvest.2012.175Get rights and content
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Abstract

Recent studies sight β-adrenergic receptor (AR) antagonists as novel therapeutic agents for melanoma, as they may reduce disease progression. Here within, we evaluated the expression of β-ARs in a series of human cutaneous melanocytic lesions, and studied the effect of their endogenous agonists, norepinephrine (NE) and epinephrine (E), on primary and metastatic human melanoma cell lines. Using immunohistochemistry, we found that both β1- and β2-ARs are expressed in tissues from benign melanocytic naevi, atypical naevi and malignant melanomas and that expression was significantly higher in malignant tumours. Melanoma cell lines (human A375 primary melanoma cell line and human Hs29-4T metastatic melanoma cell lines) also expressed β1- and β2-ARs by measuring transcripts and proteins. NE or E increased metalloprotease-dependent motility, released interleukin-6 and 8 (IL-6, IL-8) and vascular endothelial growth factor (VEGF). These effects of catecholamines were inhibited by the unselective β-AR antagonist propranolol. The role of soluble factors elicited by catecholamines seemed pleiotropic as VEGF synergized with NE increased melanoma invasiveness through 3D barriers, while IL-6 participated in stromal fibroblast activation towards a myofibroblastic phenotype. Our results indicate that NE and E produce in vitro via β-ARs activation a number of biological responses that may exert a pro-tumorigenic effect in melanoma cell lines. The observation that β-ARs are upregulated in malignant melanoma tissues support the hypothesis that circulating catecholamines NE and E, by activating their receptors, favour melanoma progression in vivo.

β-adrenoceptors
immunohistochemistry
melanoma
melanoma progression
norepinephrine/epinephrine

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Both β1- and β2-adrenoceptors are significantly up-regulated in malignant melanoma compared to melanocytic naevi, and stimulation of melanoma cell lines with norepinephrine orepinephrine causes them to increase proteolytic invasiveness and secrete pro-tumorigenic cytokines. These data suggest that circulating norepinephrine and epinephrine affect melanoma progression in vivo, at least in part through the β-adrenoceptor activation.