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

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.

• Authors: Silvia Moretti, Daniela Massi, Valentina Farini, Gianna Baroni, Matteo Parri, Stefania Innocenti, Roberto Cecchi, Paola Chiarugi
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 93 Issue 3 Pg. 279-90 (Mar 2013) ISSN: 1530-0307 [Electronic] United States
• PMID: 23318885 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• DNA Primers
• Interleukin-6
• Interleukin-8
• Receptors, Adrenergic, beta
• Vascular Endothelial Growth Factor A
• Metalloproteases
• Norepinephrine
• Epinephrine

Topics

• Adult
• Blotting, Western
• Cell Line, Tumor
• Cytokines (metabolism)
• DNA Primers (genetics)
• Epinephrine (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (physiology)
• Humans
• Immunohistochemistry
• Interleukin-6 (metabolism)
• Interleukin-8 (metabolism)
• Male
• Melanoma (metabolism)
• Metalloproteases (metabolism)
• Middle Aged
• Norepinephrine (pharmacology)
• Real-Time Polymerase Chain Reaction
• Receptors, Adrenergic, beta (metabolism)
• Skin Neoplasms (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)