Norepinephrine promotes tumor microenvironment reactivity through β3-adrenoreceptors during melanoma progression

// Maura Calvani 1 , Floriane Pelon 1 , Giuseppina Comito 1 , Maria Letizia Taddei 1 , Silvia Moretti 3 , Stefania Innocenti 4 , Romina Nassini 5 , Gianni Gerlini 2 , Lorenzo Borgognoni 2 , Franco Bambi 7 , Elisa Giannoni 1 , Luca Filippi 6 , Paola Chiarugi 1 1 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”, Florence 50134, Italy 2 Plastic Surgery Unit, Regional Melanoma Referral Center, Tuscan Tumor Institute, Santa Maria Annunziata Hospital, Florence 50012, Italy 3 Department of Surgery and Translational Medicine, Dermatology Section University of Florence, Florence, Italy 4 Division of Pathology, Pistoia Hospital, Pistoia, Italy 5 Department of Health Sciences, Clinical Pharmacology and Oncology Unit, University of Florence, Florence, Italy 6 Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital, Florence, Italy 7 Transfusion Medicine and Cell Therapy "A. Meyer" University Children's Hospital, Florence, Italy Correspondence to: Paola Chiarugi, e-mail: paola.chiarugi@unifi.it Keywords: β-adrenergic receptors, melanoma, tumor microenvironment, cancer associated fibroblasts, macrophages, mesenchymal stem cells Received: August 06, 2014      Accepted: October 27, 2014      Published: December 01, 2014 ABSTRACT Stress has an emerging role in cancer and targeting stress-related β-adrenergic receptors (AR) has been proposed as a potential therapeutic approach in melanoma. Here we report that β3-AR expression correlates with melanoma aggressiveness. In addition, we highlight that β3-AR expression is not only restricted to cancer cells, but it is also expressed in vivo in stromal, inflammatory and vascular cells of the melanoma microenvironment. Particularly, we demonstrated that β3-AR can (i) instruct melanoma cells to respond to environmental stimuli, (ii) enhance melanoma cells response to stromal fibroblasts and macrophages, (iii) increase melanoma cell motility and (iv) induce stem-like traits. Noteworthy, β3-AR activation in melanoma accessory cells drives stromal reactivity by inducing pro-inflammatory cytokines secretion and de novo angiogenesis, sustaining tumor growth and melanoma aggressiveness. β3-ARs also play a mandatory role in the recruitment to tumor sites of circulating stromal cells precursors, in the differentiation of these cells towards different lineages, further favoring tumor inflammation, angiogenesis and ultimately melanoma malignancy. Our findings validate selective β3-AR antagonists as potential promising anti-metastatic agents. These could be used to complement current therapeutic approaches for melanoma patients (e.g. propranolol) by targeting non-neoplastic stromal cells, hence reducing therapy resistance of melanoma.