title: Norepinephrine promotes tumor microenvironment reactivity through β3-adrenoreceptors during melanoma progression.
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.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Calvani
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy.
authors.forename: Floriane
authors.initials: F
authors.lastname: Pelon
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Comito
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Taddei
authors.affiliation: Department of Surgery and Translational Medicine, Dermatology Section University of Florence, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Moretti
authors.affiliation: Division of Pathology, Pistoia Hospital, Pistoia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Innocenti
authors.affiliation: Department of Health Sciences, Clinical Pharmacology and Oncology Unit, University of Florence, Florence, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Nassini
authors.affiliation: Plastic Surgery Unit, Regional Melanoma Referral Center, Tuscan Tumor Institute, Santa Maria Annunziata Hospital, Florence, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Gerlini
authors.affiliation: Plastic Surgery Unit, Regional Melanoma Referral Center, Tuscan Tumor Institute, Santa Maria Annunziata Hospital, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Borgognoni
authors.affiliation: Transfusion Medicine and Cell Therapy, "A. Meyer" University Children's Hospital, Florence, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Bambi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
authors.affiliation: Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital, Florence, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Filippi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D009638:Norepinephrine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A; D000096142:Cutaneous Malignant Melanoma
chemical_list: D000316:Adrenergic alpha-Agonists; D012333:RNA, Messenger; D022702:Receptors, Adrenergic, beta-3; D042461:Vascular Endothelial Growth Factor A; D009638:Norepinephrine
keywords: cancer-associated fibroblasts; macrophages; melanoma; mesenchymal stem cells; tumor microenvironment; β-adrenergic receptors