Abstract
Complex interactions between tumor cells and their surrounding compartment are strongly influenced by the host in which the tumor grows. In melanoma, for instance, stress-associated norephinephrine (NE), acting at β-adrenergic receptors (β-ARs), stimulates melanoma cell proliferation and tumor angiogenesis. Among β-ARs, β3-ARs play a role acting not only at tumor cells but also at non-neoplastic stromal cells within the melanoma. In the present study, we used a murine model of B16 melanoma to evaluate the role of the host β1- and β2-ARs in melanoma growth and we determined whether the role of β3-ARs can be influenced by the absence of stromal β1- and β2-ARs. As compared to wild-type mice, β1/2-AR knockout mice displayed (i) increased intratumoral levels of both NE and β3-ARs, as evidentiated at both messenger and protein levels; (ii) increased tumor vascularization; (iii) decreased tumor cell proliferation but increased tumor cell apoptosis; and (iv) increased responsiveness to intratumoral injection of the β3-AR blocker L-748,337 in terms of decrease in tumor growth, tumor vascular response, tumor cell proliferation, and increase in tumor cell death. These findings together validate the role of β-AR signaling in melanoma microenvironment suggesting that non-neoplastic stromal cells may be targeted by β-AR-related drugs. The additional fact that β3-ARs play an important role in melanoma growth suggests selective β3-AR antagonists as important proapoptotic agents.
References
Barbieri A, Palma G, Rosati A, Giudice A, Falco A, Petrillo A, Petrillo M, Bimonte S, Di Benedetto M, Esposito G, Stiuso P, Abbruzzese A, Caraglia M, Arra C (2012) Role of endothelial nitric oxide synthase (eNOS) in chronic stress-promoted tumour growth. J Cell Mol Med 16:920–926
Baker JG (2010) The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. Br J Pharmacol 160:1048–1061
Braadland PR, Ramberg H, Grytli HH, Taskén KA (2015) β-Adrenergic Receptor Signaling in Prostate Cancer. Front Oncol 4:375
Braeuer RR, Zigler M, Villares GJ, Dobroff AS, Bar-Eli M (2011) Transcriptional control of melanoma metastasis: the importance of the tumor microenvironment. Semin Cancer Biol 21:83–88
Breit A, Lagacé M, Bouvier M (2004) Hetero-oligomerization between beta2- and beta3-adrenergic receptors generates a beta-adrenergic signaling unit with distinct functional properties. J Biol Chem 279:28756–28765
Calvani M, Pelon F, Comito G, Taddei ML, Moretti S, Innocenti S, Nassini R, Gerlini G, Borgognoni L, Bambi F, Giannoni E, Filippi L, Chiarugi P (2015) Norepinephrine promotes tumor microenvironment reactivity through β3-adrenoreceptors during melanoma progression. Oncotarget 6:4615–4632
Candelore MR, Deng L, Tota L, Guan XM, Amend A, Liu Y, Newbold R, Cascieri MA, Weber AE (1999) Potent and selective human beta(3)-adrenergic receptor antagonists. J Pharmacol Exp Ther 290:649–655
Cernecka H, Pradidarcheep W, Lamers WH, Schmidt M, Michel MC (2014a) Rat β3-adrenoceptor protein expression: antibody validation and distribution in rat gastrointestinal and urogenital tissues. Naunyn Schmiedebergs Arch Pharmacol 387:1117–1127
Cernecka H, Sand C, Michel MC (2014b) The odd sibling: features of β3-adrenoceptor pharmacology. Mol Pharmacol 86:479–484
Cole SW, Sood AK (2012) Molecular pathways: beta-adrenergic signaling in cancer. Clin Cancer Res 18:1201–1206
da Silva EP, Pedro MM, Varela MG, Cortez-Dias N, Bicho MP, Madeira HC, Lopes MG (2007) Heart rate and blood pressure in mitral valve prolapse patients: divergent effects of long-term propranolol therapy and correlations with catecholamines. Anadolu Kardiyol Derg 7(Suppl 1):107–109
Dal Monte M, Cammalleri M, Mattei E, Filippi L, Bagnoli P (2015) Protective effects of β1/2 adrenergic receptor deletion in a model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 56:59–73
Dal Monte M, Casini G, Filippi L, Nicchia GP, Svelto M, Bagnoli P (2013) Functional involvement of beta3-adrenergic receptors in melanoma growth and vascularization. J Mol Med (Berl) 91:1407–1419
De Giorgi V, Gandini S, Grazzini M, Benemei S, Marchionni N, Geppetti P (2013) Effect of beta-blockers and other antihypertensive drugs on the risk of melanoma recurrence and death. Mayo Clin Proc 88:1196–1203
De Giorgi V, Grazzini M, Gandini S, Benemei S, Asbury CD, Marchionni N, Geppetti P (2012) Beta-adrenergic-blocking drugs and melanoma: current state of the art. Expert Rev Anticancer Ther 12:1461–1467
De Giorgi V, Grazzini M, Gandini S, Benemei S, Lotti T, Marchionni N, Geppetti P (2011) Treatment with beta-blockers and reduced disease progression in patients with thick melanoma. Arch Intern Med 171:779–781
Gacche RN, Meshram RJ (2014) Angiogenic factors as potential drug target: efficay and limitations of anti-angiogenic therapies. Biochim Biophys Acta 1846:161–179
Glasner A, Avraham R, Rosenne E, Bensih M, Zmora O, Shemer S, Meiboom H, Ben-Eliyahu S (2010) Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol 184:2449–2457
Gu C, Ma YC, Benjamin J, Littman D, Chao MV, Huang XY (2000) Apoptotic signaling through the beta -adrenergic receptor. A new Gs effector pathway. J Biol Chem 275:20726–20733
Hamdani N, van der Velden J (2009) Lack of specificity of antibodies directed against human beta-adrenergic receptors. Naunyn Schmiedebergs Arch Pharmacol 379:403–407
Hasegawa H, Saiki I (2002) Psychosocial stress augments tumor development through beta-adrenergic activation in mice. Jpn J Cancer Res 93:729–735
Hein L (2006) Adrenoceptors and signal transduction in neurons. Cell Tissue Res 326:541–551
Icard P, Kafara P, Steyaert JM, Schwartz L, Lincet H (2014) The metabolic cooperation between cells in solid cancer tumors. Biochim Biophys Acta 1846:216–225
Jobling P, Pundavela J, Oliveira SM, Roselli S, Walker MM, Hondermarck H (2015) Nerve-cancer cell cross-talk: a novel promoter of tumor progression. Cancer Res 75:1777–1781
Kim-Fuchs C, Le CP, Pimentel MA, Shackleford D, Ferrari D, Angst E, Hollande F, Sloan EK. (2014) Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment. Brain Behav Immun 40:40–47
Lamkin DM, Sloan EK, Patel AJ, Chiang BS, Pimentel MA, Ma JC, Arevalo JM, Morizono K, Cole SW (2012) Chronic stress enhances progression of acute lymphoblastic leukemia via beta-adrenergic signaling. Brain Behav Immun 26:635–641
Lemeshow S, Sorensen HT, Phillips G, Yang EV, Antonsen S, Riis AH, Lesinski GB, Jackson R, Glaser R (2011) Beta-blockers and survival among danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol Biomark Prev 20:2273–2279
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408
Livingstone E, Hollestein LM, van Herk-Sukel MP, Poll-Franse L, Nijsten T, Schadendorf D, de Vries E (2013) β-Blocker use and all-cause mortality of melanoma patients: results from a population-based Dutch cohort study. Eur J Cancer 49:3863–3871
May LT, Holliday ND, Hill SJ (2010) The evolving pharmacology of GPCRs. In: Gilchrist A (ed) GPCR molecular pharmacology and drug targeting: shifting paradigms and new directions. John Wiley and sons, Hoboken, pp. 27–60
McCourt C, Coleman HG, Murray LJ, Cantwell MM, Dolan O, Powe DG, Caldwell CR (2014) Beta-blocker usage after malignant melanoma diagnosis and survival: a population-based nested case-control study. Br J Dermatol 170:930–938
Michel MC, Cernecka H, Ochodnicky P (2011) Desirable properties of β3-adrenoceptor agonists: implications for the selection of drug development candidates. Eur J Pharmacol 657:1–3
Michel MC, Wieland T, Tsujimoto G (2009) How reliable are G-protein-coupled receptor antibodies? Naunyn Schmiedebergs Arch Pharmacol 379:385–338
Mittal A, Tabasum S, Singh RP (2014) Berberine in combination with doxorubicin suppresses growth of murine melanoma B16F10 cells in culture and xenograft. Phytomedicine 21:340–347
Moretti S, Massi D, Farini V, Baroni G, Parri M, Innocenti S, Cecchi R, Chiarugi P (2013) Beta-adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines. Lab Investig 93:279–290
Myers MG, de Champlain J (1983) Effects of atenolol and hydrochlorothiazide on blood pressure and plasma catecholamines in essential hypertension. Hypertension 5:591–596
Nicchia GP, Stigliano C, Sparaneo A, Rossi A, Frigeri A, Svelto M (2013) Inhibition of aquaporin-1 dependent angiogenesis impairs tumour growth in a mouse model of melanoma. J Mol Med (Berl) 91:613–623
Pattyn F, Speleman F, De Paepe A, Vandesompele J (2003) RTPrimerDB: the real-time PCR primer and probe database. Nucleic Acids Res 31:122–123
Pradidarcheep W, Stallen J, Labruyère WT, Dabhoiwala NF, Michel MC, Lamers WH (2009) Lack of specificity of commercially available antisera against muscarinergic and adrenergic receptors. Naunyn Schmiedebergs Arch Pharmacol 379:397–402
Pullar CE, Le Provost GS, O’Leary AP, Evans SE, Baier BS, Isseroff RR (2012) β2AR antagonists and β2AR gene deletion both promote skin wound repair processes. J Invest Dermatol 132:2076–2084
Rohrer DK, Chruscinski A, Schauble EH, Bernstein D, Kobilka BK (1999) Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors. J Biol Chem 274:16701–16708
Romana-Souza B, Nascimento AP, Monte-Alto-Costa A (2009) Propranolol improves cutaneous wound healing in streptozotocin-induced diabetic rats. Eur J Pharmacol 611:77–84
Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386
Sato M, Hutchinson DS, Evans BA, Summers RJ (2008) The beta3-adrenoceptor agonist 4-[[(hexylamino)carbonyl]amino]-N-[4-[2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]-phenyl]-benzenesulfonamide (L755507) and antagonist (S)-N-[4-[2-[[3-[3-(acetamidomethyl)phenoxy]-2-hydroxypropyl]amino]-ethyl]phenyl]benzenesulfonamide (L748337) activate different signaling pathways in Chinese hamster ovary-K1 cells stably expressing the human beta3-adrenoceptor. Mol Pharmacol 74:1417–1428
Schelb V, Göbel I, Khairallah L, Zhou H, Cox SL, Trendelenburg AU, Hein L, Starke K (2001) Postnatal development of presynaptic receptors that modulate noradrenaline release in mice. Naunyn Schmiedebergs Arch Pharmacol 364:359–371
Soares-da-Silva P, Davidson R (1985) Effects of 6-hydroxydopamine on dopamine and noradrenaline content in dog blood vessels and heart. Naunyn Schmiedebergs Arch Pharmacol 329:253–257
Sorriento D, Santulli G, Del Giudice C, Anastasio A, Trimarco B, Iaccarino G (2012) Endothelial cells are able to synthesize and release catecholamines both in vitro and in vivo. Hypertension 60:129–136
Stati T, Musumeci M, Maccari S, Massimi A, Corritore E, Strimpakos G, Pelosi E, Catalano L, Marano G (2014) β-Blockers promote angiogenesis in the mouse aortic ring assay. J Cardiovasc Pharmacol 64:21–27
Steinle JJ, Pierce JD, Clancy RL, Smith G (2002) Increased ocular blood vessel numbers and sizes following chronic sympathectomy in rat. Exp Eye Res 74:761–768
Susulic VS, Frederich RC, Lawitts J, Tozzo E, Kahn BB, Harper ME, Himms-Hagen J, Flier JS, Lowell BB (1995) Targeted disruption of the beta 3-adrenergic receptor gene. J Biol Chem 270:29483–29492
Tang J, Li Z, Lu L, C CH (2013) β-adrenergic system, a backstage manipulator regulating tumor progression and drug target in cancer therapy. Semin Cancer Biol 23:533–542
van Wieringen JP, Michel-Reher MB, Hatanaka T, Ueshima K, Michel MC (2013) The new radioligand [(3)H]-L 748,337 differentially labels human and rat β3-adrenoceptors. Eur J Pharmacol 720:124–130
Vrydag W, Michel MC (2007) Tools to study beta3-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 374:385–398
Wang X, Seed BA (2003) PCR primer bank for quantitative gene expression analysis. Nucleic Acids Res 31:e154
Wnorowski A, Sadowska M, Paul RK, Singh NS, Boguszewska-Czubara A, Jimenez L, Abdelmohsen K, Toll L, Jozwiak K, Bernier M, Wainer IW (2015) Activation of β2-adrenergic receptor by (R,R’)-4′-methoxy-1-naphthylfenoterol inhibits proliferation and motility of melanoma cells. Cell Signal 27:997–1007
Wrobel LJ, Le Gal FA (2015) Inhibition of human melanoma growth by a non-cardioselective β-blocker. J Invest Dermatol 135:525–531
Wuest M, Eichhorn B, Grimm MO, Wirth MP, Ravens U, Kaumann AJ (2009) Catecholamines relax detrusor through beta 2-adrenoceptors in mouse and beta 3-adrenoceptors in man. J Pharmacol Exp Ther 328:213–222
Yaniv SP, Ben-Shachar D, Klein E (2008) Norepinephrine-glucocorticoids interaction does not annul the opposite effects of the individual treatments on cellular plasticity in neuroblastoma cells. Eur J Pharmacol 596:14–24
Acknowledgments
The authors wish to thank Irene Fornaciari and Andrea Marranci for their technical assistance in the early phase of the work. Our thanks are also due to Elisabetta Mattei for providing β1-AR KO and β2-AR KO. This study is supported by grants from Ministero della Salute (RF-2011-02351158; PB), Regione Toscana (PB), and Ente Cassa di Risparmio di Firenze (PB and LF).
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The authors declare that they have no competing interests.
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Sereni, F., Dal Monte, M., Filippi, L. et al. Role of host β1- and β2-adrenergic receptors in a murine model of B16 melanoma: functional involvement of β3-adrenergic receptors. Naunyn-Schmiedeberg's Arch Pharmacol 388, 1317–1331 (2015). https://doi.org/10.1007/s00210-015-1165-7
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DOI: https://doi.org/10.1007/s00210-015-1165-7