Over the last 3 decades, an increasing body of evidence suggests that catecholamine-dependent signalling may represent a major link between chronic stress and tumor progression. Studies addressing the relationship between stress-activated pathways and cancer progression suggest that stress-induced production of adrenaline and noradrenaline, besides affecting the anti-tumor immune response also displays direct tumor-promoting effects in several types of tumors, and that beta-adrenoceptors (AR) are the key receptors mediating such effects.
The biologic effects of adrenaline and noradrenaline are mediated by adrenergic receptors, which are divided into 3 main families: alpha-1, alpha-2 and beta-AR. AR belong to the superfamily of G-protein coupled receptors and show distinct patterns of tissue distribution. Increasing evidence points to beta-AR signalling pathways as key regulators of several cancer-relevant cell types including epithelial cells, vascular myocytes and pericytes, adipocytes, fibroblasts, neural and glial cells, and most lymphoid and myeloid immune cells.
Beta-Adrenergic Regulation of Tumour Biology
After the seminal studies by Schuller and Cole in 1989 showing that the beta-AR activation by the selective beta-AR agonist isoprenaline promoted the proliferation of lung adenocarcinoma cells, many researchers have been proving in in vitro and in vivo studies that beta-AR signalling activation may result in cancer progression. Beta-AR signalling may actually regulate multiple cellular processes which directly and indirectly contribute to the progression of tumors including proliferation, inflammation, angiogenesis, apoptosis, cell migration, cellular immune response, and epithelial–mesenchymal transition.
In fact, these cancer-related molecular pathways can be influenced not only by beta-AR expressed on tumors cells but also by activation of beta-AR on other cell types present in the tumor microenvironment (e.g. macrophages, natural killer cells, vascular cells, lymphocytes etc.) although the molecular mechanisms underlying these effects are not yet fully understood. Beta-AR signalling strongly enhances macrophage recruitment into tumour parenchyma and its differentiation from M1 to M2 pro-tumour phenotype, induces a reduction of lymphocyte proliferation, decrease in NK cell cytotoxicity and reduction in T-cell to mitogen stimulation, which altogether strongly contribute to cancer progression.
Beta-AR activation also increase the expression of pro-inflammatory cytokines such as interleukin-6 (IL-6) and IL-8 by tumour cells and immune cells, VEGF-mediated increases in angiogenesis, matrix metalloproteinase (MMP)–related increases in tissue invasion, tumour cell mobilization and motility, focal adhesion kinase (FAK)–mediated resistance to anoikis apoptosis, and BAD-mediated resistance to chemotherapy-induced apoptosis. In addition some evidence also suggest that beta-adrenergic signalling can also inhibit DNA damage repair and p53-associated apoptosis which raises the possibility that this pathway might be not only involved in the tumour progression but also in its initiation or chromosomal instability.
Recently, a review by Coelho et al. (2016) provides valuable state-of-the-art information for any researcher working in this area of cancer therapeutics since it exhaustively summarizes evidence about the expression and the functional role of beta1 and beta2-AR on the cancer cells and cell lines derived from several common solid tumors, as well as the effects of beta-AR ligands upon cancer cells proliferation together with any available information about the signalling pathways possibly involved. In summary, they show that most cancer cells express both beta1- and beta2-AR and adrenergic agonists increase the proliferation of several types of cancers. The proliferative effect promoted by beta-AR agonists seems to be mediated by both beta1- and beta2-AR, through two major cAMP-dependent downstream effector systems: protein kinase A and the guanine exchange protein activated by adenylyl cyclase (EPAC).
Furthermore, work by multiple groups has shown that the beta-AR expression is increased on high grade patient’s tumors when compared with lower stage disease. Beta-AR overexpression has been reported in diverse human cancers, including breast, oral, prostate and melanoma. In many of these studies the high expression of these receptors is highly correlated with increased malignancy, poor clinic pathological features, tumour recurrence and reduced survival which suggest that these receptors may have a role in driving tumor progression.
Beta-Blockers: a Promise for a Novel Class of Antitumor Agents
Knowledge about beta-AR signalling and tumour progression may have enormous clinical implications, since numerous beta-AR ligands able to oppose the actions of adrenaline and noradrenaline on such receptors (the so called ‘beta-blockers’) are currently used in cardiovascular patients to treat hypertension, heart failure and arrhythmias, usually with a favourable risk-benefit profile, and might therefore be easily repurposed as a new class of anti-tumor agents. Although the investigation is still at its infancy, retrospective studies have shown that cancer patients taking beta-blockers survive longer due to reduced metastasis and tumor recurrence rates, and hence adjuvant use of beta-blockers in cancer chemotherapy has been actively investigated which may open a window of opportunity for therapeutic intervention in cancer using beta-blockers. For instance, propranolol has been shown being effective at multiple points in the metastatic cascade.
Beta-blockers are, however, a heterogeneous category of drugs, showing distinct pharmacological properties not only in terms of beta-AR specify but also in intrinsic sympathomimetic activity, vasodilatory effects and ability to cross the blood-brain barrier. Moreover, the relatively recent discovery that some beta-blockers are not only pure antagonists for their receptors but also partial agonists and inverse agonists, depending on their intrinsic efficacy, which can be different in distinct tissues, adds a new level of complexity in the study of beta-blockers effects not only in cancer, in which these drugs have been gaining momentum, but also in other diseases.
The complex pharmacology of beta-blockers has been recently systematically examined by Coelho et al. (2016), in the light of currently available preclinical and clinical evidence regarding the modulation of cancer cells proliferation by beta-AR. The review presents and discusses the clinical studies published so far about the effects of beta-blockers in cancer patients.
The majority of these studies is epidemiological and shows that cancer patients who are taking beta-blockers for other clinical conditions present lower mortality rates when compared with their counterparts. However, most of them do not take into account the pharmacological profile of beta-blockers more often associated with positive outcomes and which signalling pathways may be implicated in these responses.
Indeed, many beta-blockers such as propranolol may induce a “biased signalling” which might well explain many of the apparently contradictory results obtained in various studies. Actually, recent studies focusing on the characterization of the properties of clinically relevant beta-blockers at Beta1 and Beta2-AR level have shown that these drugs have divergent effects on Gas and Beta-arrestin-mediated signalling which clearly could have implications in vivo.
Open issues which should be addressed by future research include: the evaluation of beta-AR on human tumor tissues as a tool to select the patients who might preferentially benefit from beta-blockers treatment; the characterization of the beta-blockers which are more often associated with positive outcomes and which are more likely to benefit cancer patients; and the evaluation of the pharmacological properties of beta-blockers in terms of their action on Gas and beta arrestin-mediated signalling given that their implications in vivo are mostly unknown.
There is a significant volume of data from in vitro, animal and human studies to indicate that there are multiple clinically relevant anti-cancer effects associated with propranolol which might be a very strong candidate for repurposing as a new anticancer agent. Actually, several clinical trials are on-going in order to investigate the possible effects of propranolol and others beta-blockers in different clinical settings for several cancers including: prostate [NCT0185781], breast [NCT02596867; NCT01847001], melanoma [NCT01988831], colorectal [NCT00888797; ACTRN12612000852853] and hepatocellular [NCT01265576], Neuroblastoma [NCT02641314]. (https://clinicaltrials.gov/)
Coelho, M. Soares-Silva C., Brandão D. Marino F. Cosentino M. and Ribeiro L. β-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives. J Cancer Res Clin Oncol (2016). doi:10.1007/s00432-016-2278-1
Pan Pantziarka, Gauthier Bouche, Vidula Sukhatme, Lydie Meheus, Ilse Rooman and Vikas P Sukhatme. Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent. ecancer (2016), 10:680 DOI: 10.3332/ecancer.2016.680
Cole, S.W., Nagaraja, A.S., Lutgendorf, S.K., Green, P.A., Sood, A.K., Sympathetic nervous system regulation of the tumour microenvironment. Nat. Rev. Cancer (2015) 15, 563–572. doi: 10.1038/nrc3978
Steven W. Cole and Anil K. Sood. Molecular Pathways: Beta-Adrenergic Signaling in Cancer Clin Cancer Res (2012); 18:1201-1206. DOI:10.1158/1078-0432.CCR-11-0641
The contents of this article were adapted from Coelho, M. Soares-Silva C., Brandão D. Marino F. Cosentino M. and Ribeiro L. β-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives. J Cancer Res Clin Oncol (2016). doi:10.1007/s00432-016-2278-1
Coelho M1,2,3; Soares-Silva C1,2; Brandão D 1,4; Marino F3; Cosentino M3 and Ribeiro L1,2,4 – 1Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal; 2I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; 3Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy; 4Department of Medical Education and Simulation, Faculty of Medicine, University of Porto, Porto, Portugal; Corresponding author: Marisa Coelho, Email: firstname.lastname@example.org
Cover Image: The β2-adrenoceptor (blue) coupling to the heterotrimeric G protein GS (red, yellow, green) after binding of an agonist. Author: Brian Kobilka, Stanford University School of Medicine; https://en.wikipedia.org/wiki/History_of_catecholamine_research#/media/File:Receptor.kobilka.jpg Credit: Wikimedia Commons.
Cover Image Credit: Left panel, Agonist activation and coupling/signaling properties of β-adrenergic receptor subtypes. GRK indicates G protein–coupled receptor kinase; βArr, β-arrestin; PDE, phosphodiesterase; PI3K, phosphatidylinositol 3-kinase; and AC, adenylyl cyclase. Data from Hoffmann et al, 184 ; From ‘What Is the Role of β-Adrenergic Signaling in Heart Failure?’, by Martin J. Lohse Stefan Engelhardt and Thomas Eschenhagen; Circulation Research 2003;93:896–906.
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