University of Groningen Studies on the role of dopamine and serotonin in tumors and their microenvironment Peters, Marloes A.M. DOI: 10.33612/diss.135597229 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2020 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Peters, M. A. M. (2020). Studies on the role of dopamine and serotonin in tumors and their microenvironment. University of Groningen. https://doi.org/10.33612/diss.135597229 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 30-09-2021 CHAPTER 2 Dopamine and serotonin regulate tumor behavior by affecting angiogenesis Marloes A.M. Peters,1 Annemiek M.E. Walenkamp,1 Ido P. Kema,2 Coby Meijer,1 Elisabeth G.E. de Vries,1 and Sjoukje F. Oosting 1 1 Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands 2 Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Drug Resist Updat 2014; 17: 96-104. - 18 - - 19 - 548127-L-bw-Peters Processed on: 17-9-2020 PDF page: 19 ABSTRACT INTRODUCTION The biogenic amines dopamine and serotonin are neurotransmitters and hormones, Increasingly, it is recognized that apart from tumor cells also the non-tumor cells in which are mainly produced in the central nervous system and in the gastro-intestinal the microenvironment participate in tumor behavior [1,2]. Endothelial cells are part of tract. They execute local and systemic functions such as intestinal motility and tissue this microenvironment and can create new blood vessels, which provide oxygen and 2 repair. Dopamine and serotonin are primarily stored in and transported by platelets. nutrients to the tumor, and hence promote tumor growth and metastasis [3]. Besides This review focuses on the recently recognized role of dopamine and serotonin in the cells from the microenvironment, also distant host cells are attracted to the tumor and regulation of tumor behavior by affecting angiogenesis and tumor cell proliferation. contribute to tumor development. The interaction between tumor microenvironment Preclinical studies demonstrate that dopamine inhibits tumor growth via activation of and distant host cells shows similarities with the process of wound healing, in which dopamine receptor D2 on endothelial and tumor cells. Serotonin stimulates tumor immune cells and platelets are attracted to the affected tissue and participate in repair. growth via activation of serotonin receptor 2B on endothelial cells and serotonin In tumor development, attracted host cells can have a detrimental effect; they can receptors on tumor cells. Drugs that stimulate dopamine receptor D2 or inhibit contribute to tumor growth, invasiveness and metastasis [4]. Alike during wound serotonin receptors are available and therefore clinical intervention studies for cancer healing, platelets are recruited to the tumor site and adhere to the activated vascular patients are within reach. wall [5]. This leads to release of their content consisting of pro- and anti-angiogenic factors such as vascular endothelial growth factor A (VEGF-A) [6] and dopamine and serotonin [7]. Dopamine and serotonin are produced in the central nervous system (CNS) and in the gastrointestinal tract, where they play a role in several local and systemic processes [8,9]. Moreover, dopamine and serotonin are increasingly recognized to be also involved in tumor behavior by affecting angiogenesis and tumor cell proliferation [10-12]. This review therefore aims to summarize the available knowledge on the role of dopamine and serotonin as regulators of tumor behavior with a focus on angiogenesis. METHODS Articles for this review were identified by searches of PubMed and Web of Knowledge using the search terms “dopamine”, “serotonin”, “5-hydroxytryptamine”, “dopamine receptor”, “serotonin receptor”, “platelets”, “angiogenesis”, “neovascularization”, “neoplasm”, and “cancer”. Relevant references of found articles were also included. We selected English publications of all years. International Clinical Trials Registry Platform (ICTRP) accepted trial registries were searched for ongoing clinical trials. RESULTS Dopamine Dopamine is synthesized in the CNS and the gastrointestinal tract [13-15]. It is - 20 - - 21 - 548127-L-bw-Peters Processed on: 17-9-2020 PDF page: 20 ABSTRACT INTRODUCTION The biogenic amines dopamine and serotonin are neurotransmitters and hormones, Increasingly, it is recognized that apart from tumor cells also the non-tumor cells in which are mainly produced in the central nervous system and in the gastro-intestinal the microenvironment participate in tumor behavior [1,2]. Endothelial cells are part of tract. They execute local and systemic functions such as intestinal motility and tissue this microenvironment and can create new blood vessels, which provide oxygen and repair. Dopamine and serotonin are primarily stored in and transported by platelets. nutrients to the tumor, and hence promote tumor growth and metastasis [3]. Besides 2 This review focuses on the recently recognized role of dopamine and serotonin in the cells from the microenvironment, also distant host cells are attracted to the tumor and regulation of tumor behavior by affecting angiogenesis and tumor cell proliferation. contribute to tumor development. The interaction between tumor microenvironment Preclinical studies demonstrate that dopamine inhibits tumor growth via activation of and distant host cells shows similarities with the process of wound healing, in which dopamine receptor D2 on endothelial and tumor cells. Serotonin stimulates tumor immune cells and platelets are attracted to the affected tissue and participate in repair. growth via activation of serotonin receptor 2B on endothelial cells and serotonin In tumor development, attracted host cells can have a detrimental effect; they can receptors on tumor cells. Drugs that stimulate dopamine receptor D2 or inhibit contribute to tumor growth, invasiveness and metastasis [4]. Alike during wound serotonin receptors are available and therefore clinical intervention studies for cancer healing, platelets are recruited to the tumor site and adhere to the activated vascular patients are within reach. wall [5]. This leads to release of their content consisting of pro- and anti-angiogenic factors such as vascular endothelial growth factor A (VEGF-A) [6] and dopamine and serotonin [7]. Dopamine and serotonin are produced in the central nervous system (CNS) and in the gastrointestinal tract, where they play a role in several local and systemic processes [8,9]. Moreover, dopamine and serotonin are increasingly recognized to be also involved in tumor behavior by affecting angiogenesis and tumor cell proliferation [10-12]. This review therefore aims to summarize the available knowledge on the role of dopamine and serotonin as regulators of tumor behavior with a focus on angiogenesis. METHODS Articles for this review were identified by searches of PubMed and Web of Knowledge using the search terms “dopamine”, “serotonin”, “5-hydroxytryptamine”, “dopamine receptor”, “serotonin receptor”, “platelets”, “angiogenesis”, “neovascularization”, “neoplasm”, and “cancer”. Relevant references of found articles were also included. We selected English publications of all years. International Clinical Trials Registry Platform (ICTRP) accepted trial registries were searched for ongoing clinical trials. RESULTS Dopamine Dopamine is synthesized in the CNS and the gastrointestinal tract [13-15]. It is - 20 - - 21 - 548127-L-bw-Peters Processed on: 17-9-2020 PDF page: 21 produced in the cytoplasm from the amino-acid tyrosine by tyrosine hydroxylase [14]. Serotonin is metabolized in cells of the brain, gastrointestinal tract, liver, lungs and In the blood, ~99% of dopamine is stored in platelets [7], in plasma ~1% circulates in platelets by monoamine oxidase (MAO), and thereafter excreted by the kidney as 5- its free form and the remainder as inactive dopamine sulfate [16]. hydroxyindoleacetic acid (5-HIAA) [9]. In the CNS, dopamine is involved in reward mechanisms and limb movement control. In addition, after being transported by sympathetic nerves and platelets it also Platelets 2 has peripheral effects throughout the body like regulation of vascular tone [8]. Apart Platelets store dopamine and serotonin in dense granules and are their main circulating from exhibiting its