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The Role of Dopamine in Gastric Cancer

ginfreely

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Abstract​

Background: In the last few decades, it has been emphasized that dopamine, a well-known neurotransmitter with multiple roles in central nervous system, is also implicated in the activity of peripheral tissues and organs, more specifically influencing the gastrointestinal system (GI). Methods: We registered a protocol under the CRD42024547935 identifier in the Prospero register of systematic reviews. Furthermore, using the Population, Intervention, Comparison, Outcome, and Study Design strategy to guide our study rationale, and under the Preferred Reporting Items for Systematic reviews and Meta-Analyses recommendations, we conducted a qualitative systematic literature search based on the PubMed, Scopus, and Web of Science databases using the “gastric cancers AND dopamine” search criteria. We obtained 68 articles from PubMed, 142 articles from Scopus, and 99 articles from the Web of Science database. Results: Within gastric cancer biology, dopamine has notable effects on STAT-3 and DARPP-32. STAT-3, a transcription factor involved in cellular proliferation and invasion, plays a significant role in cancer progression. Conclusions: Understanding the roles of dopamine in cancer, beyond aspects such as cancer cell invasion, immune response modulation, or tumor growth, could guide the development of new cancer therapies by modulating its pathways, especially the DARPP-32/CXCR4/CXCL-12 complex axis, in order to improve the morbidity and mortality caused by this type of cancer.
Keywords:
dopamine; gastric cancer; STAT-3; DARPP-32
 

1. Introduction​

Dopamine (3-hydroxytyramine) is a member of the catecholamine family, being secreted by neurons that have a classic known origin in the substantia nigra. It is an essential neurotransmitter because it plays an important role in many physiological phenomena, including motor control, motivation, emotions, and cognitive functions [1,2]. Until recently, it was significantly associated with central nervous system (CNS) activity, while in the last few decades, it has been emphasized that dopamine presents other functions in influencing the activities of peripheral organs and tissues, including the gastrointestinal (GI) system, and is considered to be implied in the absorption and decarboxylation of cellular processes [3]. Regarding its roles in pathology, dopamine is linked to diverse degenerative diseases and disorders and also to tumorigenesis, as noted in the case of gastric cancer [4].
Gastric cancer currently represents one of the most common malignancies, with significant morbidity and mortality. This fact strongly demonstrates the need to identify the factors that influence its progression, especially biochemical regulators such as dopamine, which is crucial for the research and development of new therapeutic strategies, in order to minimize patient disability [5].
Regarding GI activity, the production of dopamine is realized by non-neuronal cells such as immune cells and gastric mucosal cells [6,7]. It is responsible for gastric acid secretion regulation and also for the functions of stomach lining integrity [6]. Additionally, it presents anti-inflammatory properties, balancing the immune response in the digestive system [6,8]. Dopamine inhibits the release of pro-inflammatory cytokines like interleukin-2 and interleukin-1B, which are often linked to gastric diseases, including gastric cancer [4].
Dopamine has additional function in influencing the blood flow in the GI tract, ensuring adequate oxygen and nutrient uptake of the stomach. This emphasizes its importance in maintaining the integrity and function of the stomach, while any disturbances in this system regulation might be responsible for the development of gastric diseases, including gastric cancer [6,9,10].

Dopamine’s action is based on its binding to dopamine receptors and triggering intracellular signaling chains. The expression of dopaminergic receptors (DRs) is widely distributed in different organs, such as the brain, retina, heart, coronary arteries, sympathetic ganglia, and GI tract. The DRs are members of the seven transmembrane G protein-coupled receptor families, which are classified into D1-like receptors and D2-like receptors. The first type, D1-like receptors, includes D1 and D5 receptors, which are involved in the activation of adenylyl cyclase activity, while the second type, D2-like receptors, represented by D2, D3, and D4 receptors, has antagonistic effects on D1-like receptors [11,12]. Moreover, through D2-like receptors, dopamine induces Vascular Endothelial Growth Factor (VEGF) inhibition, which is associated with poor prognoses in angiogenesis processes [13,14]. D2 has been found to inhibit insulin growth factor 1 (IGF-I)-induced gastric cancer cell growth. For D2-like receptors, polymorphisms within the receptor gene have been shown to be associated with colorectal cancer risk, and the expression of D2-like receptor is also inversely correlated with the prognosis of patients with gastric cancer [14,15]. In a study that evaluated 84 pairs of tumor and adjacent non-tumor tissues, immunochemical analysis was used to detect the expression levels of D2-like receptor in the tissues, and D2-like receptor was expressed at a higher level in tumors compared with adjacent matched non-tumor tissues [14]. Patients with higher expression levels of D2 DR had lower survival durations. The expression of D2-like DR was negatively associated with the survival durations of patients with gastric cancer [14].
Tumoral angiogenesis is an essential step in solid tumor growth and progression. In this direction, in the literature, it is stipulated that VEGF-mediated angiogenesis is strongly and specifically inhibited by dopamine. In some types of cancers, dopamine has been shown to inhibit angiogenesis [13]. By limiting angiogenesis, dopamine can decelerate tumor growth; the discovery of the exact mechanisms could be an important step forward in treating gastric cancer.
Dopamine is also involved in the immune system’s response with regard to the tumors’ activity. Altering the activity of the T cells immune and macrophages, it might be responsible for immune system suppression that due to the recognition and action of targeted tumoral cells [15,16]. On the one hand, dopamine inhibits cancer growth; on the other hand, it could increase the tumor activity, which could complicate the impact of cancer progression.
With regard to gastric cancer, dopamine is also a major factor involved in inflammation regulation, influencing chronic inflammation and inducing oxidative stress, DNA mutations, and anti-inflammatory effects while reducing the production of tumor necrosis factor α and interleukin 6 (IL-6) [17].
The aim of this systematic review is to assess the most recent data regarding the link between dopamine activity and gastric cancer in human patients.
 

5. Conclusions​

In summary, dopamine’s influence reaches beyond its well-known role in the brain, affecting peripheral systems like the GI tract and exhibiting important activity in gastric cancer progression. Through complex interactions with molecules such as DARPP-32, STAT-3, CXCR4, and CXCL-12, dopamine contributes to cancer cell invasion, immune response modulation, and tumor growth by stabilizing key proteins involved in angiogenesis and metastasis. These findings highlight dopamine’s potential as a therapeutic target, including DRD5 expression, suggesting that treatments aimed at modulating dopamine’s pathways could offer promising strategies for gastric cancer management. With a deeper understanding of these mechanisms, the DARPP-32/CXCR4/CXCL-12 complex axis should be considered a type of targeted therapy to inhibit tumor progression and improve outcomes in patients with gastric cancer.
 
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