Serotonin Pathway in Cancer

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine produced from the essential amino acid tryptophan. Serotonin’s role as a neurotransmitter in the central nervous system and a motility mediator in the gastrointestinal tract has been well defined, and its function in tumorigenesis in various cancers (gliomas, carcinoids, and carcinomas) is being studied. Many studies have shown a potential stimulatory effect of serotonin on cancer cell proliferation, invasion, dissemination, and tumor angiogenesis. Although the underlying mechanism is complex, it is proposed that serotonin levels in the tumor and its interaction with specific receptor subtypes are associated with disease progression. This review article describes serotonin’s role in cancer pathogenesis and the utility of the serotonin pathway as a potential therapeutic target in cancer treatment. Octreotide, an inhibitor of serotonin release, is used in well-differentiated neuroendocrine cancers, and the tryptophan hydroxylase (TPH) inhibitor, telotristat, is currently being investigated in clinical trials to treat patients with metastatic neuroendocrine tumors and advanced cholangiocarcinoma. Several in vitro studies have shown the anticancer effect of 5-HT receptor antagonists in various cancers such as prostate cancer, breast cancer, urinary bladder, colorectal cancer, carcinoid, and small-cell lung cancer. More in vivo studies are needed to assess serotonin’s role in cancer and its potential use as an anticancer therapeutic target. Serotonin is also being evaluated for its immunoregulatory properties, and studies have shown its potential anti-inflammatory effect. Therefore, it would be of interest to explore the combination of serotonin antagonists with immunotherapy in the future.

Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells

“…A highly significant observation is that a subset of cells showed higher levels of Glutamate, GABA, or 5-HT ( Figure 6 ). GABA, Glu, and 5-HT have been well characterized as neurotransmitters as well as neurotrophic factors that activate intracellular signaling pathway via the stimulation of specific sets of cell surface receptors [ 23 , 24 , 25 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ]. Evidence is emerging that they can elicit diverse non-neuronal response by stimulating their receptors in non-neuronal tissues and recent studies have shown that the extra-neuronal synthesis and release of neurotransmitters cells into the TME by the cancer cells promote tumorigenesis and tumor progression in many cancers [ 23 ].…”

“…Evidence is emerging that they can elicit diverse non-neuronal response by stimulating their receptors in non-neuronal tissues and recent studies have shown that the extra-neuronal synthesis and release of neurotransmitters cells into the TME by the cancer cells promote tumorigenesis and tumor progression in many cancers [ 23 ]. While these transmitters have been shown to stimulate cell proliferation in different cancers [ 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ], identification of them as potential oncometabolites or their role as mediators of autocrine signaling in ovarian cancer is hitherto unreported. Our results, presented here indicate that the antagonists of these metabolism-derived ligands can effectively disrupt the autocrine signaling loop and inhibit ovarian cancer cell proliferation ( Figure 7 , Figure 8 , Figure 9 , Figure 10 and Figure 11 ).…”

Shedding Light on the Role of Neurotransmitters in the Microenvironment of Pancreatic Cancer

“…5-HT is a neuromodulator with neurotransmitter and neuroendocrine functions in cancer (Balakrishna et al, 2021). Meanwhile, it also regulates a variety of immune processes, such as immune cell chemotaxis, activation, proliferation, and cytokine secretion (Herr et al, 2017).…”

Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis

“…The importance of the serotonin pathway in the context of enhancing oncogenesis has also increased significantly in recent years. The available data indicate an increased growth of cancer cells under the influence of serotonin in prostate cancer, breast cancer, small-cell lung cancer, colorectal cancer, cholangiocarcinoma, hepatocellular carcinoma, and glioma [232]. Moreover, the activity of this monoamine has been associated with an intensified epithelial-mesenchymal transformation process, increased cell migration abilities, and thus an increase in metastatic potential [233].…”