Introduction
Serotonin is a neurotransmitter well known for its positive effects on mood. In depressed people, the concentration of serotonin in the brain can decrease. The hormone also affects many other functions throughout the body. Most serotonin is not found in the brain, but is stored in platelets. Serotonin reuptake inhibitors (SSRIs), used to treat depression, increase serotonin levels in the brain but reduce peripheral serotonin in platelets. The involvement of serotonin in carcinogenesis was already known. By becoming part of the temporary or lasting mediators of inflammation, it can act as a “promoter” of cellular transformation, thanks to its ability to support chronic inflammation.
Until now, however, the underlying mechanisms had remained unclear. It is more direct to think that serotonin can stimulate tumor growth, since various types of cancer cells express receptors for this mediator. These include ovarian, kidney, lung, colon and pancreatic cancer cells.In addition, for some cancers, such as ovarian cancer, the effect on its growth caused by estrogen is thought to be partly due to the local actions of serotonin . For others, such as the breasts and uterus, it is suspected that high blood concentrations of serotonin may favor them over time. Below we will deal with some types of cancer for which there is evidence that serotonin intervenes directly or indirectly at the onset.
Prostate Cancer
Prostate cancer (CAP) is the most common cancer in males, and hormone-refractory metastatic prostate cancer is the end-stage of this progressive malignancy. Neuroendocrine cells (CENE) are types of epithelial cells in the normal prostate gland and in the basal and exocrine secretory cells. NE cells are also present in most prostate cancers, including metastatic CAP. These cells produce and secrete serotonin, along with other peptide hormones. It has been proposed that NE cells could facilitate tumor recurrence by aiding the proliferation of neighboring cells in the CAP.
Serotonin has been detected in benign prostate tissue, CAP and metastases. Its action is mediated by different subtypes of receptors in different tumor stages. Strong expression of 5-HT1A and 5-HT1B receptors was observed in aggressive forms. 5-HT4 receptors were found predominantly in high-grade tumors. On the other hand, 5-HT2B receptor expression has been associated with pathologically altered prostate tissue, suggesting that this is involved in the early stages of tumorigenesis.
Breast cancer
Serotonin promotes the growth of breast cancer cells partly through the 5-HT2A receptors. This was observed in the human breast adenocarcinoma cell line MCF-7, where serotonin and the selective 5-HT2A receptor agonist stimulated cell growth in a concentration-dependent manner. It has also been shown that the expression of the tryptophan hydroxylase (TPH1) enzyme is increased during tumor progression, which corresponds to an increase in serotonin synthesis. In a tissue microarray in 102 breast cancer patients to study the expression of various receptors, an elevated expression of 5-HT1A was observed in the plasma membrane of malignant cells, but also in the cytoplasm of non-malignant cells.
The expression of 5-HT1B and 2B was variable and was observed in the cytoplasm of both malignant and non-malignant cells. A substantial correlation was also identified between 5-HT2B and estradiol and between 5-HT4 and estrogen and progesterone receptors. A recent study investigated changes in mRNA expression of 5-HT2A and 5-HT3A receptors in breast tumor tissue relative to their marginal zone. The expression of the aforementioned receptor genes was intense within the breast tumor compared to the marginal tissue, indicating that the mitogenic nature of the 5HT receptors leads to increased tumor cell proliferation.
Lung microcytoma
Microcytoma (SCLC) is a very aggressive lung cancer with early metastases and is associated with tobacco use. SCLC has been shown to exhibit neuro-endocrine differentiation properties. Nicotine stimulates the proliferation of SCLC cells and also stimulates the release of serotonin from them. The involvement of serotonin in SCLC proliferation was observed in an in vitro study, in which the addition of serotonin to SCLC cell lines induced cell proliferation in a dose-dependent manner; a 5-HT1 receptor antagonist blocked this effect. These data suggest that a serotonergic pathway may be involved in the proliferation of SCLC. Subsequent work showed the involvement of 5-HT1D and 5-HT1A receptor subtypes in the mitogenic effect of serotonin. In the 1990s, the possibility of using serotonin antagonists for the treatment of this cancer was evaluated, but the poor knowledge of the 5-HT receptors at the time (compared to today), closed the matter shortly after.
Tumors of the biliary tract
Real-time PCR analysis showed increased TPH1 expression and reduced monoamine oxidase A (MAO-A) expression in human cholangiocarcinoma cell lines compared to non-malignant cell lines. This was also confirmed by immunohistochemical analysis of human liver biopsies of cholangiocarcinoma. Therefore, increased serotonin synthesis from cholangiocarcinoma was observed in vitro and in vivo. Human cell lines of this cancer were also found to express all 5-HT receptor subtypes. Specific inhibition of 5-HT1A, 2A, 2B, 4 and 6 receptors was associated with antiproliferative effects. Furthermore, inhibition of serotonin synthesis blocked the growth of malignant cell lines. In this regard, a TPH inhibitor currently approved by the FDA for carcinoid syndrome diarrhea, telotristat ethyl, is being studied in an ongoing phase II study in combination with first-line chemotherapy in patients with advanced cholangiocarcinoma.
Brain cancer
SSRI drugs such as fluoxetine can have a contrasting effect on the growth of the cells of grade IV astrocytoma, or glioblastoma, the more aggressive form of brain tumor. Aside from interfering with serotonin reuptake, however, fluoxetine also appears to interact with AMPA glutamate receptors and kill brain cancer cells through lethal streams of calcium ions. A similar action has a second SSRI, paroxetine. Another very common SSRI, escitalopram, interferes with the engraftment of a glioblastoma fragment in mice in the laboratory.
The intervention of the immune system
In addition to the aforementioned functions of serotonin, more recently, there is growing evidence that serotonin interacts with the peripheral immune system, particularly with T lymphocytes. Although the exact signaling mechanism of serotonin in the immune system is unclear, the studies suggest that 5-HT has an immunostimulating effect and that 5-HT1A receptor antagonists reduced T cell proliferation and cytokine production in vitro. It has also been observed that fluoxetine may exhibit an immunosuppressive role in T lymphocytes. Recently, researchers from the University of Zurich and the University Hospital of Zurich demonstrated that SSRIs or other drugs that lower peripheral serotonin levels can also slow the growth of cancer in mice.
Although new and effective treatments – such as targeted antibodies or immunotherapies – have been available for several years, most patients with advanced abdominal cancers such as colon or pancreatic cancer die within a few years of diagnosis. One problem is that cancer cells become resistant to drugs over time and are no longer recognized by the immune system. Now, the research team has discovered the role of serotonin in this resistance mechanism of cancer cells. Cancer cells use serotonin to increase the production of an immune-inhibiting molecule known as PD-L1. This molecule binds to killer T cells, a specific type of immune cell that recognizes and kills cancer cells and makes them dysfunctional. Cancer cells thus avoid being destroyed by the immune system.
PD-L1, through which serotonin exerts its effect, is also the target of modern immunotherapies, also called immune checkpoint inhibitors. In the experiments with mice, the researchers were able to show that SSRIs or peripheral inhibitors of serotonin synthesis prevent this mechanism. At a later stage, the researchers tested a dual therapeutic approach in mice: they combined immunotherapy with drugs that lower peripheral serotonin. The results were impressive: cancer growth was suppressed in long-term animal models, and in some mice the tumors disappeared completely. The results were favorable for colon cancer, but especially for pancreatic cancer. Although these two cancers are aggressive, pancreatic cancer still has a mortality rate of nearly 95% at 5 years, while colon cancer is certainly more likely to cure and resolve.
- Edited by Dott. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistr.
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Dott. Gianfrancesco Cormaci
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