Serotonin is a neurotransmitter that is well known because of its positive effects on mood. In depressed people, the concentration of serotonin in the brain is reduced. The hormone also influences many other functions throughout the body. The majority of the serotonin is not located in the brain, but is stored in the blood platelets. Serotonin reuptake inhibitors (SSRIs), which are used to treat depression, increase serotonin levels in the brain but decrease peripheral serotonin in platelets. The involvement of serotonin in carcinogenesis was already known. Until now, however, the underlying mechanisms had remained obscure. It is more direct to think that serotonin can stimulate tumor growth, given that various types of cancer cells express receptors for this mediator, such as those in ovarian, renal, lung, colon and pancreatic cancer. Indeed, for certain cancers, such as ovarian cancer, it is thought that the effect on its growth caused by estrogen is partly due to the local actions of serotonin. For others, such as the breast and uterine, there are suspicions that high blood concentrations of serotonin may favor them over time.

Now, researchers at the University of Zurich (UZH) and University Hospital Zurich (USZ) have shown that SSRIs or other drugs that lower peripheral serotonin levels can also slow cancer growth in mice.  Although new, effective treatments — such as targeted antibodies or immunotherapies — have been available for several years, most patients with advanced-stage abdominal tumors such as colon or pancreatic cancer die within a few years of diagnosis. One problem is that the tumor cells become resistant to the drugs over time and are no longer recognized by the immune system. Now, the research group has discovered the role serotonin plays in this tumor cell resistance mechanism. Cancer cells use serotonin to boost the production of a molecule that is immuno-inhibitory, known as PD-L1. This molecule binds to killer T cells, a specific type of immune cell that recognizes and eliminates tumor cells, and renders them dysfunctional. The cancer cells thus avoid being destroyed by the immune system. PD-L1, via which serotonin exerts its effect, is also the target of modern immunotherapies, also called immune checkpoint inhibitors

In experiments with mice, the researchers were able to show that SSRIs or peripheral serotonin synthesis inhibitors prevent this mechanism. In a next step, the researchers tested a dual treatment approach in mice: They combined immunotherapy, which increases the activity of killer T cells, with drugs that reduce peripheral serotonin. The results were impressive: cancer growth was suppressed in the animal models in the long term, and in some mice the tumors disappeared completely. The results were favorable for colon cancer, but especially for pancreatic cancer, Although these two types of cancer are aggressive, that of the colon is definitely more likely to cure, while that of the pancreas still has a mortality of almost 95% at 5 years. Professor Pierre-Alain Clavien, senior author of the research concluded: “This class of antidepressants and other serotonin blockers cause immune cells to recognize and efficiently eliminate tumor cells again. This slowed the growth of colon and pancreatic cancers in the mice. Our results provide hope for cancer patients, as the drugs used are already approved for clinical use. Testing such drug combinations on cancer patients in clinical trials can be fast-forwarded due to the known safety and efficacy of the drugs”.

• Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

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