Melatonin levels can be used as an indicator of tumor malignity

Brazilian researchers show that in some cancers, the higher the level of melatonin production by tumor cells, the less aggressive the disease is and the longer the patient should survive.

By Karina Toledo  |  Agência FAPESP – Evaluating the capacity of tumor cells to produce the hormone melatonin could become a novel strategy for measuring degrees of malignity in some types of cancer, such as tumors of the central nervous system, lungs, intestines, pancreas and bladder. 

In research conducted at the University of São Paulo’s Bioscience Institute (IB-USP) in Brazil, a group led by Professor Regina Pekelmann Markus has shown that in these cases, the expression level of the genes that encode melatonin-synthesizing and melatonin-degrading enzymes is a predictor of aggression, as less aggressive tumors tend to produce more melatonin. 

The group showed that increased local production of melatonin correlated with longer patient survival. “We’re working with Valtencir Zucolotto, a professor at USP’s São Carlos Physics Institute, to develop a kit that will measure melatonin levels in tumor tissue biopsy samples. This technology will aid prognosis and pave the way for new therapeutic approaches,” Markus told Agência FAPESP.

Markus has been researching melatonin since the 1990s. In experiments with rodents, she showed that the hormone that signals to the organism that it is dark and hence time to rest could be produced not only in the pineal gland but also elsewhere in the body. 

She also demonstrated the importance of the peripheral production of melatonin to the regulation of inflammatory processes in different physiological and physiopathological contexts.

“We showed initially in rodents that when there is an inflammatory stimulus in peripheral tissue and the immune system needs to establish a defensive response, as in the case of a bacterial infection, for example, melatonin synthesis is blocked by the pineal gland,” Markus said. “Because this hormone prevents the migration of defense cells from the bloodstream, its reduction is essential for immune cells to reach the site of the infection.” Markus addressed the topic in a presentation to the conference on “Next Frontiers to Cure Cancer” hosted in May 2018 by A. C. Camargo Cancer Center in São Paulo. 

Once the threat has been mitigated, defense cells themselves begin secreting melatonin in the affected tissue to prevent unnecessary damage. The organism should then return to normal, meaning that the peripheral production of melatonin should cease so that production by the central nervous system can resume.

The IB-USP group called this two-way communication between the pineal gland and the immune system the “immune-pineal axis”. Additional research showed that the transition between pineal and extrapineal melatonin synthesis is regulated by NF-κB (nuclear factor kappa B), a protein complex that is a well-studied mediator of inflammation. 

A review of the main findings on the subject in more than 20 years of research was published in 2017 in the British Journal of Pharmacology. In addition to Markus, other authors included IB-USP researchers Pedro Augusto Carlos Magno Fernandes and Gabriela Sarti Kinker.

Peripheral production and cancer

According to Markus, there are cases in which, for some reason, the organism is unable to return to its normal physiological state: the peripheral production of melatonin is maintained or production by the pineal gland does not resume, and the organism is more vulnerable to disease even though it appears to be well. “This was the rationale for our decision to investigate the relationship between melatonin and cancer,” she said.

The research began with the observation of samples of gliomas, the most common primary brain tumors in adults, obtained from patients involved in a study led by Sueli Mieko Oba Shinjo, a researcher at USP’s Medical School.

“We decided to analyze the expression in tumor cells of ASMT and AANAT, the key enzymes for melatonin synthesis,” Markus said. “We were struck by the very low level of ASMT expression. However, the number of samples was small, and we decided to investigate the same thing using established glioma cell lines.”

The group then noticed that while there was practically no local secretion of melatonin in more aggressive gliomas (grade 4), less malign gliomas (grades 1 and 2) expressed higher levels of melatonin synthesis enzymes.

The next step was to analyze tumor data from The Cancer Genome Atlas (TCGA) in the United States. In addition to data on gene expression in tumor tissue, the repository also offers access to clinical data, so the researchers were able to analyze correlations between their findings on melatonin expression and patient clinical outcomes.

“We investigated melatonin synthesis in practically all tumor types in the database. To this end, we created an index based on expression of the gene ASMT and also of the gene CYP1B1, which encodes the main enzyme responsible for melatonin degradation [high expression of this gene means rapid melatonin metabolism and low levels of the hormone in cells],” Markus said.

The study showed that the higher the index – i.e., the higher the predicted level of local melatonin production – the less aggressive was the glioma, and the longer the patient could be expected to survive. Similar results were obtained for other solid tumor types (lung, pancreas, colorectal and bladder) but not for nonsolid tumors such as leukemia and lymphoma.

Findings from the study using glioma data were published in 2016 in the Journal of Pineal Research and are part of the PhD thesis being prepared by Kinker, who continues to research the melatonergic system in gliomas at the Weizmann Institute of Science in Israel.

“Since then, we’ve focused on the mechanisms by which melatonin acts in cancer cells, and we’re now in the process of patenting prognostic methods and melatonergic agents for the treatment of some solid tumors,” Markus said.

Melatonin itself cannot be used in treatment because it might not combat tumors in some patients owing to its multiple action mechanisms.

“It’s fundamental to know the system’s possible variables before intervening, as they differ from patient to patient,” Markus said. “We believe the ideal approach would be individual therapy preceded by a lab test to show the treatment won’t be harmful. For this reason, we’re working on the development of a kit that will measure melatonin production in tumor tissue. We expect the test to be highly affordable, with a cost similar to that used to measure blood sugar.”

The researchers stressed, however, that before the prognostic technology can be brought to market, it must be validated in biopsy samples of the various types of solid tumors studied. This process is likely to take approximately three years.

“We also need to establish the best procedure for this analysis and a way to adapt the methodology for commercial use,” Markus said. “This is the time to think about converting knowledge into products. We have much to learn from Israel’s Weizmann Institute about this process.”