Melatonin and its receptors in the normal human gastrointestinal tract, pancreas and in small intestinal neuroendocrine tumours

Sammanfattning: Melatonin, “the hormone of darkness” is well known to regulate sleep and circadian rhythm. However, melatonin is also present in numerous peripheral tissues and the number of actions assigned to this neurohormone is growing steadily. Based on animal studies, it has been proposed that gastrointestinal melatonin is produced in enterochromaffin cells.The aims were to characterise the expression of melatonin and its receptors MT1 and MT2 in normal human gastrointestinal tract and pancreas as well as in tumours derived from enterochromaffin cells, small intestinal neuroendocrine tumours (SI-NET), using immunohistochemistry. Melatonin and receptor expression was furthermore compared to clinical symptoms, tumour prognostic factors and treatment response.In enterochromaffin cells from normal gastrointestinal tissue and in SI-NETs a strong immunoreactivity (IR) for melatonin and MT2 was found, while MT1 IR was low or absent. Melatonin, MT1 and MT2 IR was also seen in the large intestinal epithelium of normal gastrointestinal tract and in pancreatic islets, although the expression of MT1 in pancreatic tissue varied. Analyses of mRNA data confirmed the expression of the enzymes needed for melatonin synthesis as well as MT1 and MT2 in small intestine and pancreas.The intensity of melatonin IR in SI-NETs correlated to lower proliferation index and less symptoms of diarrhoea, which is well in line with the proposed actions of melatonin described in nimal studies. The intensity of MT2 IR was generally lower in metastases than in primary tumours. Plasma levels of melatonin in patients with SI-NETs and disease stabilisation/remission were reduced after treatment and higher levels were associated with nausea.In conclusion, melatonin and its receptors are present in the normal human gastrointestinal tract, pancreas and in SI-NETs. Melatonin IR intensity in tumours correlated significantly to less diarrhoea and to lower proliferation index. Plasma levels of melatonin in patients with SI-NETs were reduced with treatment response, indicating a possible tumour-derived origin of circulating melatonin levels.These results are in agreement with the suggested actions of melatonin on gastrointestinal motility and tumour growth.