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Melatonin Immunoreactivity in Malignant Small Intestinal Neuroendocrine Tumours
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.ORCID iD: 0000-0001-9881-769X
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164354Article in journal (Refereed) Published
Abstract [en]

Background/ Aims Small intestinal neuroendocrine tumours (SI-NETs) are derived from enterochromaffin cells. After demonstrating melatonin in enterochromaffin cells, we hypothesized that SI-NETs may express and secrete melatonin, which may have an impact on clinical factors and treatment response. Methods Tumour tissue from 26 patients with SI-NETs, representing paired sections of primary tumour and metastasis, were immunohistochemically stained for melatonin and its receptors, MT1 and MT2. Plasma melatonin and immunoreactivity (IR) for melatonin, MT1 and MT2 in tumour cells were compared to other tumour markers and clinical parameters. Melatonin was measured at two time points in fasting morning plasma from 43 patients with SI-NETs. Results Melatonin IR was found in all SI-NETS. Melatonin IR intensity in primary tumours correlated inversely to proliferation index (p = 0.022) and patients reported less diarrhoea when melatonin IR was high (p = 0.012). MT1 IR was low or absent in tumours. MT2 expression was medium to high in primary tumours and generally reduced in metastases (p = 0.007). Plasma-melatonin ranged from 4.5 to 220.0 pg/L. Higher levels were associated with nausea at both time points (p = 0.027 and p = 0.006) and flush at the second sampling. In cases with disease stabilization or remission (n = 34), circulating melatonin levels were reduced in the second sample (p = 0.038). Conclusion Immunoreactive melatonin is present in SI-NETs. Circulating levels of melatonin in patients with SI-NETs are reduced after treatment. Our results are congruent with recent understanding of melatonin's endocrine and paracrine functions and SI-NETs may provide a model for further studies of melatonin function.

Place, publisher, year, edition, pages
2016. Vol. 11, no 10, article id e0164354
National Category
Cancer and Oncology Neurology
Identifiers
URN: urn:nbn:se:uu:diva-310013DOI: 10.1371/journal.pone.0164354ISI: 000385505800057PubMedID: 27736994OAI: oai:DiVA.org:uu-310013DiVA, id: diva2:1055344
Funder
Swedish Society of MedicineSwedish Cancer SocietyAvailable from: 2016-12-12 Created: 2016-12-09 Last updated: 2019-11-18Bibliographically approved
In thesis
1. Melatonin and its receptors in the normal human gastrointestinal tract, pancreas and in small intestinal neuroendocrine tumours
Open this publication in new window or tab >>Melatonin and its receptors in the normal human gastrointestinal tract, pancreas and in small intestinal neuroendocrine tumours
2017 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Uppsala University, 2017. p. 31
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-319920 (URN)
Presentation
2017-04-25, Lilla konferensrummet, Blå korset, Akademiska sjukhuset, 75185, Uppsala, 09:15 (Swedish)
Supervisors
Available from: 2017-04-11 Created: 2017-04-11 Last updated: 2017-04-27Bibliographically approved
2. Melatonin in the gastrointestinal tract
Open this publication in new window or tab >>Melatonin in the gastrointestinal tract
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Melatonin is recognised as the pineal hormone regulating sleep and circadian rhythm. It has also been identified in peripheral tissues (mainly in animals) and thought to display a variety of actions, including anti-inflammatory properties, regulation of gastrointestinal (GI) functions, glucose homeostasis and beneficial effects in different tumour types. Patients with irritable bowel disorder commonly exhibit psychiatric co-morbidity and disturbances of the gut-brain axis have been proposed to play a role in these disorders. The focus of this thesis was to study melatonin and melatonin receptors in the normal human GI tract, the pancreas and small intestinal neuroendocrine tumours. The thesis also explores the complex relationship between GI symptoms and underlying psychiatric traits in the context of elevated levels of peripheral melatonin during waking hours.

In paper I-II, tissue samples from the normal human GI tract and pancreas and tumour tissue from small intestinal neuroendocrine tumours were analysed for expression of melatonin and melatonin receptors using immunohistochemistry. For tumour patients, melatonin was also analysed in plasma and set in relation to symptoms and outcome. In paper III-IV, a cohort of young adults (18-25 years) seeking psychiatric care was examined for GI symptoms, melatonin levels in saliva, depressive symptoms and anxiety traits. Psychiatric assessments were performed using structured or semi structured interviews. Depressive symptoms were measured using the self-rating version of the Montgomery-Åsberg Depression Rating Scale; GI symptoms were measured using the Gastrointestinal Symptoms Rating Scale for Irritable Bowel Syndrome; and personality traits were evaluated using the Swedish Universities Scales of Personality.

Melatonin and melatonin receptors were widely expressed in the normal human gut and pancreas (paper I) but even in small intestinal neuroendocrine tumours known to produce serotonin (paper II). The intensity of the melatonin immunoreactivity in tumour tissue was found to correlate with lower proliferation index. After treatment, plasma levels of melatonin were reduced in tumour patients. Young adult patients seeking psychiatric care reported more GI symptoms than healthy controls, regardless of the currently active psychotropic medication. The level of GI symptoms was associated with severity of depressive symptoms and trait anxiety (paper III). Higher postprandial levels of melatonin were associated with the GI symptoms of bloating and pain (paper IV).

In summary, these findings demonstrate the widespread presence of melatonin in the human gut and confirm a link between melatonin, psychiatric health and GI symptoms.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 63
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1616
Keywords
melatonin, MT1, MT2, gastointestinal tract, small intestinal neuroendocrine tumours, IBS, depression, anxiety, personality and affective disorder
National Category
Psychiatry Endocrinology and Diabetes Gastroenterology and Hepatology Cancer and Oncology
Research subject
Medical Science; Psychiatry
Identifiers
urn:nbn:se:uu:diva-396347 (URN)978-91-513-0814-2 (ISBN)
Public defence
2020-01-17, Humanistiska teatern, Thunbergsvägen 3, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2019-12-18 Created: 2019-11-18 Last updated: 2020-01-13

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Söderquist, FannyTiensuu Janson, EvaRasmusson, AnnicaAlit, AbirStridsberg, MatsCunningham, Janet L.

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