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      Melatonin Immunoreactivity in Malignant Small Intestinal Neuroendocrine Tumours

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          Abstract

          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, MT 1 and MT 2. Plasma melatonin and immunoreactivity (IR) for melatonin, MT 1 and MT 2 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). MT 1 IR was low or absent in tumours. MT 2 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.

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          Most cited references32

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          The cutaneous serotoninergic/melatoninergic system: securing a place under the sun.

          It was recently discovered that mammalian skin can produce serotonin and transform it into melatonin. Pathways for the biosynthesis and biodegradation of serotonin and melatonin have been characterized in human and rodent skin and in their major cellular populations. Moreover, receptors for serotonin and melatonin receptors are expressed in keratinocytes, melanocytes, and fibroblasts and these mediate phenotypic actions on cellular proliferation and differentiation. Melatonin exerts receptor-independent effects, including activation of pathways protective of oxidative stress and the modification of cellular metabolism. While serotonin is known to have several roles in skin-e.g., pro-edema, vasodilatory, proinflammatory, and pruritogenic-melatonin has been experimentally implicated in hair growth cycling, pigmentation physiology, and melanoma control. Thus, the widespread expression of a cutaneous seorotoninergic/melatoninergic syste,m(s) indicates considerable selectivity of action to facilitate intra-, auto-, or paracrine mechanisms that define and influence skin function in a highly compartmentalized manner. Notably, the cutaneous melatoninergic system is organized to respond to continuous stimulation in contrast to the pineal gland, which (being insulated from the external environment) responds to discontinuous activation by the circadian clock. Overall, the cutaneous serotoninergic/melatoninergic system could counteract or buffer external (environmental) or internal stresses to preserve the biological integrity of the organ and to maintain its homeostasis.-Slominski, A. J., Wortsman, J., Tobin, D. J. The cutaneous serotoninergic/melatoninergic system: securing a place under the sun.
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            Gastrointestinal melatonin: localization, function, and clinical relevance.

            The gastrointestinal tract of vertebrate species is a rich source of extrapineal melatonin. The concentration of melatonin in the gastrointestinal tissues surpasses blood levels by 10-100 times and there is at least 400x more melatonin in the gastrointestinal tract than in the pineal gland. The gastrointestinal tract contributes significantly to circulating concentrations of melatonin, especially during the daytime and melatonin may serve as an endocrine, paracrine, or autocrine hormone influencing the regeneration and function of epithelium, enhancing the immune system of the gut, and reducing the tone of gastrointestinal muscles. As binding sites for melatonin exhibit circadian variation in various species, it has been hypothesized that some melatonin found in the gastrointestinal tract might be of pineal origin. Unlike the photoperiodically regulated production of melatonin in the pineal, the release of gastrointestinal melatonin seems to be related to the periodicity of food intake. Phylogenetically, melatonin and its binding sites were detected in the gastrointestinal tract of lower vertebrates, birds, and mammals. Melatonin was found also in large quantities in the embryonic tissue of the mammalian and avian gastrointestinal tract. Food intake and, paradoxically, also longterm food deprivation resulted in an increase of tissue and plasma concentrations of melatonin. Melatonin release may have a direct effect on many gastrointestinal tissues but may also well influence the digestive tract indirectly, via the central nervous system and the sympathetic and parasympathetic nerves. Melatonin prevents ulcerations of gastrointestinal mucosa by an antioxidant action, reduction of secretion of hydrochloric acid, stimulation of the immune system, fostering epithelial regeneration, and increasing microcirculation. Because of its unique properties, melatonin could be considered for prevention or treatment of colorectal cancer, ulcerative colitis, gastric ulcers, irritable bowel syndrome, and childhood colic.
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              Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center.

              Little is known about factors related to prognosis in patients with carcinoid disease. In this study we have tried to identify such factors. We have evaluated 301 consecutive carcinoid patients (256 midgut, 39 foregut and six hindgut) referred during 15 years for medical treatment with respect to tumor distribution, hormone production, prognostic factors and survival. Survival was significantly shorter in midgut carcinoid patients with > or = 5 liver metastases or with high levels of urinary 5-hydroxyindoleacetic acid, plasma chromogranin A or neuropeptide K. By univariate analysis, these variables together with the presence of carcinoid syndrome were related to a higher risk of dying. In multivariate analyses, performed in the 71 patients with full information on all variables, advanced age and plasma chromogranin A > 5000 micrograms/l were independent predictors of overall survival. Poor prognostic factors for midgut carcinoid patients were multiple liver metastases, presence of carcinoid syndrome and high levels of the tumor markers studied. In this study the only independent predictors of bad prognosis in midgut, carcinoid patients were advanced age, which however is inherently related to overall survival, and plasma chromogranin A > 5000 micrograms/l. Thus, chromogranin A may prove to be an important prognostic marker for patients with carcinoid tumors.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                13 October 2016
                2016
                : 11
                : 10
                : e0164354
                Affiliations
                [1 ]Department of Neuroscience, Psychiatry, Uppsala University, Uppsala, Sweden
                [2 ]Department of Medical Sciences, Section of Endocrine Oncology, Uppsala University, Uppsala, Sweden
                [3 ]Department of Medical Sciences, Clinical Pharmacology and Osteoporosis, Uppsala University, Uppsala, Sweden
                [4 ]Department of Medical Sciences, Biochemical Endocrinology, Uppsala University, Uppsala, Sweden
                University of Alabama at Birmingham, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: FS JLC.

                • Data curation: FS JLC ETJ.

                • Formal analysis: FS JLC AR MS AA.

                • Funding acquisition: JLC.

                • Methodology: JLC ETJ MS AR AA.

                • Project administration: JLC.

                • Supervision: JLC.

                • Validation: AR.

                • Visualization: FS JLC AR.

                • Writing – original draft: FS JLC.

                • Writing – review & editing: FS JLC AR ETJ MS AA.

                Article
                PONE-D-16-06466
                10.1371/journal.pone.0164354
                5063280
                27736994
                56513496-1728-4e3c-b2fe-9641eab22489
                © 2016 Söderquist et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 February 2016
                : 23 September 2016
                Page count
                Figures: 1, Tables: 3, Pages: 14
                Funding
                Funded by: Märta och Nicke Nasvells fond
                Award Recipient :
                Funded by: Anna-Britta Gustafssons stiftelse
                Award Recipient :
                Funded by: Stiftelsen Apotekare Hedbergs Fond
                Award Recipient :
                Funded by: Erik, Karin and Gösta Selanders Stiftelse
                Award Recipient :
                Funded by: Stiftelsen Söderström-Königska sjukhemmet
                Award Recipient :
                Funded by: Swedish Medical Association
                Award Recipient :
                Funded by: Swedish Cancer Society
                Award Recipient :
                Funded by: ALF Funds from Uppsala University Hospital
                Award Recipient :
                This work was funded by grants from the Märta och Nicke Nasvells fond, Anna-Britta Gustafssons stiftelse, Stiftelsen Apotekare Hedbergs Fund, Erik, Karin and Gösta Selanders Stiftelse, Stiftelsen Söderström-Königska sjukhemmet, Swedish Medical Association, Swedish Cancer Society and ALF Funds from Uppsala University Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                Biology and Life Sciences
                Biochemistry
                Hormones
                Melatonin
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                Histochemistry and Cytochemistry Techniques
                Immunohistochemistry Techniques
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                Biochemistry
                Neurochemistry
                Neurotransmitters
                Biogenic Amines
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