The dual role of serotonin in colorectal cancer

Serotonin (5-HT) has complex effects on the central nervous system (CNS), neuroendocrine mechanisms, immunological reactions, intestinal microbiome, and cancer. It has been associated with more severe signs and symptoms of colitis, as well as promoting colorectal cancer (CRC) cells toward expansion. However, recent findings revealed that impairments in 5-HT synthesis lead to high levels of DNA damage in colonocytes, which is linked with inflammatory reactions promoting the development of CRC. Here, we review the diverse roles of 5-HT in intestinal homeostasis and in CRC and discuss how improved understanding of the modulation of the 5-HT pathway could be helpful for the design of novel anticancer therapies

Antiproliferative Effects of Fluoxetine on Colon Cancer Cells and in a Colonic Carcinogen Mouse Model

The antidepressant fluoxetine has been under discussion because of its potential influence on cancer risk. It was found to inhibit the development of carcinogen-induced preneoplastic lesions in colon tissue, but the mechanisms of action are not well understood. Therefore, we investigated anti-proliferative effects, and used HT29 colon tumor cells in vitro, as well as C57BL/6 mice exposed to intra-rectal treatment with the carcinogen N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) as models. Fluoxetine increased the percentage of HT29 cells in the G0/G1 phase of cell-cycle, and the expression of p27 protein. This was not related to an induction of apoptosis, reactive oxygen species or DNA damage. In vivo, fluoxetine reduced the development of MNNG-induced dysplasia and vascularization-related dysplasia in colon tissue, which was analyzed by histopathological techniques. An anti-proliferative potential of fluoxetine was observed in epithelial and stromal areas. It was accompanied by a reduction of VEGF expression and of the number of cells with angiogenic potential, such as CD133, CD34, and CD31-positive cell clusters. Taken together, our findings suggest that fluoxetine treatment targets steps of early colon carcinogenesis. This confirms its protective potential, explaining at least partially the lower colon cancer risk under antidepressant therapy

Making coastal research useful – cases from practice

Coastal research deals with that part of the sea, which is significantly affected by the land, and the part of the land, which is significantly affected by the sea. Coasts are in most cases densely populated, and the activities of people are shaping and changing the land/seascape of the coast. Thus, coast encompasses the coastal sea, the coastal land, coastal flora and fauna, and people. Since peoples’ economic and political preferences change and compete, the human impact on the coast changes is contested and subject to societal decision making processes. While some coastal research can help informing and constraining such decisions, many legitimate scientific efforts have little bearing on society. All decision making processes are political, so that scientific knowledge is not the dominant driver in such processes. Using cases from the Institute of Coastal Research of Helmholtz Zentrum Geesthacht, we describe some of these potentially useful parts of science, and discuss under which circumstances the potential usefulness transform into real utility. These cases do not span the full range of coastal science. Important issues are the recognition of alternative knowledge claims, the inevitableness of uncertainties and incompleteness of scientific analysis, the acceptance of the political nature of decisions and the ubiquitous presence of social values. Modesty, self-reflexivity and skepticism are needed on the side of science and an organized exchange with stakeholders and public through designated “border” services

Evaluation of marine spatial planning requires fit for purpose monitoring strategies

Marine spatial planning (MSP) has rapidly become the most widely used integrated, place-based management approach in the marine environment. Monitoring and evaluation of MSP is key to inform best practices, adaptive management and plan iteration. While standardised evaluation frameworks cannot be readily applied, accounting for evaluation essentials such as the definition of evaluation objectives, indicators and stakeholder engagement of stakeholders is a prerequisite for meaningful evaluation outcomes. By way of a literature review and eleven practical MSP case studies, we analysed present day trends in evaluation approaches and unravelled the adoption of evaluation essentials for three categories for monitoring and evaluation for plan making, plan outcomes, and policy implementation. We found that at a global scale the focus of MSP evaluation has shifted over the past decade from evaluating predominantly plan outcomes towards the evaluation of plan making. Independent of the scope of the evaluation, evaluation approaches varied greatly from formal and structured processes, building for instance on MSP goals and objectives, to informal processes based on stakeholder interviews. We noted a trend in the adoption of formalised approaches where MSP evaluations have increasingly become linked to MSP policy goals and objectives. However, the enhanced use of MSP objectives and indicators did not result in a more straightforward reporting of outcomes, e.g. such as the achievement of specific MSP objectives. Overall, we found weak linkages between defined MSP objectives, indicators and available monitoring data. While the apparent shift towards a focus on objectives is promising, we highlight the need of fit-for-purpose monitoring data to enable effective evaluation of those objectives. Hence, effective MSP and adaptive management processes require customised and concurrent monitoring and evaluation strategies and procedures. We argue that evaluation processes would also benefit from a better understanding of the general environmental, socio-economic and socio-cultural effects of MSP. Therefore, to understand better environmental effects of MSP, we praise that forthcoming MSP processes need to deepen the understanding and considerations of cause-effect pathways between human activities and changes of ecosystem state through the adoption of targeted cumulative effects assessments

Mast cells and serotonin synthesis modulate Chagas disease in the colon: clinical and experimental evidence

BACKGROUND: Trypanosoma cruzi (T. cruzi) infects millions of Latin Americans each year and can induce chagasic megacolon. Little is known about how serotonin (5-HT) modulates this condition. Aim We investigated whether 5-HT synthesis alters T. cruzi infection in the colon. MATERIALS AND METHODS: Forty-eight paraffin-embedded samples from normal colon and chagasic megacolon were histopathologically analyzed (173/2009). Tryptophan hydroxylase 1 (Tph1) knockout (KO) mice and c-Kit(W-sh) mice underwent T. cruzi infection together with their wild-type counterparts. Also, mice underwent different drug treatments (16.1.1064.60.3). RESULTS: In both humans and experimental mouse models, the serotonergic system was activated by T. cruzi infection (p  0.05), rescuing its synthesis promoted trypanosomiasis (p  0.05). Further experimentation revealed that pharmacologically inhibiting mast cell activity reduced colonic infection (p  0.05). However, inhibiting mast cell activity in Tph1KO mice increased colonic trypanosomiasis (p < 0.01). CONCLUSION: We show that mast cells may modulate the T. cruzi-related increase of 5-HT synthesis in the intestinal colon

Serotonin synthesis protects the mouse colonic crypt from DNA damage and colorectal tumorigenesis

Serotonin (5-HT) signaling pathways are thought to be involved in colorectal tumorigenesis (CRT), but the role of 5-HT synthesis in the early steps of this process is presently unknown. In this study, we used carcinogen treatment in the tryptophan hydroxylase 1 knockout (Tph1KO) and transgenic (Tph1(fl/fl) Villin(Cre) mouse models defective in 5-HT synthesis to investigate the early mutagenic events associated with CRT. Our observations of the colonic crypt post-treatment followed a timeline designed to understand how disruption of 5-HT synthesis affects the initial steps leading to CRT. We found Tph1KO mice had decreased development of both allograft tumors and colitis-related CRT. Interestingly, carcinogenic exposure alone induced multiple colon tumors and increased cyclooxygenase-2 (Ptgs2) expression in Tph1KO mice. Deletion of interleukin 6 (Il6) in Tph1KO mice confirmed that inflammation was a part of the process. 5-HT deficiency increased colonic DNA damage but inhibited genetic repair of specific carcinogen-related damage, leading to CRT-related inflammatory reactions and dysplasia. To validate a secondary effect of 5-HT deficiency on another DNA repair pathway, we exposed Tph1KO mice to ionizing radiation and found an increase in DNA damage associated with reduced levels of ataxia telangiectasia and Rad3 related (Atr) gene expression in colonocytes. Restoring 5-HT levels with 5-hydroxytryptophan treatment decreased levels of DNA damage and increased Atr expression. Analysis of Tph1(fl/fl) Villin(Cre) mice with intestine-specific loss of 5-HT synthesis confirmed that DNA repair was tissue specific. In this study, we report a novel protective role for 5-HT synthesis that promotes DNA repair activity during the early stages of colorectal carcinogenesis