The nervous system plays an important role in the regulation of epithelial homeostasis and has also been postulated to play a role in tumorigenesis. We provide evidence that proper innervation is critical at all stages of gastric tumorigenesis. In three separate mouse models of gastric cancer, surgical or pharmacological denervation of the stomach (bilateral or unilateral truncal vagotomy, or local injection of botulinum toxin type A) markedly reduced tumor incidence and progression, but only in the denervated portion of the stomach. Vagotomy or botulinum toxin type A treatment also enhanced the therapeutic effects of systemic chemotherapy and prolonged survival. Denervation-induced suppression of tumorigenesis was associated with inhibition of Wnt signaling and suppression of stem cell expansion. In gastric organoid cultures, neurons stimulated growth in a Wnt-mediated fashion through cholinergic signaling. Furthermore, pharmacological inhibition or genetic knockout of the muscarinic acetylcholine M3 receptor suppressed gastric tumorigenesis. In gastric cancer patients, tumor stage correlated with neural density and activated Wnt signaling, whereas vagotomy reduced the risk of gastric cancer. Together, our findings suggest that vagal innervation contributes to gastric tumorigenesis via M3 receptor–mediated Wnt signaling in the stem cells, and that denervation might represent a feasible strategy for the control of gastric cancer.

No abstract

Background-In contrast with the histamine2 (H2) blockers, proton pump inhibitors have not been shown to give rebound hypersecretion of acid. Taking into consideration the hyperplasia of the enterochromaffin-like (ECL) cell provoked by hypergastrinaemia secondary to profound acid inhibition and the central role of histamine from ECL cells in the regulation of acid secretion, the lack of any rebound acid hypersecretion after treatment with proton pump inhibitors has been questioned. Aims-To reassess the effect of treatment with omeprazole on post-treatment acid secretion. Methods and Patients-Basal and pentagastrin stimulated acid secretion were determined in nine patients with reflux oesophagitis before and 14 days after termination of a 90 day treatment period with the proton pump inhibitor omeprazole (40 mg daily). Basal gastrin values as well as meal stimulated gastrin release were determined before and during omeprazole treatment. Furthermore, biopsy samples from the oxyntic mucosa were taken before and at the end of the treatment period for chemical (histamine and chromogranin A (CgA)) evaluation of the ECL cell mass. Results-A substantial increase in meal stimulated gastrin release during omeprazole treatment resulted in an increased ECL cell mass. Furthermore, CgA in serum increased during omeprazole treatment suggesting that serum CgA may be used as a test to evaluate ECL cell hyperplasia. A significant increase in basal and a marked (50%) and significant increase in pentagastrin stimulated acid secretion were found after treatment with omeprazole. Conclusions-Increased acid secretion after a conventional treatment period with a proton pump inhibitor is probably due to ECL cell hyperplasia and may have negative consequences for acid related diseases.

BackgroundIn inflammatory bowel disease (IBD), genetic susceptibility together with environmental factors disturbs gut homeostasis producing chronic inflammation. The two main IBD subtypes are Ulcerative colitis (UC) and Crohn’s disease (CD). We present the to-date largest microarray gene expression study on IBD encompassing both inflamed and un-inflamed colonic tissue. A meta-analysis including all available, comparable data was used to explore important aspects of IBD inflammation, thereby validating consistent gene expression patterns.MethodsColon pinch biopsies from IBD patients were analysed using Illumina whole genome gene expression technology. Differential expression (DE) was identified using LIMMA linear model in the R statistical computing environment. Results were enriched for gene ontology (GO) categories. Sets of genes encoding antimicrobial proteins (AMP) and proteins involved in T helper (Th) cell differentiation were used in the interpretation of the results. All available data sets were analysed using the same methods, and results were compared on a global and focused level as t-scores.ResultsGene expression in inflamed mucosa from UC and CD are remarkably similar. The meta-analysis confirmed this. The patterns of AMP and Th cell-related gene expression were also very similar, except for IL23A which was consistently higher expressed in UC than in CD. Un-inflamed tissue from patients demonstrated minimal differences from healthy controls.ConclusionsThere is no difference in the Th subgroup involvement between UC and CD. Th1/Th17 related expression, with little Th2 differentiation, dominated both diseases. The different IL23A expression between UC and CD suggests an IBD subtype specific role. AMPs, previously little studied, are strongly overexpressed in IBD. The presented meta-analysis provides a sound background for further research on IBD pathobiology.