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.

The effects of feed restriction, cold exposure, and the initiation of feeding on blood glucose metabolism, other blood metabolites, hormones, and tissue responsiveness and sensitivity to insulin were measured in sheep. The sheep consumed orchardgrass hay ad libitum (AL) or were restricted to 82% of the ME requirement for maintenance (RE) and were exposed to a thermoneutral (20 degrees C) or a cold environment (2 degrees C). An isotope dilution method and a glucose clamp approach were applied to determine blood glucose metabolism and insulin action, respectively. Plasma NEFA and insulin concentrations were influenced by feed restriction. Concentrations of plasma glucose, NEFA, insulin, and glucagon were influenced by cold exposure. Plasma NEFA concentration for RE decreased after the initiation of feeding and plasma insulin concentration increased transiently for all treatments. [U-13C]Glucose was continuously infused for 8 or 7 h after a priming injection starting 3 h before the initiation of either feeding or insulin infusion, respectively. When responses to feeding were studied, blood glucose turnover rate was less (P < .001) for RE than for AL, and it was greater (P < .001) during cold exposure than in the thermoneutral environment. The rate changed little after the initiation of feeding. For the glucose clamp approach, insulin was infused over four sequential 1-h periods at rates from .64 to 10 mU x kg BW(-1) x min(-1), with concomitant glucose infusion to maintain preinfusion plasma glucose concentrations. The rates of glucose infusion and blood glucose turnover increased (P < .001) dose-dependently with insulin infusion rate. The maximal glucose infusion rate was greater (P < .05) for RE than for AL and was greater (P < .001) during cold exposure than in the thermoneutral environment. The plasma insulin concentration at half-maximal glucose infusion rate was lower (P < .1) during cold exposure. Blood glucose turnover rate tended to be greater (P = .10) for RE than for AL, and it was greater (P < .001) during cold exposure than in the thermoneutral environment. The ratio of endogenous production to utilization of glucose was suppressed by insulin infusion. In sheep fed a roughage diet, blood glucose turnover rate seems to be influenced by both intake level and environmental temperature, but not by the act of feeding. Moreover, the action of insulin on glucose metabolism is enhanced during cold exposure, and the effect of feed restriction is somewhat enhanced.

Cancer cells can develop an attenuated immunogenicity and/or create an immunosuppressive microenvironment to prevent tumor eradication by host immune system, the so-called "cancer immunoediting" hypothesis. The aim of the present study was to find evidence for this hypothesis by using a rat orthotopic bladder cancer model. Fisher rats were inoculated with AY-27 cells (a Fisher rat bladder cancer cell line). Cultured cancer cells, rat and human bladder cancer tissues, and publicly available microarray data from human bladder cancer were analyzed by means of bioinformatics and morphology. Results showed that 12 of 24 differentially expressed pathways were concordant in connection to cell cycle and proliferation between rats and humans (both non-muscle-invasive and muscle-invasive tumors) and that 11 of the 24 pathways, including major histocompatibility complex, were related to host immunosurveillance with activations of T cells and natural killer cells in rats. The altered pathways and morphogenesis of this rat model corresponded more closely with those of human muscle-invasive rather than non-muscle-invasive tumors. A unique ultrastructure displaying microvillus-formed niches was found in small areas within the tumor of both rats and humans. These niches were interconnected with desmosomes between cancer cells and without infiltration of lymphocytes. The expression of E-cadherin, selectins, PGP9.5, vascular endothelial growth factor, caspase-3, CD133, Oct-4, nestin, CD3, and CD45RA was lower in the tumor than in the adjacent normal epithelium. We suggest that the microvillus-formed niche that harbors a few implanted cancer cells might be the compartment that prevents the tumor eradication by the host immune system.

Based on the present study, we may suggest that VBLOC induces satiety through vagal signaling, leading to reduced food intake and loss of body weight.

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