133 Histamine Deficiency Upregulates Cd11b+Ly6g+ Tumor-Associated Neutrophils and Promotes Colon Carcinogenesis

Abstract

Background/aim: The anterior and posterior vagal trunks supply the each side of the gastric mucosa separately, and the denervation of either side does not impair the functional capacity of the other, leaving gastric acid output and circulating gastrin levels unchanged. In this study, we investigated the importance of the neural innervation and the brain-gut axis in cancer initiation by performing vagotomy in hypergastrinemic transgenic (INS-GAS) mice with a phenotype of spontaneous gastric cancer. Methods: Age/sex matched wild-type (WT) and INS-GAS mice were killed at 1, 2, 4, 6, 8, 10 and 12 months of age (at least 10 mice/ group) for histological examination of gastric cancer. INS-GAS mice at 6 months of age were randomized into 4 groups of surgery: unilateral anterior truncal vagotomy (29 mice), bilateral truncal vagotomy with pyloroplasty (24), pyloroplasty (27), and sham operation (25). Both the anterior and posterior sides of the stomachs were removed at 6 months postoperatively (i.e., 12 months of age) for pathological and immunohistochemical analyses. Results: Gastric cancer was found neither in WT mice regardless of age nor in INS-GAS mice that were <10 months of age. At 12 months of age, the incidence of gastric cancer was 78% in sham-operated INS-GAS mice and 86% in INS-GAS mice with pyloroplasty. Interestingly, in INS-GAS mice that underwent anterior vagotomy, the tumor incidence in the anterior side was 14% in contrast to 76% at posterior side. In INS-GAS mice that underwent bilateral vagotomy, the tumor incidence was reduced to 11-22%. The tumors in the innervated stomach showed high-grade dysplasia and lamina propria invasion, whereas in the denervated stomach, the tissue architecture appeared to be normal with numerous H+K+-ATPase-positive parietal cells. The thickness of mucosa was reduced in the denervated side compared to the innervated side. Degrees of inflammation, hyperplasia, metaplasia and gastric dysplasia were lower in the denervated anterior than the innervated posterior mucosa in INS-GAS mice with unilateral vagotomy. Proliferation (Ki67 and PCNA) and putative stem cell markers (Dclk1) were decreased. Markers for carcinogenesis (CD44 and β-catenin) and neuroendocrine differentiation (chromogranin A, PGP9.5 and synaptophysin) were downregulated, whereas M3 receptors were upregulated in the denervated mucosa of the stomach. Conclusions: Selective vagotomy inhibited gastric cancer initiation specifically in the area of denervation, demonstrating the importance of the neural niche in cancer In Vivo. We also suggest that a genetic predisposition to gastric cancer might be prohibited by the disruption of the brain-gut axis.