Extrinsic intestinal denervation modulates tumor development in the small intestine of ApcMin/+ mice

Abstract

Background Innervation interacts with enteric immune responses. Chronic intestinal inflammation is associated with increased risk of colorectal cancer. We aimed to study potential extrinsic neuronal modulation of intestinal tumor development in a mouse model. Methods Experiments were performed with male ApcMin/+ or wild type mice (4 weeks old, body weight approximately 20 g). Subgroups with subdiaphragmatic vagotomy (apcV/wtV), sympathetic denervation of the small intestine (apcS/wtS) or sham operated controls (apcC/wtC) were investigated (n = 6-14 per group). Three months after surgical manipulation, 10 cm of terminal ileum were excised, fixed for 48 h in 4% paraformaldehyde and all tumors were counted and their area determined in mm2 (mean ± standard error of the mean (SEM)). Whole mounts of the muscularis of terminal ileum and duodenum (internal positive control) were also stained for tyrosine hydroxylase to confirm successful sympathetic denervation. Results Tumor count in ApcMin/+ mice was 62 ± 8 (apcC), 46 ± 11 (apcV) and 54 ± 8 (apcS) which was increased compared to wildtype controls with 4 ± 0.5 (wtC), 5 ± 0.5 (wtV) and 5 ± 0.6 (wtS; all p < 0.05). For ApcMin/+ groups, vagotomized animals showed a trend towards decreased tumor counts compared to sham operated ApcMin/+ controls while sympathetic denervation was similar to sham ApcMin/+. Area covered by tumors in ApcMin/+ mice was 55 ± 10 (apcC), 31 ± 8 (apcV) and 42 ± 8 (apcS) mm2, which was generally increased compared to wildtype controls with 7 ± 0.6 (wtC), 7 ± 0.4 (wtV) and 7 ± 0.6 (wtS) mm2 (all p < 0.05). In ApcMin/+ groups, tumor area was decreased in vagotomized animals compared to sham operated controls (p < 0.05) while sympathetically denervated mice showed a minor trend to decreased tumor area compared to controls. Conclusions Extrinsic innervation of the small bowel is likely to modulate tumor development in ApcMin/+ mice. Interrupted vagal innervation, but not sympathetic denervation, seems to inhibit tumor growth.