Extrinsic intestinal denervation modulates tumor development in the small intestine of Apc(Min/+) mice.
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 Apc(Min/+) 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 mm(2) (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 Apc(Min/+) 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 Apc(Min/+) groups, vagotomized animals showed a trend towards decreased tumor counts compared to sham operated Apc(Min/+) controls while sympathetic denervation was similar to sham Apc(Min/+). Area covered by tumors in Apc(Min/+) mice was 55 ± 10 (apcC), 31 ± 8 (apcV) and 42 ± 8 (apcS) mm(2), which was generally increased compared to wildtype controls with 7 ± 0.6 (wtC), 7 ± 0.4 (wtV) and 7 ± 0.6 (wtS) mm(2) (all p < 0.05). In Apc(Min/+) 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 Apc(Min/+) mice. Interrupted vagal innervation, but not sympathetic denervation, seems to inhibit tumor growth.
Department of General-, Visceral- and Vascular Surgery, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, D-12000, Berlin, Germany. verena.liu@charite.de.
Verena
V
Liu
Department of General-, Visceral- and Vascular Surgery, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, D-12000, Berlin, Germany. Calexandra_dietrich@gmx.de.
Alexandra
A
Dietrich
Department of Surgery, Ludwig-Maximilian´s University, Campus Grosshadern, Munich, Germany. michael.kasparek@med.uni-muenchen.de.
Michael S
MS
Kasparek
Department of Surgery, Ludwig-Maximilian´s University, Campus Grosshadern, Munich, Germany. benhaqi@gmx.de.
Petra
P
Benhaqi
Gene Center, LMU Munich, Munich, Germany. schnder@lmb.uni-muenchen.de.
Marlon R
MR
Schneider
Human Biology, Technische Universität München, Freising, Germany. schemann@wzw.tum.de.
Michael
M
Schemann
Department of General-, Visceral- and Vascular Surgery, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, D-12000, Berlin, Germany. hendrik.seeliger@charite.de.
Hendrik
H
Seeliger
Department of General-, Visceral- and Vascular Surgery, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, D-12000, Berlin, Germany. martin.kreis@charite.de.
Martin E
ME
Kreis
D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency; D000818:Animals; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000473:pathology*; D003714:Denervation; D004195:Disease Models, Animal; D007082:Ileum / Q000473:pathology; D007421:Intestine, Small / Q000294:innervation*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047368:Tumor Burden
D025601:Adenomatous Polyposis Coli Protein