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Extrinsic intestinal denervation modulates tumor development in the small intestine of Apc(Min/+) mice.

Liu V, Dietrich A, Kasparek MS, Benhaqi P, Schneider MR, Schemann M, Seeliger H, Kreis ME - J. Exp. Clin. Cancer Res. (2015)

Bottom Line: 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.Experiments were performed with male Apc(Min/+) or wild type mice (4 weeks old, body weight approximately 20 g).

View Article: PubMed Central - PubMed

Affiliation: Department of General-, Visceral- and Vascular Surgery, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, D-12000, Berlin, Germany. verena.liu@charite.de.

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 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.

No MeSH data available.


Related in: MedlinePlus

Representative images of adenoma growth in the small intestine. A: Single polyp in C57BL/6 (wt)-mice, B: Adenomas in ApcMin/+ mice. Representative images of adenomas in wild type (A) and ApcMin/+ animals (B). Note the obvious difference in count and area of adenomas between both genotypes.
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Fig3: Representative images of adenoma growth in the small intestine. A: Single polyp in C57BL/6 (wt)-mice, B: Adenomas in ApcMin/+ mice. Representative images of adenomas in wild type (A) and ApcMin/+ animals (B). Note the obvious difference in count and area of adenomas between both genotypes.

Mentions: Three months after surgery, animals were sacrificed and a segment of 10 cm of terminal ileum beginning 1 cm proximal to the ileo-colic junction was excised in all subgroups. The segment was cut along the mesenteric border to expose the mucosa for evaluation of tumor numbers and area. Then it was fixed for 48 h in 4%-paraformaldehyde and the tumor number and area were evaluated (Figure 2). The distal duodenum was also harvested for staining with tyrosine hydroxylase (Merck Millipore, Merck Chemicals, Schwalbach) as a positive internal control in animals that had undergone denervation at the level of the superior mesenteric artery (Figure 3).Figure 2


Extrinsic intestinal denervation modulates tumor development in the small intestine of Apc(Min/+) mice.

Liu V, Dietrich A, Kasparek MS, Benhaqi P, Schneider MR, Schemann M, Seeliger H, Kreis ME - J. Exp. Clin. Cancer Res. (2015)

Representative images of adenoma growth in the small intestine. A: Single polyp in C57BL/6 (wt)-mice, B: Adenomas in ApcMin/+ mice. Representative images of adenomas in wild type (A) and ApcMin/+ animals (B). Note the obvious difference in count and area of adenomas between both genotypes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4440557&req=5

Fig3: Representative images of adenoma growth in the small intestine. A: Single polyp in C57BL/6 (wt)-mice, B: Adenomas in ApcMin/+ mice. Representative images of adenomas in wild type (A) and ApcMin/+ animals (B). Note the obvious difference in count and area of adenomas between both genotypes.
Mentions: Three months after surgery, animals were sacrificed and a segment of 10 cm of terminal ileum beginning 1 cm proximal to the ileo-colic junction was excised in all subgroups. The segment was cut along the mesenteric border to expose the mucosa for evaluation of tumor numbers and area. Then it was fixed for 48 h in 4%-paraformaldehyde and the tumor number and area were evaluated (Figure 2). The distal duodenum was also harvested for staining with tyrosine hydroxylase (Merck Millipore, Merck Chemicals, Schwalbach) as a positive internal control in animals that had undergone denervation at the level of the superior mesenteric artery (Figure 3).Figure 2

Bottom Line: 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.Experiments were performed with male Apc(Min/+) or wild type mice (4 weeks old, body weight approximately 20 g).

View Article: PubMed Central - PubMed

Affiliation: Department of General-, Visceral- and Vascular Surgery, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, D-12000, Berlin, Germany. verena.liu@charite.de.

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 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.

No MeSH data available.


Related in: MedlinePlus