Liu Verena, Dietrich Alexandra, Kasparek Michael S, Benhaqi Petra, Schneider Marlon R, Schemann Michael, Seeliger Hendrik, Kreis Martin E
Department of General-, Visceral- and Vascular Surgery, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, D-12000, Berlin, Germany.
Department of Surgery, Ludwig-Maximilian´s University, Campus Grosshadern, Munich, Germany.
J Exp Clin Cancer Res. 2015 Apr 29;34(1):39. doi: 10.1186/s13046-015-0159-0.
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.
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.
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.
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.
神经支配与肠道免疫反应相互作用。慢性肠道炎症与结直肠癌风险增加相关。我们旨在研究小鼠模型中肠道肿瘤发生的潜在外在神经调节作用。
对雄性Apc(Min/+)或野生型小鼠（4周龄，体重约20克）进行实验。研究膈下迷走神经切断术亚组（apcV/wtV）、小肠交感神经去支配亚组（apcS/wtS）或假手术对照组（apcC/wtC）（每组n = 6 - 14只）。手术操作三个月后，切除10厘米末端回肠，在4%多聚甲醛中固定48小时，计数所有肿瘤并测定其面积（平方毫米）（平均值±平均标准误差（SEM））。对末端回肠和十二指肠肌层（内部阳性对照）的整装标本也进行酪氨酸羟化酶染色，以确认交感神经去支配成功。
Apc(Min/+)小鼠的肿瘤计数分别为62±8（apcC）、46±11（apcV）和54±8（apcS），与野生型对照组[4±0.5（wtC）、5±0.5（wtV）和5±0.6（wtS）；所有p < 0.05]相比有所增加。对于Apc(Min/+)组，与假手术的Apc(Min/+)对照组相比，迷走神经切断的动物肿瘤计数有下降趋势，而交感神经去支配组与假手术的Apc(Min/+)组相似。Apc(Min/+)小鼠肿瘤覆盖面积分别为55±10（apcC）、31±8（apcV）和42±8（apcS）平方毫米，与野生型对照组[7±0.6（wtC）、7±0.4（wtV）和7±0.6（wtS）平方毫米]相比总体增加（所有p < 0.05）。在Apc(Min/+)组中，与假手术对照组相比，迷走神经切断的动物肿瘤面积减小（p < 0.05），而交感神经去支配的小鼠与对照组相比肿瘤面积有轻微下降趋势。
小肠的外在神经支配可能调节Apc(Min/+)小鼠的肿瘤发生。迷走神经支配中断似乎可抑制肿瘤生长，而交感神经去支配则不然。
