TITLE:
Role of Cholinergic Receptors in Colorectal Cancer: Potential Therapeutic Implications of Vagus Nerve Stimulation?
AUTHORS:
Marjolaine Pelissier-Rota, Michèle Lainé, Benjamin Ducarouge, Bruno Bonaz, Muriel Jacquier-Sarlin
KEYWORDS:
Cell Adhesion; Colorectal Cancer; Tumor Progression; Cholinergic Receptors; Inflammation; Vagus Nerve
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.4 No.6,
July
29,
2013
ABSTRACT: Inflammatory
Bowel Disease (IBD) patients, such as Crohn’s disease or ulcerative colitis suffer from chronic and relapsing intestinal inflammation that favours the
development of colitis associated cancer (CAC). This inflammation is initiated
by aberrant activations of the innate immune responses associated to intestinal
barrier defects. The conventional medical therapies consist to decrease the
inflammatory response, which also decrease the risk of colon carcinoma but lead
to severe side-effects. Recently, a number of animal studies have demonstrated
that innate immune responses are attenuated by stimulation of the efferent arm
of vagus nerve (VN) through its neurotransmitter acetylcholine (ACh), that acts
on resident macrophages α7 nicotinic
receptor (α7 nAChR). ACh also acts as
a signalling molecule in epithetlial cells
through cholinergic receptors such as nAChR or muscarinic (mAChR) receptors. In
the current study, we aimed to extend these findings to CAC prevention by
treating human adenocarcinoma cell lines through targeting cholinergic receptors with nicotine (which binds nAChR) and
ACh (which binds both cholinergic receptors). Using HT-29 and Caco-2 cell
lines, we demonstrated that ACh-induced activation of mAChR results in cell
dissociation together with changes in expression and localization of intestinal
tight and adherens junction proteins. ACh-induced modulation of cell adhesion
proprieties correlates with the acquisition of invasive potential. By contrast,
nicotine-mediated activation of nAChR maintains epithelial cell organisation.
ACh-released by VN stimulation (VNS) could effectively preserve epithelium
integrity thus limiting inflammatory response and tumor development. However,
attention should be paid on the nature of the cholinergic receptor solicited.
Indeed, regarding to the protective effects of nAChR signalling on epithelial
cells, activation of mAChR would worsen the disease and led to increase
inflammation. These data have important
repercussions on the therapeutic potential of VNS in IBD and CAC, which may
represent “the yin and yang” of the intestinal homeostasis.