Neuropeptides in the Development of Colon Cancer

The American neuro-gastroenterologist Gershon has precisely nicknamed the intestines as ‘The second brain’, taking into account the size and complexity of the enteric nervous system (ENS). Enterochromaffin cells (EC) are functionally connected with the ENS and can also synthesize neuropeptides to control intestinal functions. Novel evidence has shown that EC indeed differentiates from the intestinal cryptal stem cell niche. Besides, mammalian bombesinlike peptides, cholecystokinin (CCK), gastrin, and neurotensin are gastrointestinal neuropeptides that impact on the body development, inflammation, tissue regeneration, and neoplastic transformation.

These molecules signal through their receptors that are highly expressed in the human colon but have, however, a differentiated pattern of expression for each one of them, which might illustrate their specific physiological roles. Hence, GRP receptors, Y2 receptors, PACAP type1-receptors, cholecystokinin-A receptors, neurotensin1 and somatostatin st2 receptors were abundantly expressed in the myenteric plexus, whereas VIP/PACAP and sst2 receptors were found in lymphoid follicles, and Y2, VIP type1 and sst2 receptors were present in the colonic mucosa. Specific binding sites for VIP, have been characterized in isolated human colonic epithelial cells in the early 80s. Given that the intestinal neuro-immune axis plays a significant role in regulating the severity of inflammation, it possibly has a pivotal role in the colon cancer development. For instance, neuropeptides might have either anti-inflammatory (VIP and galanin) or pro-inflammatory effects (NPY, substance P, serotonin, and neurotensin). The activation of specific immune signaling pathways might be the key to understanding the complex and controversial effects of these neuropeptides, from which inflammatory signals increase in a cascade of events. Corticotropin-releasing factor (CRF), which is a stress peptide, has been shown to control the colonic IL-6 release and neuronal activation, a fact that helps to clarify the effects of stressful conditions on the development of colonic inflammation.

Whether colitis increases the expression of neuropeptide Y (NPY) in the enteric nervous system, NPY knockout mice showed reduced intestinal inflammation. Pharmacological inhibition of vasoactive intestinal peptide (VIP), which is a neurotransmitter and vasodilator, protected experimental models from colitis. VIP-deficient mice, authors have also found reduced inflammation in trinitrobenzene sulfonic acid-induced colitis. Then, glucagon-like peptide 2 (GLP-2), which is an enteroendocrine hormone trophic for intestinal mucosa, has been shown to increase enteric neuronal expression of VIP. Sigalet et al. suggested that GLP-2 acts on enteric neurons and glial cells via a PI3Kγ/Akt pathway, stimulating neuronal differentiation via mTOR and ERK pathways, as well as the expression of receptors and ligands for IGF-I and ErbB pathways. Conversely, the anti-inflammatory and blood flow effects of GLP-2 are related to VIP and nitric oxide synthesizes and release from submucosal enteric neurons.