Exploiting unique features of the gut-brain interface to combat gastrointestinal cancer

Abstract

Conflict of interest: Aspects of treating cancer with anticholinergic agents are the subject of a patent ("Hybrid cholinergic agents and compositions, methods of making, and methods of using to treat a cholinergic disorder," US 6,624,155) issued on September 23, 2003, to the University of Arkansas; JPR is an inventor on this patent. JPR owns equities in Agile Therapeutics, Gilead Sciences, and Procter & Gamble.

Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer

“…Colon cancer initiation is associated with altered functioning of immunocytes in the tumor microenvironment; these immunocytes also express muscarinic receptors ( Table 1 ) [ 1 ]. Human T cells release ACh for autocrine and paracrine signaling, a process promoted by activation of M 3 R, T cell activation by immunomodulators (e.g., lipopolysaccharide), and activation of adhesion molecules on the T cell surface; production and secretion of ACh was also identified in human B cells, macrophages, and dendritic cells [ 1 , 106 ].…”

“…Colon cancer initiation is associated with altered functioning of immunocytes in the tumor microenvironment; these immunocytes also express muscarinic receptors ( Table 1 ) [ 1 ]. Human T cells release ACh for autocrine and paracrine signaling, a process promoted by activation of M 3 R, T cell activation by immunomodulators (e.g., lipopolysaccharide), and activation of adhesion molecules on the T cell surface; production and secretion of ACh was also identified in human B cells, macrophages, and dendritic cells [ 1 , 106 ]. Given the immune cell-rich environment of the GI tract, particularly the colon, it is plausible that regulation of the immune system via M 3 R also modulates carcinogenesis, for example by producing cytokines that facilitate perineural invasion or otherwise enhancing the tumor microenvironment [ 107 ].…”

“…The enteric nervous system (ENS), the GI tract’s intrinsic nervous system, consists of neurons and glial cells organized into two concentric plexuses around the lumen. ENS neurons and glia participate in muscarinic signaling, and the ENS’s location in the GI milieu uniquely positions it to influence GI cancers [ 1 , 112 , 113 ]. For example, nerves underlying the gastric mucosa provide much of that region’s ACh, which activates M 3 R to trigger the release of additional neurotrophic factors [ 112 ].…”

“…The role of neurotransmitters in modulating cancer cell behavior has emerged as a major focus of investigation and a promising avenue for developing novel therapeutics [ 1 , 2 , 3 ]. This takes on particular importance for cancers of the organs in the gastrointestinal (GI) tract that are innervated by both the central and enteric nervous systems [ 1 , 4 ].…”

“…The role of neurotransmitters in modulating cancer cell behavior has emerged as a major focus of investigation and a promising avenue for developing novel therapeutics [ 1 , 2 , 3 ]. This takes on particular importance for cancers of the organs in the gastrointestinal (GI) tract that are innervated by both the central and enteric nervous systems [ 1 , 4 ]. The complexity of this field is highlighted by evidence that so-called neurotransmitters (e.g., acetylcholine, ACh) can be produced and released by non-neural cells (e.g., immunocytes, stromal cells, and cancer cells themselves) ( Figure 1 ).…”