Abstract
Cancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the biological behavior of these cancers is highly dependent on bioactive molecules released by neurocrine, paracrine, and autocrine mechanisms within the tumor microenvironment. For many decades after its discovery as a neurotransmitter, acetylcholine was thought to be synthesized and released uniquely from neurons and considered the sole physiological ligand for muscarinic receptor subtypes, which were believed to have similar or redundant actions. In the intervening years, we learned this former dogma is not tenable. (1) Acetylcholine is not produced and released only by neurons. The cellular machinery required to synthesize and release acetylcholine is present in immune, cancer, and other cells, as well as in lower organisms (e.g., bacteria) that inhabit the gut. (2) Acetylcholine is not the sole physiological activator of muscarinic receptors. For example, selected bile acids can modulate muscarinic receptor function. (3) Muscarinic receptor subtypes anticipated to have overlapping functions based on similar G protein coupling and downstream signaling may have unexpectedly diverse actions. Here, we review the relevant research findings supporting these conclusions and discuss how the complexity of muscarinic receptor biology impacts health and disease, focusing on their role in the initiation and progression of gastric, pancreatic, and colon cancers.
Highlights
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]
Because there is an abundance of novel information and the incidence of tumors in these organs is increasing in younger populations [6,7], we focus on the differential actions of activating muscarinic receptor subtypes on the evolution and progression of cancers of the stomach, pancreas, and colon
In pancreatic ductal adenocarcinoma (PDAC), prominent differential actions of muscarinic receptor subtypes are reported, i.e., M1 R activation protects against neoplasia whereas M3 R activation promotes pancreatic cancer progression
Summary
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]. Because there is an abundance of novel information and the incidence of tumors in these organs is increasing in younger populations [6,7], we focus on the differential actions of activating muscarinic receptor subtypes on the evolution and progression of cancers of the stomach, pancreas, and colon Innovative therapies for these cancers are urgently needed since effective treatment options are limited once adenocarcinomas arisInt. J. Sci. 2021, 22, 13153 ing from these organs progress to surgically unresectable, advanced, and invasive stages [8,9] For these GI cancers, even novel immunomodulators, like PD-1 checkpoint inhibitors, appear to hold little promise for successful treatment as their effects tend to be dynamics of these interactions and in their underlying mechanisms is likely to open the modest and lackthe durability [10,11]. Unravel their complexity, a systems biology approach may be helpful and, based on the implications for cancer therapeutics, appears warranted
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