Role of Muscarinic Acetylcholine Signaling in Gastrointestinal Cancers

Abstract

In the tumor microenvironment, various stromal and immune cells accumulate and interact with cancer cells to contribute to tumor progression. Among stromal players, nerves have recently been recognized as key regulators of tumor growth. More neurotransmitters, such as catecholamines and acetylcholine (ACh), are present in tumors, as the cells that secrete neurotransmitters accumulate by the release of neurotrophic factors from cancer cells. In this short review, we focus on the role of nerve signaling in gastrointestinal (GI) cancers. Given that muscarinic acetylcholine receptor signaling seems to be a dominant regulator of GI stem cells and cancers, we review the function and mechanism of the muscarinic ACh pathway as a regulator of GI cancer progression. Accumulating evidence suggests that ACh, which is secreted from nerves and tuft cells, stimulates GI epithelial stem cells and contributes to cancer progression via muscarinic receptors.

Tumor microenvironment in gastric cancers

“…Recruitment, growth, or differentiation of CAFs and blood vessels is caused by numerous interactions between tumor cells and other stromal components. Recent studies have suggested that nerves and neurotransmitters also play a critical role within the tumor microenvironment for many cancers, including gastric cancers 109‐115 . Some tumor stromal components may be anti‐tumorigenic, 7,58,116 but tumor cells and other stromal cells appear to acquire the ability to escape this anti‐tumorigenic host defense.…”

Therapeutic Assessment of Fractions of Hawthorn on Gastrointestinal Motility Disorder by UPLC-MS/MS-based Metabolomics

“…Acetylcholine is the most important excitatory neurotransmitter in the gastrointestinal nervous system. It can excite the smooth muscle of the gastrointestinal tract and thus depolarize the cell membrane of the smooth muscle [15,16]. Atropine sulfate can block the excitatory action of muscarinic receptors to inhibit acetylcholine, thereby reducing the excitability of the gastrointestinal smooth muscle, and reducing the amplitude and frequency of gastrointestinal peristalsis [17][18][19].…”

Acetylcholine From Tuft Cells: The Updated Insights Beyond Its Immune and Chemosensory Functions

“…Although tuft cells were firstly discovered in rat trachea, they have been well described in most mucosal epithelia. In rodents, they have been found through respiratory system (nasal cavity Finger et al, 2003 ; Ogura et al, 2010 , and trachea Krasteva et al, 2011 ; Saunders et al, 2013 ) to the digestive system (salivary glands ( Sato and Miyoshi, 1988 ), gastrointestinal tract ( Bezencon et al, 2008 ; Schütz et al, 2015 ; Hayakawa et al, 2017 ; Konishi et al, 2019 ), biliary tract ( Schütz et al, 2015 ) and colon ( Silva, 1966 ; Howitt et al, 2016 ) and the urogenital tract ( Deckmann et al, 2015 ), as well as the thymus ( Panneck et al, 2014 ), auditory tube ( Krasteva et al, 2012b ), and taste buds ( Sukumaran et al, 2017 ).…”

“…This abnormal cholinergic signaling regulates Wnt and YAP pathways to promote the initiation of tumors. The shift in tuft cells and cholinergic innervation suggests that tuft cells, in part, interfere tumor initiation in the early stage ( Hayakawa et al, 2017 ; Konishi et al, 2019 ).…”

“…However, although ChAT antagonist showed potent antitumor effects in mice, it has not been tested in human cancers. The anti-tumor effects of M3R antagonist has been well established in multiple cancers, such as gastrointestinal cancers and lung cancers ( Friedman et al, 2019 ; Konishi et al, 2019 ).…”