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

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.

The effect of butylscopolamine on [18F]FDG uptake in the gastrointestinal tract is negligible and regionally variable

“…As these serve as a background measures for the visual detection of areas with elevated uptake, the reduction of bowel uptake may be relevant in terms of target/background ratio. In contrast, the salivary glands and the liver demonstrated a significant decrease in uptake with the use of butylscopolamine, probably due to its anticholinergic effect on the muscarinic tissues of the glandular ducts and the biliary system [ 28 ]. Thus, the biological effect of the premedication could also be verified and quantified by PET in non-GIT organs.…”

“…Thus, the biological effect of the premedication could also be verified and quantified by PET in non-GIT organs. Other organs with muscarinic acetylcholine receptors like inner ocular muscles, smooth muscles of the urogenital system or perspiratory glands can hardly be visualized with PET because of their small size or the retention of tracer-containing urine [ 28 ]. Because of the likewise reduction of uptake in the liver by butylscopolamine, a bowel-to-liver ratio, as it has been performed in former studies for comparison, may be ineligible [ 20 , 22 ].…”

Mechanistic Clues Provided by Concurrent Changes in the Expression of Genes Encoding the M1 Muscarinic Receptor, β-Catenin Signaling Proteins, and Downstream Targets in Adenocarcinomas of the Colon

“…To address this concern, more must be learned about the molecular mechanisms that modulate progression from primary colon cancer to locoregional and distant metastases. An emerging area, and the focus of our current research, is the role muscarinic receptors (MRs) and alterations in post-MR signaling play in cancer progression ( Ali et al, 2021 ; Schledwitz et al, 2021a ; Tolaymat et al, 2021 ). The five MR subtypes, M 1 R–M 5 R, respectively, encoded by CHRM1 - CHRM5 , are G protein-coupled receptors comprised of seven transmembrane helix domains with an extracellular acetylcholine (ACh)-binding region, and extracellular allosteric binding regions for a variety of non-ACh ligands ( Maeda et al, 2019 ; Tolaymat et al, 2021 ).…”

Muscarinic receptor activation in colon cancer selectively augments pro-proliferative microRNA-21, microRNA-221 and microRNA-222 expression

“…Of the five muscarinic receptor subtypes, the M3 subtype (M 3 R) is a conditional oncogene when expressed in cells capable of proliferation [ 6 ]. M 3 R is widely expressed in the intestine and overexpressed in colon cancer [ 7 , 8 ]. We previously showed that activation of M 3 R governs key hallmarks of colon cancer progression including cell proliferation, survival, migration, and invasion [ 7 , 9 – 11 ].…”