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Enteric Glia Play a Critical Role in Promoting the Development of Colorectal Cancer.

ABSTRACT: Enteric glia are a distinct population of peripheral glial cells in the enteric nervous system that regulate intestinal homeostasis, epithelial barrier integrity, and gut defense. Given these unique attributes, we investigated the impact of enteric glia depletion on tumor development in azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice, a classical model of colorectal cancer (CRC). Depleting GFAP⁺ enteric glia resulted in a profoundly reduced tumor burden in AOM/DSS mice and additionally reduced adenomas in the Apc^Min ^/+ mouse model of familial adenomatous polyposis, suggesting a tumor-promoting role for these cells at an early premalignant stage. This was confirmed in further studies of AOM/DSS mice, as enteric glia depletion did not affect the properties of established malignant tumors but did result in a marked reduction in the development of precancerous dysplastic lesions. Surprisingly, the protective effect of enteric glia depletion was not dependent on modulation of anti-tumor immunity or intestinal inflammation. These findings reveal that GFAP⁺ enteric glia play a critical pro-tumorigenic role during early CRC development and identify these cells as a potential target for CRC prevention.

SUBMITTER: Yuan R

PROVIDER: S-EPMC7691584 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Enteric Glia Play a Critical Role in Promoting the Development of Colorectal Cancer.

Yuan Robert R Bhattacharya Nupur N Kenkel Justin A JA Shen Jeanne J DiMaio Michael A MA Bagchi Sreya S Prestwood Tyler R TR Habtezion Aida A Engleman Edgar G EG

Frontiers in oncology 20201113

Enteric glia are a distinct population of peripheral glial cells in the enteric nervous system that regulate intestinal homeostasis, epithelial barrier integrity, and gut defense. Given these unique attributes, we investigated the impact of enteric glia depletion on tumor development in azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice, a classical model of colorectal cancer (CRC). Depleting GFAP<sup>+</sup> enteric glia resulted in a profoundly reduced tumor burden in AOM/DSS mice and ...[more]

PMID: 33282743

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Project description:BackgroundMechanosensation is an important trigger of physiological processes in the gastrointestinal tract. Aberrant responses to mechanical input are associated with digestive disorders, including visceral hypersensitivity. Transient Receptor Potential Vanilloid 4 (TRPV4) is a mechanosensory ion channel with proposed roles in visceral afferent signaling, intestinal inflammation, and gut motility. While TRPV4 is a potential therapeutic target for digestive disease, current mechanistic understanding of how TRPV4 may influence gut function is limited by inconsistent reports of TRPV4 expression and distribution.MethodsIn this study we profiled functional expression of TRPV4 using Ca2+ imaging of wholemount preparations of the mouse, monkey, and human intestine in combination with immunofluorescent labeling for established cellular markers. The involvement of TRPV4 in colonic motility was assessed in vitro using videomapping and contraction assays.ResultsThe TRPV4 agonist GSK1016790A evoked Ca2+ signaling in muscularis macrophages, enteric glia, and endothelial cells. TRPV4 specificity was confirmed using TRPV4 KO mouse tissue or antagonist pre-treatment. Calcium responses were not detected in other cell types required for neuromuscular signaling including enteric neurons, interstitial cells of Cajal, PDGFRα+ cells, and intestinal smooth muscle. TRPV4 activation led to rapid Ca2+ responses by a subpopulation of glial cells, followed by sustained Ca2+ signaling throughout the enteric glial network. Propagation of these waves was suppressed by inhibition of gap junctions or Ca2+ release from intracellular stores. Coordinated glial signaling in response to GSK1016790A was also disrupted in acute TNBS colitis. The involvement of TRPV4 in the initiation and propagation of colonic motility patterns was examined in vitro.ConclusionsWe reveal a previously unappreciated role for TRPV4 in the initiation of distension-evoked colonic motility. These observations provide new insights into the functional role of TRPV4 activation in the gut, with important implications for how TRPV4 may influence critical processes including inflammatory signaling and motility.

Dataset Information

Enteric Glia Play a Critical Role in Promoting the Development of Colorectal Cancer.

Publications

Enteric Glia Play a Critical Role in Promoting the Development of Colorectal Cancer.

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