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Review

Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway

by 1,2,3,*, 1,2,3 and 1,2
1
Central Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
2
Guangdong Provincial Engineering Research Center for Esophageal Cancer Precise Therapy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
3
School of Life Sciences, University of Technology Sydney, Broadway, Sydney, NSW 2007, Australia
*
Author to whom correspondence should be addressed.
Academic Editor: Olga Sukocheva
Cancers 2022, 14(3), 535; https://doi.org/10.3390/cancers14030535
Received: 13 December 2021 / Revised: 15 January 2022 / Accepted: 18 January 2022 / Published: 21 January 2022
Obesity, an ongoing global pandemic, is a major contributor to inflammation and cancers of the digestive system. High saturated fat diets and being overweight are associated with chronic inflammation and increased cancer risk. Signalling molecules made from saturated fats known as bioactive sphingolipids play essential roles in healthy gastrointestinal immunity. In excess, these sphingolipid molecules can compromise our immune system leading to chronic, low-grade inflammation within the digestive system preceding many metabolic diseases including cancer. Sphingosine-1-phosphate is a bioactive sphingolipid and, in excess, contributes to chronic inflammation. Drugs that block sphingosine-1-phosphate activity have the potential to prevent chronic inflammation and reduce gastrointestinal cancer risk. We review how disruption of the sphingosine-1-phosphate pathway contributes to gastrointestinal inflammation and cancer. We also discuss the use of modulators of the sphingospine-1-phosphate pathway in clinical trials and in the clinic as therapeutics for inflammatory gastrointestinal diseases with the benefit of reducing cancer risk.
Incidence of gastrointestinal (GI) cancers is increasing, and late-stage diagnosis makes these cancers difficult to treat. Chronic and low-grade inflammation are recognized risks for most GI cancers. The GI mucosal immune system maintains healthy homeostasis and signalling molecules made from saturated fats, bioactive sphingolipids, play essential roles in healthy GI immunity. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid, is a key mediator in a balanced GI immune response. Disruption in the S1P pathway underlies systemic chronic metabolic inflammatory disorders, including diabetes and GI cancers, providing a strong rationale for using modulators of the S1P pathway to treat pathological inflammation. Here, we discuss the effects of bioactive sphingolipids in immune homeostasis with a focus on S1P in chronic low-grade inflammation associated with increased risk of GI carcinogenesis. Contemporary information on S1P signalling involvement in cancers of the digestive system, from top to bottom, is reviewed. Further, we discuss the use of novel S1P receptor modulators currently in clinical trials and their potential as first-line drugs in the clinic for chronic inflammatory diseases. Recently, ozanimod (ZeposiaTM) and etrasimod have been approved for clinical use to treat ulcerative colitis and eosinophilic oesophagitis, respectively, which may have longer term benefits in reducing risk of GI cancers. View Full-Text
Keywords: sphingosine-1-phosphate (S1P); sphingosine kinase (SphK); gastrointestinal cancers; digestive system; S1P modulators; inflammation; immunotherapy sphingosine-1-phosphate (S1P); sphingosine kinase (SphK); gastrointestinal cancers; digestive system; S1P modulators; inflammation; immunotherapy
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MDPI and ACS Style

McGowan, E.M.; Lin, Y.; Chen, S. Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway. Cancers 2022, 14, 535. https://doi.org/10.3390/cancers14030535

AMA Style

McGowan EM, Lin Y, Chen S. Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway. Cancers. 2022; 14(3):535. https://doi.org/10.3390/cancers14030535

Chicago/Turabian Style

McGowan, Eileen M., Yiguang Lin, and Size Chen. 2022. "Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway" Cancers 14, no. 3: 535. https://doi.org/10.3390/cancers14030535

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