Abstract
Simple SummaryObesity, 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.
Highlights
Cancers of the digestive system (gastro-intestinal (GI) and associated GI cancers), in general, have low overall 5-year survival rates mainly due to their late-stage diagnosis [1].Incidence and mortality rates of all GI tract cancer patients are predicted to increase significantly over the 20 years (Table 1) [2,3,4,5]
S1PR1 is the most well studied and ubiquitously expressed on all immune cells, both S1PR2 and S1PR4 are expressed on macrophages, monocytes, eosinophils, and mast cells, S1PR3 is expressed on neutrophils during inflammation as well dendritic cells, and S1PR5 is expressed on patrolling monocytes and natural killer cells
There are two major types of primary liver cancer: hepatocellular carcinoma (HCC), which arise from the hepatocytes and represent 80–90% of cases, and intrahepatic cholangiocarcinoma, a group of bile duct cancers comprising around 10–15% of cases
Summary
Cancers of the digestive system (gastro-intestinal (GI) and associated GI cancers), in general, have low overall 5-year survival rates mainly due to their late-stage diagnosis [1]. The digestive system has evolved a unique mucosal immune system, maintaining a strong presence at the mucosal boundary of the GI tract, the gut-associated lymphoid tissues (GALT), consisting of lymphocytes, macrophages, and other immune-responsive cells [12]. This mucosal lining of the GI tract is the first immune defence, maintaining gut homeostasis and protection against pathogens [13]. The unintentional disruption of the homeostatic reset control in the inflammatory process can potentiate long-term chronic inflammatory states that fail to resolve and underlie the well-documented association between inflammation and diseases such as diabetes and cancer [10,11,17,18]. We provide an update on S1P modulators in clinical trials and in clinical therapy for GI inflammation, which may have longer term benefits in reducing the risk of GI cancers
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