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

Abstract

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.

Sphingosine 1‐phosphate lyase facilitates cancer progression through converting sphingolipids to glycerophospholipids

“…SPL is responsible for irreversible degradation of S1P, as described in the Introduction section, therefore, SPL may regulate not only the intracellular levels of S1P, but also the amount of S1P available for extracellular export, by influencing autocrine or paracrine signaling through extracellular S1P receptors, especially in colon cancer, in which the S1P release system is up‐regulated 21 . Moreover, the importance of the sphingolipids in chronic inflammation of the digestive system has accumulated attentions and these recent advances could promote the therapeutic applications, targeting SKs, S1P and S1PRs 82–84 . Therefore, both the SPL‐mediated pathway and S1P‐S1P receptors might be useful therapeutic targets for the treatment cancer and the importance of these targets might depend on the cancer species.…”

“…21 Moreover, the importance of the sphingolipids in chronic inflammation of the digestive system has accumulated attentions and these recent advances could promote the therapeutic applications, targeting SKs, S1P and S1PRs. [82][83][84] Therefore, both the SPL-mediated pathway and S1P-S1P receptors might be useful therapeutic targets for the treatment cancer and the importance of these targets might depend on the cancer species. Further studies are necessary to address these points.…”

Expression Profile of Sphingosine Kinase 1 Isoforms in Human Cancer Tissues and Cells: Importance and Clinical Relevance of the Neglected 1b-Isoform

“…The SphK1 isoenzyme is expressed in most tissues ( Figure 4 ), and its role as a major player in development and disease has been widely researched over the past 20 years, including its role in cancers, diabetes, and liver pathology [ 9 , 13 , 14 , 27 , 52 , 53 , 57 , 58 ]. The relevance and consequence of individual SphK1 isoform expression, especially the longer SphK1b isoform, in cancer cells are underexplored and unclear.…”

“…Tere is substantial evidence to show that SphK1 plays a critical role in many types of cancer progression, as well as many other chronic diseases [13,14,[52][53][54][55]. For example, in estrogen-responsive breast cancer cells, elevated SphK1 is associated with endocrine resistance [24,28], and the spatial organization of SphK1 in ER positive breast tumors is aligned with the prognostic outcome [56].…”

“…Te sphingosine kinase 1 (SphK1) isoforms are bioactive lipid enzymes involved in the phosphorylation of sphingosine to produce the active form sphingosine-1-phosphate (S1P), thereby regulating the balance between S1P, sphingosine, and ceramide [1][2][3]. Maintaining the balance of SphK/S1P signaling is important in normal cellular and physiological processes including cell proliferation, survival, cell death, adhesion, angiogenesis, migration, and infammation, and it is key in the prevention and progression of cancer [4][5][6][7][8][9][10][11][12][13][14].…”