The role of sphingosine‐1‐phosphate in inflammation and cancer progression

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Abstract

Many inflammatory mediators are involved in the process of carcinogenesis and cancer progression. In addition to cytokines and chemokines, lipid mediators have recently attracted attention as signaling molecules associated with inflammatory diseases. Sphingosine‐1‐phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival and migration, immune cell recruitment, angiogenesis and lymphangiogenesis. S1P also plays a significant role in inflammation and cancer. The gradation of S1P concentration in the blood, lymph and tissue regulates lymphocyte trafficking, an important component of inflammation. Furthermore, cancer cells produce elevated levels of S1P, contributing to the tumor microenvironment and linking cancer and inflammation. Future technological advances may reveal greater detail about the mechanisms of S1P regulation in the tumor microenvironment and the contribution of S1P to cancer progression. Considering the critical role of S1P in linking inflammation and cancer, it is possible that the S1P signaling pathway could be a novel therapeutic target for cancers with chronic inflammation.

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Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

Mehrdad Matloubian, Charles G. Lo, Guy Cinamon … (2004)

Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.

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Sphingosine-1-phosphate: an enigmatic signalling lipid.

Sarah Spiegel, Sheldon Milstien (2003)

The evolutionarily conserved actions of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), in yeast, plants and mammals have shown that it has important functions. In higher eukaryotes, S1P is the ligand for a family of five G-protein-coupled receptors. These S1P receptors are differentially expressed, coupled to various G proteins, and regulate angiogenesis, vascular maturation, cardiac development and immunity, and are important for directed cell movement.

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Sphingolipid metabolism in cancer signalling and therapy

Besim Ogretmen (2017)

Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure-function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P-S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.

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Author and article information

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PubMed ID:: 30238699

PMC ID:: 6272099

DOI:: 10.1111/cas.13802

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http://creativecommons.org/licenses/by-nc/4.0/

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer,inflammation,lipid mediator,sphingosine‐1‐phosphate,tumor microenvironment

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer, inflammation, lipid mediator, sphingosine‐1‐phosphate, tumor microenvironment

The role of sphingosine‐1‐phosphate in inflammation and cancer progression

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Karger: Oncology

Most cited references 61

Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

Sphingosine-1-phosphate: an enigmatic signalling lipid.

Sphingolipid metabolism in cancer signalling and therapy

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