Dear Colleagues,

It has been about 30 years since it was discovered that lysophospholipids such as lysophosphatidic acid (lysophosphatidate, LPA) and sphingosine 1-phosphate (S1P) are bioactive. The identifications of six G-protein-coupled receptors for LPA and five for S1P were major breakthroughs in understanding the roles of LPA and S1P in signaling. Equally important was the identification of enzymes that regulate the synthesis and degradation of LPA and S1P. For example, the role of autotaxin (ATX), which produces most of the extracellular LPA, and a family of three lipid phosphate phosphatases (LPP1–3) that dephosphorylate LPA and S1P was vital to understanding how signaling is regulated. In the case of S1P, its formation de novo is controlled by serine palmitoyltransferase, and S1P is also formed from sphingosine by two sphingosine kinases. Intracellular S1P is reversibly converted to sphingosine by two sphingosine 1-phosphate phosphatases and it is irreversibly degraded by sphingosine 1-phosphate lyase 1. LPA and S1P signal by different mechanisms and receptors, but there are many similarities in signaling outcomes and there is cross-talk between the signaling pathways. There are also several other lysophospholipids that have signaling properties that we know less about.

This Special Issue of Cancers will focus on signaling by LPA, S1P, and other lysophospholipids in cancers. The net effects of LPA and S1P signaling in cancers are increased in various tumors through increased LPA and S1P production coupled with a decrease in the expression of LPP1 and LPP3. LPA and S1P signaling are now recognized as central mediators of the progression of chronic inflammation in the tumor microenvironment and a component of several of the hallmarks of cancer. LPA and S1P promote tumor growth and metastasis. LPA also facilitates immune evasion. The roles of LPA and S1P in promoting pro-survival signals explains why they decrease the efficacy of several chemotherapeutic agents and protect cancer cells from cell death. It is critical to understand how each lysolipid signals and also how this signaling intersects.

There are now a variety of therapeutic agents that inhibit LPA and S1P synthesis and signaling through their respective receptors. For example, inhibiting autotaxin or LPA receptors shows promise in the treatment of fibrotic diseases. Drugs such as fingolimod, which is an analog of S1P, provides an effective treatment for multiple sclerosis. So far, these approaches have not been used in the clinic to decrease the adverse effects of LPA and S1P signaling in the management of cancer patients. We are now at the exciting point of being able to target LPA and S1P signaling as a novel paradigm for improving existing cancer treatments.

This is an area of special interest for us. It is also the theme of the FASEB SRC on “Lysophospholipid and Related Mediators: From Bench to Clinic”, which “Cancers” helped to sponsor and which many of us attend every two years. We hope that this special issue will further enhance the standing of our research field and that you will consider submitting a research article or a review as part of this special issue by 30 May 2022.

Prof. Dr. David Brindley
Dr. Denise Hemmings
Guest Editors

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• angiogenesis
• apoptosis
• cell division
• chemotherapy
• fibrosis
• immune evasion, metastasis, radiotherapy
• tumor micro-environment