S1P Regulation of Macrophage Functions in the Context of Cancer

Andreas      Weigert; Benjamin      Weichand; Bernhard      Brune

Abstract

The sphingolipid sphingosine-1-phosphate (S1P) is an important regulator of immune cell functions in vivo. Besides recruiting lymphocytes to blood and lymph, it may promote immune cell survival and proliferation, but also interferes with their activation. Hereby, S1P may act as an intracellular second messenger or cofactor or, upon being secreted from cells, may bind to and activate a family of specific G-protein-coupled receptors (S1PR1-5). Extracellular versus intracellular S1P hereby might trigger synergistic/identical or fundamentally distinct responses. Furthermore, engagement of different S1PRs is connected to different functional outcome. This complexity is exemplified by the influence of S1P on the inflammatory potential of macrophages, shaping their role in inflammatory pathologies such as atherosclerosis and cancer. Here, we summarize the recent progress in understanding the impact of S1P signaling in macrophage biology, discuss its impact in solid as well as ‘wet’ tumors and elaborate potential options to interfere with S1P signaling in the context of cancer.

Keywords: Apoptosis, Inflammation, Macrophages, Sphingolipids, Sphingosine kinase, Sphingosine 1-phosphate, ABC transporters, lymphangiogenesis, HDAC, CREB, TNF