title: The role of sphingosine-1-phosphate in the tumor microenvironment and its clinical implications.
abstract: Elucidating the interaction between cancer and non-cancer cells, such as blood vessels, immune cells, and other stromal cells, in the tumor microenvironment is imperative in understanding the mechanisms underlying cancer progression and metastasis, which is expected to lead to the development of new therapeutics. Sphingosine-1-phosphate is a bioactive lipid mediator that promotes cell survival, proliferation, migration, angiogenesis/lymphangiogenesis, and immune responsiveness, which are all factors involved in cancer progression. Sphingosine-1-phosphate is generated inside cancer cells by sphingosine kinases and then exported into the tumor microenvironment. Although sphingosine-1-phosphate is anticipated to play an important role in the tumor microenvironment and cancer progression, determining sphingosine-1-phosphate levels in the tumor microenvironment has been difficult due to a lack of established methods. We have recently developed a method to measure sphingosine-1-phosphate levels in the interstitial fluid that bathes cancer cells in the tumor microenvironment, and reported that high levels of sphingosine-1-phosphate exist in the tumor interstitial fluid. Importantly, sphingosine-1-phosphate can be secreted from cancer cells and non-cancer components such as immune cells and vascular/lymphatic endothelial cells in the tumor microenvironment. Furthermore, sphingosine-1-phosphate affects both cancer and non-cancer cells in the tumor microenvironment promoting cancer progression. Here, we review the roles of sphingosine-1-phosphate in the interaction between cancer and non-cancer cells in tumor microenvironment, and discuss future possibilities for targeted therapies against sphingosine-1-phosphate signaling for cancer patients.
authors.affiliation: 1 Division of Digestive and General Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: 1 Division of Digestive and General Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagahashi
authors.affiliation: 2 Michael and Dianne Bienes Comprehensive Cancer Center, Holy Cross Hospital, Fort Lauderdale, FL, USA.|3 Massachusetts General Hospital, Boston, MA, USA.|4 Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: Omar M
authors.initials: OM
authors.lastname: Rashid
authors.affiliation: 5 Division of Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.|6 Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
authors.affiliation: 1 Division of Digestive and General Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Wakai
mesh_terms: D006801:Humans; D008246:Lysophospholipids / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D009369:Neoplasms / Q000209:etiology* / Q000628:therapy; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: Tumor microenvironment; angiogenesis; cancer progression; lipid mediator; sphingosine-1-phosphate