title: Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation.
abstract: Many tumours originate from cancer stem cells (CSCs), which is a small population of cells that display stem cell properties. However, the molecular mechanisms that regulate CSC frequency remain poorly understood. Here, using microarray screening in aldehyde dehydrogenase (ALDH)-positive CSC model, we identify a fundamental role for a lipid mediator sphingosine-1-phosphate (S1P) in CSC expansion. Stimulation with S1P enhances ALDH-positive CSCs via S1P receptor 3 (S1PR3) and subsequent Notch activation. CSCs overexpressing sphingosine kinase 1 (SphK1), an S1P-producing enzyme, show increased ability to develop tumours in nude mice, compared with parent cells or CSCs. Tumorigenicity of CSCs overexpressing SphK1 is inhibited by S1PR3 knockdown or S1PR3 antagonist. Breast cancer patient-derived mammospheres contain SphK1(+)/ALDH1(+) cells or S1PR3(+)/ALDH1(+) cells. Our findings provide new insights into the lipid-mediated regulation of CSCs via Notch signalling, and rationale for targeting S1PR3 in cancer.
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Hirata
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Shoda
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kurihara
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekino
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Kanda
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase
chemical_list: D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D051880:Receptors, Notch; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase; C577483:sphingosine-1-phosphate receptor-3, human; C060506:sphingosine 1-phosphate