title: Bioactive lipids S1P and C1P are prometastatic factors in human rhabdomyosarcoma, and their tissue levels increase in response to radio/chemotherapy.
abstract: Evidence suggests that bioactive lipids may regulate pathophysiologic functions such as cancer cell metastasis. Therefore, we determined that the bioactive lipid chemoattractants sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) strongly enhanced the in vitro motility and adhesion of human rhabdomyosarcoma (RMS) cells. Importantly, this effect was observed at physiologic concentrations for both bioactive lipids, which are present in biologic fluids, and were much stronger than the effects observed in response to known RMS prometastatic factors such as stromal derived factors-1 (SDF-1/CXCL12) or hepatocyte growth factor/scatter factor (HGF/SF). We also present novel evidence that the levels of S1P and C1P were increased in several organs after γ-irradiation or chemotherapy, which indicates an unwanted prometastatic environment related to treatment. Critically, we found that the metastasis of RMS cells in response to S1P can be effectively inhibited in vivo with the S1P-specific binder NOX-S93 that is based on a high-affinity Spiegelmer. These data indicate that bioactive lipids play a vital role in dissemination of RMS and contribute to the unwanted side effects of radio/chemotherapy by creating a prometastatic microenvironment.
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Louisville, KY 40202, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Schneider
authors.forename: Ewa
authors.initials: E
authors.lastname: Bryndza
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdel-Latif
authors.forename: Janina
authors.initials: J
authors.lastname: Ratajczak
authors.forename: Magdalena
authors.initials: M
authors.lastname: Maj
authors.forename: Maciej
authors.initials: M
authors.lastname: Tarnowski
authors.forename: Yuri M
authors.initials: YM
authors.lastname: Klyachkin
authors.forename: Peter
authors.initials: P
authors.lastname: Houghton
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Axel
authors.initials: A
authors.lastname: Vater
authors.forename: Sven
authors.initials: S
authors.lastname: Klussmann
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kucia
authors.forename: Mariusz Z
authors.initials: MZ
authors.lastname: Ratajczak
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D002448:Cell Adhesion / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D060833:Cellular Microenvironment / Q000187:drug effects / Q000528:radiation effects; D002518:Ceramides / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009362:Neoplasm Metastasis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; D002518:Ceramides; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C065576:ceramide 1-phosphate; C060506:sphingosine 1-phosphate; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D013110:Sphingosine