title: Oncostatin M is a growth factor for Ewing sarcoma.
abstract: Primary bone tumors, osteosarcomas and chondrosarcomas, derive from mesenchymal stem cells committed into osteoblasts and chondrocytes; in Ewing sarcomas (ESs), the oncogenic fusion protein EWS-FLI1 prevents mesenchymal differentiation and induces neuroectodermic features. Oncostatin M (OSM) is a cytokine from the IL-6 family that modulates proliferation and differentiation in numerous cells. The basis for inhibition versus induction of proliferation by this cytokine is obscure, although MYC was described as a potent molecular switch in OSM signaling. We show herein that, in contrast to osteosarcomas and chondrosarcomas, for which OSM was cytostatic, OSM induced proliferation of ES cell lines. Knockdown experiments demonstrated that growth induction by OSM depends on both types I [leukemia inhibitory factor receptor (LIFR)] and II [OSM receptor (OSMR)] receptors, high STAT3 activation, and induction of MYC to a high expression level. Indeed, ES cell lines, mice xenografts, and patient biopsy specimens poorly expressed LIF, precluding LIFR lysosomal degradation and OSMR transcriptional induction, thus leading to a high LIFR/OSMR ratio. Because other neuroectodermic tumors (ie, glioma, medulloblastoma, and neuroblastoma) had a similar expression profile, the main role of EWS-FLI1 could be through maintenance of stemness and neuroectodermic features, characterized by a low LIF, a high LIFR/OSMR ratio, and high MYC expression. Thus, this study on rare bone malignancies gives valuable insights on more common cancer regulatory mechanisms and could provide new therapeutic opportunities.
authors.affiliation: INSERM, UMR, Ligue Team 2012, Nantes, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: David
authors.forename: Franck
authors.initials: F
authors.lastname: Tirode
authors.forename: Marc
authors.initials: M
authors.lastname: Baud'huin
authors.forename: Pierre
authors.initials: P
authors.lastname: Guihard
authors.forename: Karine
authors.initials: K
authors.lastname: Laud
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Marie F
authors.initials: MF
authors.lastname: Heymann
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.forename: Françoise
authors.initials: F
authors.lastname: Redini
authors.forename: Frédéric
authors.initials: F
authors.lastname: Blanchard
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002813:Chondrosarcoma / Q000378:metabolism / Q000473:pathology; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D053683:Oncostatin M / Q000378:metabolism* / Q000494:pharmacology; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D021122:Protein Subunits / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000378:metabolism; D053606:Receptors, OSM-LIF / Q000378:metabolism; D053677:Receptors, Oncostatin M / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology*
chemical_list: C106031:EWS-FLI fusion protein; D036341:Intercellular Signaling Peptides and Proteins; D053605:Leukemia Inhibitory Factor; D015514:Oncogene Proteins, Fusion; D021122:Protein Subunits; D051789:Proto-Oncogene Protein c-fli-1; D016271:Proto-Oncogene Proteins c-myc; D034802:RNA-Binding Protein EWS; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D050796:STAT3 Transcription Factor; D053683:Oncostatin M; D050822:Cytokine Receptor gp130