title: Direct anti-cancer effect of oncostatin M on chondrosarcoma.
abstract: The cytokine Oncostatin M (OSM) is cytostatic, pro-apoptotic and induces differentiation of osteosarcoma cells into osteocytes, suggesting new adjuvant treatment for these bone-forming sarcomas. However, OSM systemic over-expression could lead to adverse side effects such as generalized inflammation, neoangiogenesis and osteolysis. We determine here the effect of OSM on chondrosarcoma, another primary bone sarcoma characterized by the production of cartilage matrix and altered bone remodelling. Chondrosarcomas are resistant to conventional chemotherapy and radiotherapy, and wide surgical excision remains the only available treatment. We found that OSM blocked the cell cycle in four of five chondrosarcoma cell lines, independently of p53 and presumably through the JAK3/STAT1 pathway. In two tested cell lines, OSM induced a hypertrophic chondrocyte differentiation, with an induced Cbfa1/SOX9 ratio and induced Coll10, matrix metalloproteinase 13 (MMP13) and RANKL expression. Adenoviral gene transfer of OSM (AdOSM) in the Swarm rat chondrosarcoma (SRC) model indicated that local intra-tumoral OSM over-expression reduces chondrosarcoma development not only with reduced tumor proliferation and enhanced apoptosis but also with enhanced RANKL expression, osteoclast formation and reduced bone volumes. Flu-like symptoms were induced by the AdOSM, but there was no effect on tumor angiogenesis. Therefore, OSM could be considered as a new adjuvant anti-cancer agent for chondrosarcomas. A local application of this cytokine is presumably needed to overcome the poor vascularization of these tumors and to limit the deleterious effect on other tissues. Its side effect on bone remodeling could be managed with anti-resorption agents, thus offering potential new lines of therapeutic interventions.
authors.affiliation: INSERM, U957, Nantes, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: David
authors.forename: Pierre
authors.initials: P
authors.lastname: Guihard
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Brounais
authors.forename: Anne
authors.initials: A
authors.lastname: Riet
authors.forename: Céline
authors.initials: C
authors.lastname: Charrier
authors.forename: Séverine
authors.initials: S
authors.lastname: Battaglia
authors.forename: François
authors.initials: F
authors.lastname: Gouin
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Ponsolle
authors.forename: Ronan Le
authors.initials: RL
authors.lastname: Bot
authors.forename: Carl D
authors.initials: CD
authors.lastname: Richards
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.forename: Françoise
authors.initials: F
authors.lastname: Rédini
authors.forename: Frédéric
authors.initials: F
authors.lastname: Blanchard
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002813:Chondrosarcoma / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D053683:Oncostatin M / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050659:Core Binding Factor Alpha 1 Subunit; C507936:Jak3 protein, rat; D053245:RANK Ligand; D012333:RNA, Messenger; D055758:SOX9 Transcription Factor; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D016159:Tumor Suppressor Protein p53; D053683:Oncostatin M; D053616:Janus Kinase 3; D053509:Matrix Metalloproteinase 13