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.

Global Gene Expression Profiling of Human Osteosarcomas Reveals Metastasis-Associated Chemokine Pattern

“…OSM has been shown to induce bone loss and sensitized rat osteosarcoma to apoptosis [30] and induce differentiation of chondrosarcoma and osteosarcoma cells [31, 32]. However, several studies show that OSM may enhance tumour progression and metastasis.…”

The Bone Niche of Chondrosarcoma: A Sanctuary for Drug Resistance, Tumour Growth and also a Source of New Therapeutic Targets

“…Oncostatin (OSM), a member of IL-6 cytokine family, induces a hypertrophic differentiation, with reduced SOX9 and induced Cbfa1, Coll10, MMP13, VEGF, and RANKL expression in chondrosarcoma cells. RANKL being a pro-osteoclastogenesis factor and then a proresorptive factor, OSM enhances osteoclast formation at the tumour/bone interface and reduces the ectopic bone neoformation [66]. …”

“…Cytokinic treatment represents another relevant therapeutic approach of chondrosaroma [2]. Oncostatin M, a member of the IL-6 cytokine family mainly produced by macrophages, neutrophils, and T lymphocytes, is a cytostatic factor for chondrosarcomas in vitro and in vivo [66]. This growth inhibitory effect is also observed with two other cytokines of the same family able to reduce chondrosarcoma expansion but with a lower efficiency: IL-6 in association with its soluble receptor and IL-27 [66].…”

The Enigmatic Cytokine Oncostatin M and Roles in Disease

“…Furthermore, more recent data suggests that c-myc serves as a switch to alter breast cancer cell responses to OSM, where c-myc elevation reduces its antiproliferative effects and elevates anchorage independent growth, indicative of a metastatic phenotype [168]. Indeed, while OSM has inhibitory effects on osteosarcoma and chondrocarcoma [169], its growth stimulatory effect on Ewing sarcoma was associated with elevated c-myc [170]. In addition, OSM can induce epithelial-to-mesenchymal transition (EMT) and cancer stem cell-like features in breast cancer cells in vitro [171, 172].…”