Direct anti-cancer effect of oncostatin M on chondrosarcoma

David, Emmanuelle; Guihard, Pierre; Brounais, Bénédicte; Riet, Anne; Charrier, Céline; Battaglia, Séverine; Ponsolle, Stéphanie; Bot, Ronan Le; Richards, Carl D.; Heymann, Dominique; Rédini, Françoise; Blanchard, Frédéric

doi:10.1016/j.bone.2010.10.100

Cited by 8 publications

(15 citation statements)

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“…Activation of STAT1 has been reported to be critical for the efficacy of anti-metastatic immunotherapies (43). The anticancer effect of OSM against chondrosarcoma is thought to work through the JAK3/STAT1 pathway (27). The activation of STAT1 upon OSM treatment was confirmed in the LAC cells ( Supplementary Fig.…”

Section: Oncostatin M Mediated the Msc-dependent Inhibition Of Cell Pmentioning

confidence: 83%

“…OSM induces osteogenesis in MSCs (23) and is involved in the differentiation of hepatocytes from human ESCs (22,46,47). OSM has also been reported to inhibit the proliferation of several tumor cell lines, including melanoma, glioblastoma, and breast cancer cells (21,(24)(25)(26)(27)(28). Yamashita and colleagues further showed that OSM renders liver cancer stem cells sensitive to chemotherapy by inducing hepatocyte differentiation (21).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, OSM was shown to promote MSC differentiation into osteoblasts (23). OSM is also reported to have antiproliferation effects against several types of cancers and is thus considered a potential therapeutic target (21,(24)(25)(26)(27)(28). However, the role of OSM in tumor progression and metastasis has yet to be evaluated.…”

Section: Introductionmentioning

confidence: 99%

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Oncostatin M Modulates the Mesenchymal–Epithelial Transition of Lung Adenocarcinoma Cells by a Mesenchymal Stem Cell-Mediated Paracrine Effect

et al. 2012

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Mesenchymal stem cells (MSC) are strongly associated with tumor progression and have been used as novel cell-based agents to deliver anticancer drugs to tumors. However, controversies about the direct involvement of MSCs in tumor progression suggest that MSCs mediate tumor progression in a cancer type-dependent manner. In this report, we analyzed the functional interactions between human MSCs and lung adenocarcinoma (LAC) cells to determine the therapeutic potential of MSCs in lung cancer. We showed that MSCs effectively inhibited the migration, invasion, and cell-cycle progression of several LAC cell lines. MSCs also enhanced the mesenchymalepithelial transition (MET) pathway, as evidenced by the reduction of several epithelial-mesenchymal transitionrelated markers in LAC cells cocultured with MSCs or in MSC-conditioned medium (MSC-CM). By cytokine array analysis, we determined that Oncostatin M (OSM), a differentiation-promoting cytokine, was elevated in the MSC-CM derived from primary MSC cultures. Furthermore, OSM treatment had the same effects as MSC-CM on LAC, whereas neutralizing antibodies to OSM reversed them. Notably, short hairpin RNAs against STAT1, an important downstream target of OSM, hindered the OSM-dependent induction of MET. In vivo xenograft tumor studies indicated that OSM inhibited tumor formation and metastasis of LAC cells, whereas neutralizing OSM in the MSC-CM hampered its inhibitory effects. In conclusion, this study showed that OSM is a paracrine mediator of MSC-dependent inhibition of tumorigenicity and activation of MET in LAC cells. These effects of OSM may serve as a basis for the development of new drugs and therapeutic interventions targeting cancer cells. Cancer Res; 72(22); 6051-64. Ó2012 AACR.

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Section: Oncostatin M Mediated the Msc-dependent Inhibition Of Cell Pmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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Oncostatin M Modulates the Mesenchymal–Epithelial Transition of Lung Adenocarcinoma Cells by a Mesenchymal Stem Cell-Mediated Paracrine Effect

et al. 2012

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“…Before confluence, cells were scraped in PBS containing 0.02% EDTA (Lonza), counted using a hemocytometer and reseeded. Several frozen biopsies were also dissociated with 2 mg/ml collagenase A (40.15 U/mg; Roche Diagnostics, Bazel, Switzerland) 27 and then cultured as described above. When passage 25 was reached, cells were considered stable and immortal.…”

Section: Establishment Of the Cell Linesmentioning

confidence: 99%

“…The real-time PCR (qPCR) mixture contained 10 ng reverse-transcribed total RNA, 200-300 nM previously described primers, 27,30 and SYBR Green PCR MasterMix (Bio-Rad). Analysis was performed using CYC1 and HPRT as invariant controls.…”

Section: Diferentiation Assaysmentioning

confidence: 99%

New chondrosarcoma cell lines and mouse models to study the link between chondrogenesis and chemoresistance

Monderer

Luseau²,

Bellec

et al. 2013

Laboratory Investigation

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Chondrosarcomas are cartilage-forming, poorly vascularized tumors. They represent the second malignant primary bone tumor of adults after osteosarcoma, but in contrast to osteosarcoma they are resistant to chemotherapy and radiotherapy, surgical excision remaining the only therapeutic option. Few cell lines and animal models are available, and the mechanisms behind their chemoresistance remain largely unknown. Our goal was to establish new cell lines and animal cancer models from human chondrosarcoma biopsies to study their chemoresistance. Between 2007 and 2012, 10 chondrosarcoma biopsies were collected and used for cell culture and transplantation into nude mice. Only one transplanted biopsy and one injected cell line has engrafted successfully leading to conventional central high-grade chondrosarcoma similar to the original biopsies. In culture, two new stable cell lines were obtained, one from a dedifferentiated and one from a grade III conventional central chondrosarcoma biopsy. Their genetic characterization revealed triploid karyotypes, mutations in IDH1, IDH2, and TP53, deletion in CDKN2A and/or MDM2 amplification. These cell lines expressed mesenchymal membrane markers (CD44, 73, 90, 105) and were able to produce a hyaline cartilaginous matrix when cultured in chondrogenic three-dimensional (3D) pellets. Using a high-throughput quantitative RT-PCR approach, we observed that cell lines cultured in monolayer had lost expression of several genes implicated in cartilage development (COL2A1, COMP, ACAN) but restored their expression in 3D cultures. Chondrosarcoma cells in monolayer were sensitive to several conventional chemotherapeutic agents but became resistant to low doses of mafosfamide or doxorubicin when cultured in 3D pellets, in parallel with an altered nucleic accumulation of the drug. Our results indicate that the cartilaginous matrix produced by chondrosarcoma cells may impair diffusion of several drugs and thus contribute to chemoresistance. Therefore, 3D chondrogenic cell pellets constitute a more relevant model to study chondrosarcoma chemoresistance and may be a valuable alternative to animal experimentations.

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Induction of Osteogenesis in Mesenchymal Stem Cells by Activated Monocytes/Macrophages Depends on Oncostatin M Signaling

et al. 2012

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Bone resorption by osteoclasts and bone formation by osteoblasts are tightly coupled processes implicating factors in TNF, bone morphogenetic protein, and Wnt families. In osteoimmunology, macrophages were described as another critical cell population regulating bone formation by osteoblasts but the coupling factors were not identified. Using a high-throughput approach, we identified here Oncostatin M (OSM), a cytokine of the IL-6 family, as a major coupling factor produced by activated circulating CD14 1 or bone marrow CD11b 1 monocytes/macrophages that induce osteoblast differentiation and matrix mineralization from human mesenchymal stem cells while inhibiting adipogenesis. Upon activation of toll-like receptors (TLRs) by lipopolysaccharide or endogenous ligands, OSM was produced in classically activated inflammatory M1 and not M2 macrophages, through a cyclooxygenase-2 and prostaglandin-E2 regulatory loop. Stimulation of osteogenesis by activated monocytes/macrophages was prevented using neutralizing antibodies or siRNA to OSM, OSM receptor subunits gp130 and OSMR, or to the downstream transcription factor STAT3. The induced osteoblast differentiation program culminated with enhanced expression of CCAAT-enhancer-binding protein d, Cbfa1, and alkaline phosphatase. Overexpression of OSM in the tibia of mice has led to new bone apposition with no sign of bone resorption. Two other cytokines have also a potent role in bone formation induced by monocytes/macrophages and activation of TLRs: IL-6 and leukemia inhibitory factor. We propose that during bone inflammation, infection, or injury, the IL-6 family signaling network activated by macrophages and TLR ligands stimulates bone formation that is largely uncoupled from bone resorption and is thus an important target for anabolic bone therapies. STEM CELLS 2012;30:762-772 Disclosure of potential conflicts of interest is found at the end of this article.

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Direct anti-cancer effect of oncostatin M on chondrosarcoma

Cited by 8 publications

References 0 publications

Oncostatin M Modulates the Mesenchymal–Epithelial Transition of Lung Adenocarcinoma Cells by a Mesenchymal Stem Cell-Mediated Paracrine Effect

Oncostatin M Modulates the Mesenchymal–Epithelial Transition of Lung Adenocarcinoma Cells by a Mesenchymal Stem Cell-Mediated Paracrine Effect

New chondrosarcoma cell lines and mouse models to study the link between chondrogenesis and chemoresistance

Induction of Osteogenesis in Mesenchymal Stem Cells by Activated Monocytes/Macrophages Depends on Oncostatin M Signaling

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