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Cyr61 silencing reduces vascularization and dissemination of osteosarcoma tumors

Oncogene volume 34, pages 3207–3213 (2015)Cite this article

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Abstract

Osteosarcoma is the most prevalent primary pediatric cancer-related bone disease. These tumors frequently develop resistance to chemotherapy and are highly metastatic, leading to poor outcome. Thus, there is a need for new therapeutic strategies that can prevent cell dissemination. We previously showed that CYR61/CCN1 expression in osteosarcoma cells is correlated to aggressiveness both in vitro and in vivo in mouse models, as well as in patients. In this study, we found that CYR61 is a critical contributor to the vascularization of primary tumor. We demonstrate that silencing CYR61, using lentiviral transduction, leads to a significant reduction in expression level of pro-angiogenic markers such as VEGF, FGF2, PECAM and angiopoietins concomitantly to an increased expression of major anti-angiogenic markers such as thrombospondin-1 and SPARC. Matrix metalloproteinase-2 family member expression, a key pathway in osteosarcoma metastatic capacity was also downregulated when CYR61 was downregulated in osteosarcoma cells. Using a metastatic murine model, we show that CYR61 silencing in osteosarcoma cells results in reduced tumor vasculature and slows tumor growth compared with control. We also find that microvessel density correlates with lung metastasis occurrence and that CYR61 silencing in osteosarcoma cells limits the number of metastases. Taken together, our data indicate that CYR61 silencing can blunt the malignant behavior of osteosarcoma tumor cells by limiting primary tumor growth and dissemination process.

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Acknowledgements

NH is a recipient of a PhD award from the Ministère de la Recherche (Paris, France). This work was supported in part by Inserm (France), by Fondation de l’Avenir pour la Recherche Médicale Appliquée (Paris, France), by Red Temática de Investigación Cooperativa (TERCEL, Spain) and SAF2012-33404 from MINECO (Spain). We thank the Department of Medical Biology and Pathology of Gustave Roussy Institute (Dr Adam; Villejuif, France) for their contribution.

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Author notes

  1. M Vilalta

    Present address: 8Current address: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, USA.,

Authors and Affiliations

  1. Inserm U981, Institut de cancérologie Gustave Roussy, Villejuif, France

    N Habel & O Fromigué

  2. Gustave Roussy, Villejuif, France

    N Habel, O Bawa, P Opolon & O Fromigué

  3. Université Paris Sud, Orsay, France

    N Habel, O Bawa, P Opolon & O Fromigué

  4. Université Paris Diderot, Paris, France

    N Habel

  5. Cell therapy group, Institute for Advanced Chemistry of Catalonia (CSIC), Barcelona, Spain

    M Vilalta & J Blanco

  6. Institut de Recherche Intégrée en cancérologie à Villejuif (IRCIV), Laboratoire de pathologie expérimentale, Gustave Roussy, Villejuif, France

    O Bawa & P Opolon

  7. Networking Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain

    J Blanco

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Correspondence to O Fromigué.

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Habel, N., Vilalta, M., Bawa, O. et al. Cyr61 silencing reduces vascularization and dissemination of osteosarcoma tumors. Oncogene 34, 3207–3213 (2015). https://doi.org/10.1038/onc.2014.232

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