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Cyr61 silencing reduces vascularization and dissemination of osteosarcoma tumors

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. INTRODUCTION Osteosarcoma is a highly vascular and extremely destructive bone malignancy that mainly affects children and young adults. It represents the most frequent pediatric cancer-related disease. Despite the introduction, during the 70 s, of aggressive multi-agent chemotherapy in addition to tumor ablation surgery, the long-term survival (45 years) increased from 10-60% for patients with localized primary tumors, but to o 30% for patients presenting metastases at initial diagnosis. Nowadays, knowledge of the mechanisms underlying osteosarcoma metastasis is quite limited. Thus, in order to improve the clinical outcomes for patients with poor prognosis and to manage primary osteosar-coma by preventing development of metastatic disease, it is imperative to find new approaches to block the metastasis process. Degradation of the extracellular matrix, facilitated by the action of matrix metalloproteinases (MMPs), is a prerequisite of tumor invasion and metastasis in a variety of cancers including osteosarcoma. MMP-2 and MMP-9 have been repetitively implicated in osteosarcoma cell invasion, 1-3 and increased expression of membrane type-1 MMP correlated with decreased overall survival. 4 A correlation was recently reported between the expression of the extracellular MMP inducer EMMPRIN (CD147) and vascular endothelial growth factor (VEGF) in osteosarcoma ,
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N Habel, M Vilalta, O Bawa, P. Opolon, J Blanco, et al.. Cyr61 silencing reduces vascularization and dissemination of osteosarcoma tumors. Oncogene, Nature Publishing Group, 2015, 34 (24), pp.3207-3213. ⟨10.1038/onc.2014.232⟩. ⟨inserm-02472136⟩

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