title: 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.
authors: 1] Inserm U981, Institut de cancérologie Gustave Roussy, Villejuif, France [2] Gustave Roussy, Villejuif, France [3] Université Paris Sud, Orsay, France [4] Université Paris Diderot, Paris, France.
authors: N
authors: N
authors: Habel
authors: Cell therapy group, Institute for Advanced Chemistry of Catalonia (CSIC), Barcelona, Spain.
authors: M
authors: M
authors: Vilalta
authors: 1] Gustave Roussy, Villejuif, France [2] Université Paris Sud, Orsay, France [3] Institut de Recherche Intégrée en cancérologie à Villejuif (IRCIV), Laboratoire de pathologie expérimentale, Gustave Roussy, Villejuif, France.
authors: O
authors: O
authors: Bawa
authors: 1] Gustave Roussy, Villejuif, France [2] Université Paris Sud, Orsay, France [3] Institut de Recherche Intégrée en cancérologie à Villejuif (IRCIV), Laboratoire de pathologie expérimentale, Gustave Roussy, Villejuif, France.
authors: P
authors: P
authors: Opolon
authors: 1] Cell therapy group, Institute for Advanced Chemistry of Catalonia (CSIC), Barcelona, Spain [2] Networking Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain.
authors: J
authors: J
authors: Blanco
authors: 1] Inserm U981, Institut de cancérologie Gustave Roussy, Villejuif, France [2] Gustave Roussy, Villejuif, France [3] Université Paris Sud, Orsay, France.
authors: O
authors: O
authors: Fromigué
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D055515:Cysteine-Rich Protein 61 / Q000235:genetics*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics*; D012516:Osteosarcoma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D014407:Tumor Cells, Cultured
chemical_list: C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61