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Involvement of Chemokine Receptor 4/Stromal Cell–Derived Factor 1 System during Osteosarcoma Tumor Progression

Department of Oncological Sciences and Laboratories of ¹ Clinical Oncology and ² Molecular Angiogenesis, University of Turin Medical School, IRCC Institute for Cancer Research and Treatment, Turin, Italy

Requests for reprints: Giuliana Cavalloni, Department of Oncological Sciences, Institute for Cancer Research and Treatment, Strada Provinciale 142, 10060 Candiolo, Turih, Italy. Phone: 39-011-9933523; Fax: 39-011-9933524; E-mail: giuliana.cavalloni{at}ircc.it.

Despite intensive chemotherapy and surgery treatment, lung and bone metastasis develop in about 30% of patients with osteosarcoma. Mechanisms for this preferential metastatic behavior are largely unknown. We investigated the role of the chemokine receptor 4 (CXCR4)/stromal cell–derived factor 1 (SDF-1) system to drive the homing of osteosarcoma cells. We analyzed the expression of the CXCR4 and SDF-1 proteins on several osteosarcoma cell lines and the effects of SDF-1 on migration, adhesion, and proliferation of these cancer cells. In vitro assays showed that the migration of osteosarcoma cells expressing CXCR4 receptor follows an SDF-1 gradient and that their adhesion to endothelial and bone marrow stromal cells is promoted by SDF-1 treatment. Moreover, the production of matrix metalloproteinase-9 is increased after SDF-1 exposure. We finally proved in a mouse model our hypothesis of the CXCR4/SDF-1 axis involvement in the metastatic process of osteosarcoma cells. Development of lung metastasis after injection of osteosarcoma cells was prevented by the administration of a CXCR4 inhibitor, the T134 peptide. These data show a possible explanation for the preferential osteosarcoma metastatic development into the lung, where SDF-1 concentration is high, and suggest that molecular strategies aimed at inhibiting the CXCR4/SDF-1 pathway, such as small-molecule inhibitors or anti-CXCR4 antibodies, might prevent the dissemination of osteosarcoma cells.

Key Words: osteosarcoma • chemokines • chemokine receptors • tumor progression

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