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

• Published in: Clinical cancer research 2005-01, Vol.11 (2), p.490-497
• Main Authors: PERISSINOTTO, Eliana, CAVALLONI, Giuliana, AGLIETTA, Massimo, LEONE, Francesco, FONSATO, Valentina, MITOLA, Stefania, GRIGNANI, Giovanni, SURRENTI, Nadia, SANGIOLO, Dario, BUSSOLINO, Federico, PIACIBELLO, Wanda
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Cell Adhesion; Cell Movement; Cell Proliferation; Chemokine CXCL12; chemokine receptors; chemokines; Chemokines, CXC - metabolism; Disease Progression; Diseases of the osteoarticular system; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; osteosarcoma; Osteosarcoma - metabolism; Osteosarcoma - pathology; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - metabolism; Signal Transduction; Stromal Cells - metabolism; Stromal Cells - pathology; Tumor Cells, Cultured; tumor progression; Tumors of striated muscle and skeleton
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.490.11.2

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.