Involvement of chemokine receptor 4/stromal cell-derived factor 1 system during osteosarcoma tumor progression.

Abstract

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.

• Authors: Eliana Perissinotto, Giuliana Cavalloni, Francesco Leone, Valentina Fonsato, Stefania Mitola, Giovanni Grignani, Nadia Surrenti, Dario Sangiolo, Federico Bussolino, Wanda Piacibello, Massimo Aglietta
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 2 Pt 1 Pg. 490-7 (Jan 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 15701832 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCL12 protein, human
• Chemokine CXCL12
• Chemokines, CXC
• Cxcl12 protein, mouse
• Peptide Fragments
• Receptors, CXCR4
• Matrix Metalloproteinase 9

Topics

• Animals
• Bone Marrow Cells (metabolism, pathology)
• Bone Neoplasms (metabolism, pathology)
• Cell Adhesion
• Cell Movement
• Cell Proliferation
• Chemokine CXCL12
• Chemokines, CXC (metabolism)
• Disease Progression
• Endothelial Cells (metabolism, pathology)
• Female
• Humans
• Lung Neoplasms (metabolism, prevention & control, secondary)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred BALB C
• Osteosarcoma (metabolism, pathology)
• Peptide Fragments (pharmacology)
• Receptors, CXCR4 (antagonists & inhibitors, metabolism)
• Signal Transduction
• Stromal Cells (metabolism, pathology)
• Tumor Cells, Cultured