Involvement of chemokine receptor 4/stromal cell-derived factor 1 system during osteosarcoma tumor progression.
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.
Perissinotto
Eliana
E
Department of Oncological Sciences and Laboratories of Clinical Oncology, University of Turin Medical School, IRCC Institute for Cancer Research and Treatment, Strada Provinciale 142, 10060 Candiolo, Turin, Italy.
Cavalloni
Giuliana
G
Leone
Francesco
F
Fonsato
Valentina
V
Mitola
Stefania
S
Grignani
Giovanni
G
Surrenti
Nadia
N
Sangiolo
Dario
D
Bussolino
Federico
F
Piacibello
Wanda
W
Aglietta
Massimo
M
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D010446:Peptide Fragments; D019718:Receptors, CXCR4; D020780:Matrix Metalloproteinase 9