Perissinotto Eliana, Cavalloni Giuliana, Leone Francesco, Fonsato Valentina, Mitola Stefania, Grignani Giovanni, Surrenti Nadia, Sangiolo Dario, Bussolino Federico, Piacibello Wanda, Aglietta Massimo
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.
Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):490-7.
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.
尽管进行了强化化疗和手术治疗，但约30%的骨肉瘤患者仍会发生肺和骨转移。这种优先转移行为的机制在很大程度上尚不清楚。我们研究了趋化因子受体4（CXCR4）/基质细胞衍生因子1（SDF-1）系统在驱动骨肉瘤细胞归巢中的作用。我们分析了几种骨肉瘤细胞系上CXCR4和SDF-1蛋白的表达，以及SDF-1对这些癌细胞迁移、黏附和增殖的影响。体外试验表明，表达CXCR4受体的骨肉瘤细胞的迁移遵循SDF-1梯度，并且SDF-1处理可促进它们与内皮细胞和骨髓基质细胞的黏附。此外，SDF-1暴露后基质金属蛋白酶-9的产生增加。我们最终在小鼠模型中证实了我们关于CXCR4/SDF-1轴参与骨肉瘤细胞转移过程的假设。注射骨肉瘤细胞后肺转移的发生可通过给予CXCR4抑制剂T134肽来预防。这些数据为骨肉瘤优先转移至肺（其中SDF-1浓度较高）提供了一种可能的解释，并表明旨在抑制CXCR4/SDF-1途径的分子策略，如小分子抑制剂或抗CXCR4抗体，可能会阻止骨肉瘤细胞的扩散。
