INSERM, Equipe Ligue Contre le Cancer 2012, UMR-957, Nantes F-44035, France.
BMC Cancer. 2014 Mar 10;14:169. doi: 10.1186/1471-2407-14-169.
Ewing's sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties.
Invasion assays were performed in vitro in Boyden's chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology.
ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and -9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases.
These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs.
尤因肉瘤（ES）是青少年中第二常见的原发性恶性骨肿瘤，对于高危患者的预后非常差，主要是当检测到肺转移时（5 年总生存率<15%）。唑来膦酸（ZA）是一种强效的骨吸收抑制剂，可诱导破骨细胞凋亡。我们之前的研究表明，ZA 具有很强的治疗潜力，因为它在体外抑制 ES 细胞生长，并在骨部位开发的小鼠模型中体内抑制 ES 原发性肿瘤生长。然而，尚无关于肺转移的数据。因此，本研究旨在确定 ZA 对 ES 细胞侵袭和转移特性的影响。
在体外 Boyden 室中进行侵袭实验，该室覆盖有 Matrigel。通过 ES 细胞培养上清液中的明胶酶谱分析基质金属蛋白酶（MMP）活性。在体内，通过将 106 个人 ES 细胞原位注射到裸鼠胫骨骨髓腔中来诱导自发肺转移的相关模型，这些细胞从原发性 ES 肿瘤中扩散。研究了 ZA（50 μg/kg，3x/周）在 4 周内的作用。通过尸检观察到肺转移并通过组织学进行分析。
ZA 强烈抑制 ES 细胞侵袭，可能是由于明胶酶谱分析显示 MMP-2 和 -9 活性下调所致。在体内，ZA 抑制自发性肺转移从原发性 ES 肿瘤的扩散，但对已建立的肺转移的生长没有影响。
这些结果表明，ZA 可早期用于 ES 的治疗，以抑制骨肿瘤生长，但也可预防早期向肺部转移的事件。
