Zoledronic acid blocks the interaction between mesenchymal stem cells and breast cancer cells: implications for adjuvant therapy of breast cancer
Zoledronic acid blocks the interaction between mesenchymal stem cells and breast cancer cells: implications for adjuvant therapy of breast cancer
复制标题
DOI：
10.1093/annonc/mdr159
复制
发表时间：
2012-03-01
影响因子：
50.5
通讯作者：
Normanno, N.
中科院分区：
文献类型：
--
作者：
Gallo, M.;De Luca, A.;Normanno, N.
背景：唑来膦酸（ZA）可减少雌激素受体（ER）阳性乳腺癌患者的局部和远处转移。由于ZA迅速集中在骨静脉注射给药后，我们假设，这种现象涉及ZA在骨tissue.Materials和方法的作用机制：迁移试验进行了纤连蛋白包被的Boyden室。用磷蛋白阵列分析信号蛋白的活化。结果：ZA能显著降低骨髓间充质干细胞（MSCs）AKT和丝裂原活化蛋白激酶（MAPK）的活化及其迁移能力。与来自未处理的MSC的条件培养基（CM）相比，来自ZA处理的MSC的条件培养基（CM）显示出降低的促进ER阳性MCF-7乳腺癌细胞迁移的能力。用ZA处理后，MSC-CM中趋化因子（C-C基序）配体5（CCL 5，也称为RANTES -活化调节、正常T细胞表达和分泌）和白细胞介素（IL）-6的水平显著降低。抗RANTES和抗IL-6抗体几乎完全阻断MSC-CM诱导的MCF-7细胞迁移。重组RANTES和IL-6可显著诱导MCF-7细胞迁移，二者联合应用具有协同作用。结论：ZA可能通过抑制MSC迁移和抑制MSC分泌与乳腺癌进展相关的因子而发挥其抗肿瘤作用。
Background: Zoledronic acid (ZA) reduces locoregional and distant metastases in estrogen receptor (ER)-positive breast cancer patients. Since ZA rapidly concentrates in the bone following i.v. administration, we hypothesized that this phenomenon involves the mechanism of action of ZA in bone tissue.Materials and methods: Migration assays were carried out in fibronectin-coated Boyden chambers. Activation of signaling proteins was analyzed with a phosphoprotein array. Chemokines and growth factors were measured by immunoassays and real-time PCR.Results: ZA significantly reduced in bone marrow-derived mesenchymal stem cells (MSCs) the activation of AKT and mitogen-activated protein kinase and their ability to migrate. Conditioned medium (CM) from ZA-treated MSCs showed a reduced capacity to promote the migration of ER-positive MCF-7 breast cancer cells as compared with CM from untreated MSCs. The levels of the chemokine (C-C motif) ligand 5 (CCL5, also known as RANTES - Regulated upon Activation, Normal T-cell Expressed, and Secreted) and interleukin (IL)-6 were significantly reduced in MSC-CM following treatment with ZA. Anti-RANTES and anti-IL-6 antibodies almost completely abolished the migration of MCF-7 cells induced by MSC-CM. Recombinant RANTES and IL-6 significantly induced MCF-7 cell migration and their combination showed a cooperative effect. Similar results were observed in different breast cancer cell lines.Conclusion: ZA might exert its antitumor activity by inhibiting MSC migration and blocking MSCs' secretion of factors involved in breast cancer progression.