Department of Surgery, National University of Ireland Galway, Galway, Ireland.
Breast Cancer Res Treat. 2010 Nov;124(2):317-26. doi: 10.1007/s10549-010-0734-1. Epub 2010 Jan 20.
Bone marrow-derived mesenchymal stem cells (MSCs) are known to specifically migrate to and engraft at tumour sites. Understanding interactions between cancer cells and MSCs has become fundamental to determining whether MSC-tumour interactions should be harnessed for delivery of therapeutic agents or considered a target for intervention. Breast Cancer Cell lines (MDA-MB-231, T47D & SK-Br3) were cultured alone or on a monolayer of MSCs, and retrieved using epithelial specific magnetic beads. Alterations in expression of 90 genes associated with breast tumourigenicity were analysed using low-density array. Expression of markers of epithelial-mesenchymal transition (EMT) and array results were validated using RQ-PCR. Co-cultured cells were analysed for changes in protein expression, growth pattern and morphology. Gene expression and proliferation assays were also performed on indirect co-cultures. Following direct co-culture with MSCs, breast cancer cells expressed elevated levels of oncogenes (NCOA4, FOS), proto-oncogenes (FYN, JUN), genes associated with invasion (MMP11), angiogenesis (VEGF) and anti-apoptosis (IGF1R, BCL2). However, universal downregulation of genes associated with proliferation was observed (Ki67, MYBL2), and reflected in reduced ATP production in response to MSC-secreted factors. Significant upregulation of EMT specific markers (N-cadherin, Vimentin, Twist and Snail) was also observed following co-culture with MSCs, with a reciprocal downregulation in E-cadherin protein expression. These changes were predominantly cell contact mediated and appeared to be MSC specific. Breast cancer cell morphology and growth pattern also altered in response to MSCs. MSCs may promote breast cancer metastasis through facilitation of EMT.
骨髓间充质干细胞（MSCs）被发现能特异性迁移到肿瘤部位并植入。了解癌细胞与 MSCs 之间的相互作用，对于确定是否应该利用 MSC-肿瘤相互作用来输送治疗剂，或者是否应该将其视为干预的靶点，已变得至关重要。将乳腺癌细胞系（MDA-MB-231、T47D 和 SK-Br3）单独培养或在 MSC 的单层上培养，并使用上皮细胞特异性磁珠回收。使用低密度阵列分析与乳腺癌发生相关的 90 个基因的表达变化。使用 RQ-PCR 验证 EMT 标志物的表达和阵列结果。分析共培养细胞的蛋白表达、生长模式和形态变化。还对间接共培养进行了基因表达和增殖测定。与 MSCs 直接共培养后，乳腺癌细胞表达高水平的癌基因（NCOA4、FOS）、原癌基因（FYN、JUN）、与侵袭相关的基因（MMP11）、血管生成（VEGF）和抗凋亡基因（IGF1R、BCL2）。然而，观察到与增殖相关的基因普遍下调（Ki67、MYBL2），并且对 MSC 分泌因子的反应中 ATP 产生减少。与 MSCs 共培养后，还观察到 EMT 特异性标志物（N-钙粘蛋白、波形蛋白、Twist 和 Snail）的显著上调，E-钙粘蛋白蛋白表达下调。这些变化主要是细胞接触介导的，并且似乎是 MSC 特异性的。乳腺癌细胞形态和生长模式也因 MSCs 而改变。MSCs 可能通过促进 EMT 来促进乳腺癌转移。
