Human macrophages promote the motility and invasiveness of osteopontin-knockdown tumor cells
Human macrophages promote the motility and invasiveness of osteopontin-knockdown tumor cells
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DOI：
10.1158/0008-5472.can-06-4763
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发表时间：
2007-06-01
期刊：
影响因子：
11.2
通讯作者：
Zhuang, Shi-Mei
中科院分区：
文献类型：
--
作者：
Cheng, Jiasen;Huo, De-Hua;Zhuang, Shi-Mei
越来越多的证据表明，肿瘤间质中的巨噬细胞可以显著改变肿瘤的恶性表型。骨桥蛋白（OPN）在高转移能力的癌症中经常过表达，因此被认为是潜在的治疗靶点。为了了解巨噬细胞是否可以影响OPN敲低肿瘤细胞的结果，我们使用RNA干扰（RNAi）来稳定沉默高度侵袭性人肝癌细胞系SK-Hep-1中的OPN表达。OPN的沉默显著降低SK-Hep-1细胞的运动性和侵袭性。使用该细胞模型的进一步研究表明，与人巨噬细胞或巨噬细胞条件培养基共培养在很大程度上恢复了OPN敲除肿瘤细胞的迁移和侵袭潜力。此外，这种巨噬细胞促进的运动性可以通过向共培养的培养基中添加OPN中和抗体或通过沉默巨噬细胞中的OPN表达来有效地阻断。这些结果表明，巨噬细胞来源的OPN可以补偿OPN的减少，从而恢复OPN敲除肿瘤细胞的转移潜力。进一步表征的潜在机制揭示，巨噬细胞源性骨桥蛋白发挥其功能的肌动蛋白细胞骨架重排或激活的基质金属蛋白酶和Rho家族。我们的研究结果表明，癌细胞和基质细胞之间存在微调的复杂相互作用，这可能会改变癌症治疗的结果，因此应考虑合理设计的抗癌策略。
increasing evidence indicates that macrophages in tumor stroma can significantly modify the malignant phenotypes of tumors. Osteopontin (OPN) is frequently overexpressed in cancers with high metastatic capacity and, thus, has been considered as a potential therapeutic target. To find out whether macrophages can affect the outcome of OPN-knockdown tumor cells, we used RNA interference (RNAi) to stably silence the OPN expression in the highly invasive human hepatoma cell line SK-Hep-1. Silencing of OPN markedly decreased the motility and invasiveness of the SK-Hep-1 cells. Further studies using this cell model revealed that coculture with human macrophages or macrophage-conditioned medium largely restored the migration and invasion potential of OPN-knockdown tumor cells. Moreover, such macrophage-promoted motility can be effectively blocked either by the addition of OPN-neutralizing antibody to the cocultured medium or by silencing OPN expression in macrophages. These results indicate that macrophage-derived OPN can compensate for the decrease of OPN and thereby restore the metastatic potential of OPN-knockdown tumor cells. Further characterization of the underlying mechanisms disclosed that macrophage-derived OPN exerted its function independently of the actin cytoskeleton rearrangement or the activation of matrix metalloproteinase and Rho families. Our results suggest that there are fine-tuned complex interactions between cancer cells and stroma cells, which may modify the outcome of cancer therapy, and therefore should be considered for the rational design of anticancer strategy.