Human umbilical cord mesenchymal stem cells delivering sTRAIL home to lung cancer mediated by MCP-1/CCR2 axis and exhibit antitumor effects
Human umbilical cord mesenchymal stem cells delivering sTRAIL home to lung cancer mediated by MCP-1/CCR2 axis and exhibit antitumor effects
复制标题
人脐带间充质干细胞通过 MCP-1/CCR2 轴介导将 sTRAIL 传递至肺癌并表现出抗肿瘤作用
DOI：
10.1007/s13277-015-4746-7
复制
发表时间：
2016-06-01
期刊：
影响因子：
--
通讯作者：
Ren, Xiubao
中科院分区：
文献类型：
--
作者：
Yan, Cihui;Song, Xinmiao;Ren, Xiubao
骨髓间充质干细胞（Mesenchymal stem cells，MSCs）是一种潜在的肿瘤归巢载体，但其归巢机制尚不清楚。凋亡配体肿瘤坏死因子相关凋亡诱导配体（TNF-related apoptosis-inducing ligand，TRAIL）具有选择性诱导癌细胞凋亡而不影响正常细胞的优点，被认为是肿瘤基因治疗的一个有希望的候选者。将异亮氨酸拉链（isoleucinezipper，ISZ）加到可分泌的可溶性TRAIL（secretablesolubleTRAIL，sTRAIL）的N-末端，可产生三聚体形式的TRAIL（ISZ-sTRAIL），提高其抗肿瘤潜力。然而，低效率的递送和毒性仍然是其使用的障碍。本研究通过transwell迁移实验和动物生物发光成像技术，观察人脐带间充质干细胞（human umbilical cord mesenchymal stem cells，HUMSC）在体内外向肺癌的迁移情况。我们发现，无论是敲低肺癌细胞中单核细胞趋化蛋白-1（MCP-1）的表达，还是阻断HUMSC表面表达的CCR 2，HUMSC的归巢能力都受到抑制，表明MCP-1/CCR 2轴在HUMSC向肺癌的趋化性中起重要作用。此外，我们对HUMSC进行了遗传修饰，以特异性地将ISZ-sTRAIL递送至肿瘤部位。这种靶向治疗系统在异种移植小鼠模型中表现出有希望的凋亡诱导和抗肿瘤潜力，且没有明显的副作用。结论：表达ISZ-sTRAIL的HUMSC可能是一种有效的抗肺癌治疗方法，MCP-1/CCR 2轴对HUMSC的肿瘤嗜性至关重要。
Mesenchymal stem cells (MSCs) are believed to be a potential vehicle delivering antitumor agents for their tumor-homing capacity, while the underlying mechanism is yet to be explored. The apoptotic ligand TNF-related apoptosis-inducing ligand (TRAIL) has been suggested as a promising candidate for cancer gene therapy owing to its advantage of selectively inducing apoptosis in cancer cells while sparing normal cells. An isoleucine zipper (ISZ) added to the N-terminal of secretable soluble TRAIL (sTRAIL) can generate the trimeric form of TRAIL (ISZ-sTRAIL) and increase its antitumor potential. However, the inefficient delivery and toxicity are still obstacles for its use. In this study, the migration of human umbilical cord mesenchymal stem cells (HUMSCs) to lung cancer was observed through transwell migration assay and animal bioluminescent imaging both in vitro and in vivo. We found that the homing ability of HUMSCs was suppressed after either knocking down the expression of monocyte chemoattractant protein-1(MCP-1) in lung cancer cells or blocking CCR2 expressed on the surface of HUMSCs, indicating the important role of MCP-1/CCR2 axis in the tropism of HUMSCs to lung cancer. Furthermore, we genetically modified HUMSCs to deliver ISZ-sTRAIL to tumor sites specifically. This targeted therapeutic system exhibited promising apoptotic induction and antitumor potential in a xenograft mouse model without obvious side effects. In conclusion, HUMSCs expressing ISZ-sTRAIL might be an efficient therapeutic approach against lung cancer and MCP-1/CCR2 axis is essential for the tumor tropism of HUMSCs.