Department of Gynecology and Obstetrics, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, China.
Kingmed College of Laboratory Medicine, Guangzhou Medical University, Guangzhou 510182, China.
J Immunol Res. 2014;2014:318098. doi: 10.1155/2014/318098. Epub 2014 May 26.
Mesenchymal stem cells (MSCs) can exhibit either prooncogenic or antitumor properties depending on the context. Based on our previous study, we hypothesized that MSCs engineered to deliver IFN-γ would kill cancer cells through persistent activation of the TRAIL pathway. Human bone-marrow (BM-) derived MSCs were isolated, amplified, and transduced with a lentiviral vector encoding the IFN-γ gene under the control of the EF1α promoter. The IFN-γ-modified MSCs effectively secreted functional IFN-γ, which led to long-term expression of TRAIL. More importantly, the IFN-γ-modified MSCs selectively induced apoptosis in lung tumor cells through caspase-3 activation within the target cells. The percentage of activated-caspase-3-positive tumor cells in IFN-γ-modified MSCs cocultures was significantly higher than in control MSCs cocultures. Treatment with anti-TRAIL antibody dramatically suppressed the caspase-3 activation observed in H460 cells. After injection into nude mice, the IFN-γ-modified MSCs inhibited the growth and progression of lung carcinoma compared with control cells. Collectively, our results provide a new strategy for tumor therapy that utilizes IFN-γ-modified MSCs.
间充质干细胞（MSCs）的表现可以是致癌的或抗肿瘤的，这取决于具体情况。基于我们之前的研究，我们假设通过持续激活 TRAIL 途径来传递 IFN-γ 的工程 MSC 将通过杀死癌细胞。从人骨髓（BM）中分离、扩增和转导了一种慢病毒载体，该载体在 EF1α 启动子的控制下编码 IFN-γ 基因。IFN-γ 修饰的 MSC 有效地分泌了功能性 IFN-γ，导致 TRAIL 的长期表达。更重要的是，IFN-γ 修饰的 MSC 通过靶细胞内 caspase-3 的激活选择性地诱导肺癌细胞凋亡。IFN-γ 修饰的 MSC 共培养物中活化 caspase-3 阳性肿瘤细胞的百分比明显高于对照 MSC 共培养物。用抗 TRAIL 抗体处理可显著抑制 H460 细胞中观察到的 caspase-3 激活。IFN-γ 修饰的 MSC 注射到裸鼠后，与对照细胞相比，抑制了肺癌的生长和进展。总的来说，我们的结果为利用 IFN-γ 修饰的 MSC 进行肿瘤治疗提供了一种新策略。
