Yan Fengqi, Li Xia, Li Nan, Zhang Rui, Wang Qinhao, Ru Yi, Hao Xiaoke, Ni Jianxin, Wang He, Wu Guojun
Department of Urology, Tang Du Hospital, The Fourth Military Medical University, Shaanxi, Xian, 710038, China; Department of Urology, Xi Jing Hospital, The Fourth Military Medical University, Shaanxi, Xian, 710032, China.
Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Shaanxi, Xian, 710032, China.
Cancer Lett. 2017 Aug 28;402:32-42. doi: 10.1016/j.canlet.2017.05.003. Epub 2017 May 19.
Highly efficient target therapy is urgently needed for prostate cancer with overexpression of γ-seminoprotein (γ-SM). Recent studies indicated that mesenchymal stem cells (MSCs) are attractive candidate for cell-based, targeted therapy due to their tumor tropism. Here we designed a dual-target therapeutic system in which MSCs were engineered to produce and deliver scFv-Fdt-tBid, a novel γ-SM-targeted immunoproapoptotic molecule. Such engineered MSCs (MSC.scFv-Fdt-tBid) would home to tumor sites and release the fusion protein to induce the apoptosis of prostate cancer cells. Our data demonstrated that scFv-Fdt-tBid showed a selective, potent and dose-dependent inhibition for γ-SM-positive cells (LNCaP, C4-2, 22Rv1) rather than γ-SM-negative cells and MSCs. Importantly, MSC.scFv-Fdt-tBid caused cell death through an apoptosis-dependent manner. Further, the tropism of MSC.scFv-Fdt-tBid to prostate cancer was verified both in vitro and in vivo. Finally, the in vivo experiments demonstrated that MSC.scFv-Fdt-tBid significantly inhibited γ-SM-positive tumor growth without toxic side effects. Collectively, this study represented a novel immunoproapoptotic molecule scFv-Fdt-tBid for γ-SM-positive tumors and demonstrated the therapeutic efficiency and safety of scFv-Fdt-tBid-modified MSCs against prostate cancers.
对于γ-精蛋白（γ-SM）过表达的前列腺癌，迫切需要高效的靶向治疗。最近的研究表明，间充质干细胞（MSC）因其肿瘤趋向性而成为基于细胞的靶向治疗的有吸引力的候选者。在此，我们设计了一种双靶点治疗系统，其中对MSC进行工程改造以产生并递送scFv-Fdt-tBid，一种新型的γ-SM靶向免疫促凋亡分子。这种经过工程改造的MSC（MSC.scFv-Fdt-tBid）将归巢至肿瘤部位并释放融合蛋白以诱导前列腺癌细胞凋亡。我们的数据表明，scFv-Fdt-tBid对γ-SM阳性细胞（LNCaP、C4-2、22Rv1）而非γ-SM阴性细胞和MSC表现出选择性、强效且剂量依赖性的抑制作用。重要的是，MSC.scFv-Fdt-tBid通过依赖凋亡的方式导致细胞死亡。此外，在体外和体内均验证了MSC.scFv-Fdt-tBid对前列腺癌的趋向性。最后，体内实验表明，MSC.scFv-Fdt-tBid显著抑制γ-SM阳性肿瘤生长且无毒性副作用。总体而言，本研究提出了一种针对γ-SM阳性肿瘤的新型免疫促凋亡分子scFv-Fdt-tBid，并证明了scFv-Fdt-tBid修饰的MSC对前列腺癌的治疗效果和安全性。
