Mesenchymal stromal cell delivery of full-length tumor necrosis factor–related apoptosis-inducing ligand is superior to soluble type for cancer therapy

作者：Zhengqiang Yuan, Krishna Kalyan Kolluri, Elizabeth Kathryn Sage, Kate H.C. Gowers, Sam M. Janes · 发表于：Cytotherapy · 年份：2015 · DOI：10.1016/j.jcyt.2015.03.603 · 被引用次数：70 · 研究领域：Mesenchymal stem cell research、RNA Interference and Gene Delivery、Virus-based gene therapy research

BACKGROUND AIMS: Mesenchymal stromal cell (MSC) delivery of pro-apoptotic tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an attractive strategy for anticancer therapy. MSCs expressing full-length human TRAIL (flT) or its soluble form (sT) have previously been shown to be effective for cancer killing. However, a comparison between the two forms has never been performed, leaving it unclear which approach is most effective. This study addresses the issue for the possible clinical application of TRAIL-expressing MSCs in the future. METHODS: MSCs were transduced with lentiviruses expressing flT or an isoleucine zipper-fused sT. TRAIL expression was examined and cancer cell apoptosis was measured after treatment with transduced MSCs or with MSC-derived soluble TRAIL. RESULTS: The transduction does not adversely affect cell phenotype. The sT-transduced MSCs (MSC-sT) secrete abundant levels of soluble TRAIL but do not present the protein on the cell surface. Interestingly, the flT-transduced MSCs (MSC-flT) not only express cell-surface TRAIL but also release flT into medium. These cells were examined for inducing apoptosis in 20 cancer cell lines. MSC-sT cells showed very limited effects. By contrast, MSC-flT cells demonstrated high cancer cell-killing efficiency. More importantly, MSC-flT cells can overcome some cancer cell resistance to recombinant TRAIL. In addition, both cell surface flT and secreted flT are functional for inducing apoptosis. The secrete...