Abstract
Background aimsMesenchymal 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. MethodsMSCs 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. ResultsThe 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 secreted flT was found to have higher cancer cell-killing capacity than either recombinant TRAIL or MSC-secreted sT. ConclusionsThese observations demonstrate that MSC delivery of flT is superior to MSC delivery of sT for cancer therapy.
Highlights
Cancers are one of the leading causes of human death in the world
Well-characterized human adult Mesenchymal stromal cell (MSC) were purchased from the Texas A&M Health Science Center and were shown to be able to differentiate into chondrogenic, osteogenic and adipogenic lineages
TRAIL-transduced MSCs (MOI 2) were examined by flow cytometry with the use of a PE-conjugated anti-human TRAIL antibody, which demonstrated that more than 98% of flTtransduced MSCs (MSC-full-length human TRAIL (flT)) were positive for TRAIL expression, whereas only approximately 1% of control green fluorescent protein (GFP) virus-infected cells were positive, which indicated TRAIL expression was not the result of endogenous TRAIL induction after lentivirus infection (Figure 1B)
Summary
Cancers are one of the leading causes of human death in the world. Each year, more than 10 million new cases of cancer occur globally. 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. TRAIL expression was examined and cancer cell apoptosis was measured after treatment with transduced MSCs or with MSC-derived soluble TRAIL. The flT-transduced MSCs (MSC-flT) express cell-surface TRAIL and release flT into medium. These cells were examined for inducing apoptosis in 20 cancer cell lines. MSC-flT cells can overcome some cancer cell resistance to recombinant TRAIL Both cell surface flT and secreted flT are functional for inducing apoptosis. These observations demonstrate that MSC delivery of flT is superior to MSC delivery of sT for cancer therapy
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