Abstract
Ewing sarcoma (EWS) is the second most frequent pediatric malignant bone tumor. EWS patients have not seen any major therapeutic progress in the last 30 years, in particular in the case of metastatic disease, which requires new therapeutic strategies. The pro-apoptotic cytokine TNF-Related Apoptosis Inducing Ligand (TRAIL) can selectively kill tumor cells while sparing normal cells, making it a promising therapeutic tool in several types of cancer. However, certain EWS cell lines appear resistant to recombinant human (rh) TRAIL-induced apoptosis. We therefore hypothesized that a TRAIL presentation at the surface of the carrier cells might overcome this resistance and trigger apoptosis. For this purpose, human adipose mesenchymal stromal/stem cells (MSC) transfected in a stable manner to express full-length human TRAIL were co-cultured with several human EWS cell lines, inducing apoptosis by cell-to-cell contact even in cell lines initially resistant to rhTRAIL or AMG655, an antibody agonist to the death receptor, DR5. In vivo, TRAIL delivered by MSCs was able to counteract tumor progression in two orthotopic models of Ewing sarcoma, associated with caspase activation, indicating that a cell-based delivery of a potent apoptosis-inducing factor could be relevant in EWS.
Highlights
Ewing sarcoma (EWS), the second most common malignant bone tumor in pediatric patients after osteosarcoma, is a rare form of cancer
This was confirmed by flow cytometry analysis, showing that TNFRelated Apoptosis Inducing Ligand (TRAIL) expression was exclusively present in AD-mesenchymal stromal/stem cells (MSC) TRAIL, both as a surface and a intracellular protein (Figure 1F)
MSC can be engineered to express TRAIL and a recent study has demonstrated that these cells can induce apoptosis in a variety of sarcomas by activation of caspase-820, paving the way for MSC-TRAIL-based therapies in these still deathly forms of cancer
Summary
Ewing sarcoma (EWS), the second most common malignant bone tumor in pediatric patients after osteosarcoma, is a rare form of cancer. It is highly metastatic and causes serious disruption to bone remodeling. A recruitment and activation cascade leads to tumor cell death by the extrinsic apoptosis pathway This mechanism can be amplified in certain cell types by activating the intrinsic apoptosis pathway, depending on the mitochondria and apoptosome. Both pathways lead to the final cleavage of pro-caspase-3 into active caspase-34
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