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TRAIL delivered by mesenchymal stromal/stem cells counteracts tumor development in orthotopic Ewing sarcoma models
Romain Guiho1,2, Kevin Biteau1,2, Giulia Grisendi3
1INSERM, UMR-957, Equipe labellisée LIGUE contre le CANCER 2012, Nantes, F-44035, France.
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.
Insights
Mesenchymal stem cells delivering TNF-Related Apoptosis Inducing Ligand (TRAIL) effectively triggered apoptosis in resistant Ewing sarcoma (EWS) cells. This cell-based approach showed promise in counteracting tumor progression in vivo, offering new therapeutic avenues for pediatric bone cancer.
Area of Science:
- Oncology
- Biotechnology
- Cell Biology
Background:
- Ewing sarcoma (EWS) is a significant pediatric bone cancer with limited therapeutic advancements, especially for metastatic cases.
- TNF-Related Apoptosis Inducing Ligand (TRAIL) is a promising pro-apoptotic cytokine, but EWS exhibits resistance to its direct application.
- Novel strategies are crucial to overcome therapeutic resistance in EWS.
Purpose of the Study:
- To investigate if cell-surface presentation of TRAIL via mesenchymal stem cells (MSCs) can overcome EWS resistance to apoptosis.
- To evaluate the efficacy of MSC-mediated TRAIL delivery in preclinical models of Ewing sarcoma.
Main Methods:
- Human adipose mesenchymal stromal/stem cells (MSCs) were engineered for stable expression of full-length human TRAIL.
- Co-culture experiments were performed between TRAIL-expressing MSCs and various human EWS cell lines.
- In vivo studies utilized orthotopic EWS models to assess tumor progression and apoptosis induction.
Main Results:
- Co-culture with TRAIL-expressing MSCs induced apoptosis in EWS cell lines, including those resistant to recombinant TRAIL (rhTRAIL) or AMG655.
- In vivo, MSC-delivered TRAIL effectively counteracted tumor progression in orthotopic EWS models.
- Evidence of caspase activation confirmed apoptosis induction in the in vivo models.
Conclusions:
- Cell-based delivery of TRAIL by MSCs represents a viable strategy to overcome resistance and induce apoptosis in Ewing sarcoma.
- This approach demonstrates therapeutic potential for treating Ewing sarcoma, particularly in overcoming resistance mechanisms.
- Further development of cell-based TRAIL delivery systems could offer new hope for EWS patients.
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