Mesenchymal Progenitors Expressing TRAIL Induce Apoptosis in Sarcomas
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Sarcomas are frequent tumors in children and young adults that, despite a relative chemo-sensitivity, show high relapse rates with up to 80% of metastatic patients dying in 5 years from diagnosis. The real ontogeny of sarcomas is still debated and evidences suggest they may derive from precursors identified within mesenchymal stromal/stem cells (MSC) fractions. Recent studies on sarcoma microenvironment additionally indicated that MSC could take active part in generation of a supportive stroma. Based on this knowledge, we conceived to use modified MSC to deliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) targeting different sarcoma histotypes. Gene modified MSC expressing TRAIL were cocultured with different osteosarcoma, rhabdomyosarcoma, and Ewing's Sarcoma (ES) cell lines assessing viability and caspase-8 activation. An in vivo model focused on ES was then implemented considering the impact of MSC-TRAIL on tumor size, apoptosis, and angiogenesis. MSC expressing TRAIL induced significantly high apoptosis in all tested lines. Sarcoma death was specifically associated with caspase-8 activation starting from 8 hours of coculture with MSC-TRAIL. When injected into pre-established ES xenotransplants, MSC-TRAIL persisted within its stroma, causing significant tumor apoptosis versus control groups. Additional histological and in vitro studies reveal that MSC-TRAIL could also exert potent antiangiogenic functions. Our results suggest that MSC as TRAIL vehicles could open novel therapeutic opportunities for sarcoma by multiple mechanisms.
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Grisendi et al. demonstrated the effectiveness of TRAIL-expressing ADMSCs in a metastatic lung model of Ewing's sarcoma, with ADMSCs migrating into the lung and persisting after last inoculation.
“Grisendi et al. also demonstrated the effectiveness of the approach in a metastatic lung model of Ewing's sarcoma, as ADMSCs were capable of migrating into the lung and persisting after last inoculation [140].”
From Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice (2019) · cites this paper as [140]
The Discussion says the attempted Ewing’s sarcoma lung-metastasis model was unsuccessful: injected tumor cells did not form lung nodules, so the paper did not demonstrate treatment effectiveness in that model. It did find that systemically administered AD-MSCs reached the lung and persisted after the last inoculation. The antitumor effect reported elsewhere in the paper was in a subcutaneous xenograft model. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredTransduced MSCs expressing TRAIL have anticancer activity in sarcoma models, causing extensive apoptosis of sarcoma and potent antiangiogenic functions both in vitro and in vivo.
“Transduced MSCs expressing TRAIL have anticancer activity in sarcoma models causing extensive apoptosis of sarcoma and potent antiangiogenic functions both in vitro and in vivo.”
From Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice (2019) · cites this paper as [140]
The pro-apoptotic effect of TRAIL-expressing MSCs in sarcoma models is thought to be controlled by activation of caspase-8.
“This pro-apoptotic effect is thought to be controlled by the activation of caspase-8 [140].”
From Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice (2019) · cites this paper as [140]
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- Authors
- Grisendi, G., Spano, C., D'souza, N., Rasini, V., Veronesi, E., Prapa, M., Petrachi, T., Piccinno, S., Rossignoli, F., Burns, J. S., Fiorcari, S., Granchi, D., Baldini, N., Horwitz, E. M., Guarneri, V., Conte, P., Paolucci, P., & Dominici, M.
- Affiliations
- University of Modena and Reggio Emilia (IT)
- Division of Oncology, Department of Medical and Surgical Sciences for Children & AdultsUniversity‐Hospital of Modena and Reggio EmiliaModena Italy
- Istituto Ortopedico Rizzoli (IT)
- Nationwide Children's Hospital (US)
- University of Padua (IT)
- Corresponding author
- Dominici, Massimo
- ORCID
- Venue
- STEM CELLS
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-02-17
- Volume
- 33
- Issue
- 3
- Pages
- 859-869
- ISSN
- 1066-5099 (ISSN-L)
- 1549-4918
- OpenAlex
- W1924899997
- Cited by
- 48
- References
- 54
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 6 · 2022: 2 · 2021: 6 · 2020: 6 · 2019: 8 · 2018: 6 · 2017: 4 · 2016: 4 · 2015: 1
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Stem Cells (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro (IG2012, 12755)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Keywords
- mesenchymal stem cells, TRAIL, sarcoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, apoptosis, caspase-8, tumor microenvironment, antiangiogenic activity, gene-modified stem cells, tumor stroma
- MeSH terms
- Animals, Bone Neoplasms, Female, Humans, Male, Rhabdomyosarcoma, Sarcoma, Sarcoma, Ewing, Osteosarcoma, Mice, Inbred NOD, Apoptosis, Mesenchymal Stem Cell Transplantation, Cell Line, Tumor, Mice, TNF-Related Apoptosis-Inducing Ligand, Mesenchymal Stem Cells
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