title: Mesenchymal progenitors expressing TRAIL induce apoptosis in sarcomas.
abstract: 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.
authors.affiliation: Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Grisendi
authors.forename: Carlotta
authors.initials: C
authors.lastname: Spano
authors.forename: Naomi
authors.initials: N
authors.lastname: D'souza
authors.forename: Valeria
authors.initials: V
authors.lastname: Rasini
authors.forename: Elena
authors.initials: E
authors.lastname: Veronesi
authors.forename: Malvina
authors.initials: M
authors.lastname: Prapa
authors.forename: Tiziana
authors.initials: T
authors.lastname: Petrachi
authors.forename: Serena
authors.initials: S
authors.lastname: Piccinno
authors.forename: Filippo
authors.initials: F
authors.lastname: Rossignoli
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Burns
authors.forename: Stefania
authors.initials: S
authors.lastname: Fiorcari
authors.forename: Donatella
authors.initials: D
authors.lastname: Granchi
authors.forename: Nicola
authors.initials: N
authors.lastname: Baldini
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Horwitz
authors.forename: Valentina
authors.initials: V
authors.lastname: Guarneri
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Conte
authors.forename: Paolo
authors.initials: P
authors.lastname: Paolucci
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001859:Bone Neoplasms / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D012516:Osteosarcoma / Q000473:pathology / Q000628:therapy; D012208:Rhabdomyosarcoma / Q000473:pathology / Q000628:therapy; D012509:Sarcoma / Q000473:pathology / Q000628:therapy*; D012512:Sarcoma, Ewing / Q000473:pathology / Q000628:therapy; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand
keywords: Adipose stromal/stem cells; Ewing's sarcoma; Sarcoma; TRAIL