Mesenchymal progenitors expressing TRAIL induce apoptosis in sarcomas

Giulia Grisendi, Carlotta Spano, Naomi D'Souza, Valeria Rasini, Elena Veronesi, Malvina Prapa, Tiziana Petrachi, Serena Piccinno, Filippo Rossignoli, Jorge S. Burns, Stefania Fiorcari, Donatella Granchi, Nicola Baldini, Edwin M. Horwitz, Valentina Guarneri, Pierfranco Conte, Paolo Paolucci, Massimo Dominici

Research output: Contribution to journalArticlepeer-review

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. Stem Cells 2015;33:859-869

Original languageEnglish
Pages (from-to)859-869
Number of pages11
JournalStem Cells
Volume33
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

Keywords

  • Adipose stromal/stem cells
  • Ewing's sarcoma
  • Sarcoma
  • TRAIL

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine
  • Medicine(all)

Fingerprint

Dive into the research topics of 'Mesenchymal progenitors expressing TRAIL induce apoptosis in sarcomas'. Together they form a unique fingerprint.

Cite this