Irradiation enhances the tumor tropism and therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand-secreting human umbilical cord blood-derived mesenchymal stem cells in glioma therapy

Stem Cells. 2010 Dec;28(12):2217-28. doi: 10.1002/stem.543.


Irradiation is a standard therapy for gliomas and many other cancers. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for cancer gene therapy. Here, we show that tumor irradiation enhances the tumor tropism of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) and the therapeutic effect of TRAIL delivered by UCB-MSCs. The sequential treatment with irradiation followed by TRAIL-secreting UCB-MSCs (MSC-TRAIL) synergistically enhanced apoptosis in either TRAIL-sensitive or TRAIL-resistant glioma cells by upregulating the death receptor 5 and by inducing caspase activation. Migration assays showed greater MSC migration toward irradiated glioma cells and the tumor site in glioma-bearing mice compared with unirradiated tumors. Irradiated glioma cells had increased expression of interleukin-8 (IL-8), which leads to the upregulation of the IL-8 receptor on MSCs. This upregulation, which is involved in the migratory capacity of UCB-MSCs, was confirmed by siRNA inhibition and an antibody-neutralizing assay. In vivo survival experiments in orthotopic xenografted mice showed that MSC-based TRAIL gene delivery to irradiated tumors had greater therapeutic efficacy than a single treatment. These results suggest that clinically relevant tumor irradiation increases the therapeutic efficacy of MSC-TRAIL by increasing tropism of MSCs and TRAIL-induced apoptosis, which may be a more useful strategy for cancer gene therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspases / metabolism
  • Cell Death / drug effects
  • Cell Death / radiation effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / radiation effects
  • Combined Modality Therapy
  • Enzyme Activation / drug effects
  • Enzyme Activation / radiation effects
  • Gamma Rays*
  • Glioma / enzymology
  • Glioma / pathology
  • Glioma / radiotherapy
  • Glioma / therapy*
  • Humans
  • Interleukin-8 / metabolism
  • Male
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism*
  • Mesenchymal Stem Cells / radiation effects
  • Mice
  • Mice, Nude
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Recombinant Proteins / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Tropism / drug effects
  • Tropism / radiation effects*
  • Umbilical Cord / cytology*
  • Up-Regulation / drug effects
  • Up-Regulation / radiation effects
  • Xenograft Model Antitumor Assays


  • Interleukin-8
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • Caspases