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

Abstract

Irradiation is a standard therapy for gliomas and many other cancers. Tumor necrosis factor-related apoptosisinducing 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 UCBMSCs. 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 UCBMSCs, was confirmed by siRNA inhibition and an antibodyneutralizing 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. STEM CELLS

Application of Stem Cells in Targeted Therapy of Breast Cancer: A Systematic Review

“…might be achieved using repeated dose of MSC-NIS and radioiodide, as other studies have demonstrated that tumor irradiation stimulates increased MSC engraftment (Klopp et al, 2007;Spaeth et al, 2008;Zielske et al, 2009;Kim et al, 2010). This approach may cause greater stimulation of MSC engraftment in remaining disease and could be applied as an effective treatment in metastatic cancer.…”

In vivo near-infrared imaging for the tracking of systemically delivered mesenchymal stem cells: tropism for brain tumors and biodistribution

“…Several therapeutic strategies for gene delivery by engineered MSCs have been developed using herpes simplex virus thymidine kinase, interferons, interleukins, apoptosis-inducing agents, or oncolytic viruses, and these engineered cells exhibit potent antitumor activity. [7][8][9][10][11][12] However, several issues remain to be clarified before the clinical application of MSC-based gene therapy for the treatment of glioma, including questions about cell survival, migration, and distribution after transplantation. An appropriate in vivo imaging tool to evaluate the biology of transplanted cells in association with the therapeutic effects of gene therapy using MSCs is needed.…”

Synergistic effect of TRAIL and irradiation in elimination of glioblastoma stem-like cells

“…Moreover, it is very interesting that the expression of DR5 was much lower in GSLCs compared to non-GSLCs as previously reported [23]. Since TRAIL-induced apoptosis is mainly through TRAIL/DR5 pathway, low expression of DR5 could directly lead to TRAIL insensitivity [25], and this is probably the primary reason for TRAIL resistance in GSLCs. Considering that DR5 was expressed fairly low in GSLCs and could sharply increase after irradiation, the combined TRAIL with irradiation achieved the maximum killing effect on GSLCs.…”

“…To the best of our knowledge, this is the first comprehensive report on the study of the synergistic effects of TRAIL and X-ray on elimination of GSLCs [25,28]. GSLC was the most vicious cell type in GBM cells, involving in treatment resistance and recurrence of GBMs [2,5].…”

“…For TRAIL alone group and IR alone group, cells were harvested 48 h after treatment for protein extraction or apoptosis measurement. For TRAIL combined IR group, cells were treated with TRAIL 24 h after irradiation and harvested for experiments 48 h after irradiation [25].…”