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

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. STEM CELLS 2010;28:2217–2228

[1]  T. Lawrence,et al.  Radiation increases invasion of gene-modified mesenchymal stem cells into tumors. , 2009, International journal of radiation oncology, biology, physics.

[2]  R. Carroll,et al.  Human Bone Marrow‐Derived Mesenchymal Stromal Cells Expressing S‐TRAIL as a Cellular Delivery Vehicle for Human Glioma Therapy , 2009, Stem cells.

[3]  S. Kalkanis,et al.  ANTITUMOR TREATMENT USING INTERLEUKIN‐ 12‐SECRETING MARROW STROMAL CELLS IN AN INVASIVE GLIOMA MODEL , 2009, Neurosurgery.

[4]  S. de Jong,et al.  TRAIL receptor signalling and modulation: Are we on the right TRAIL? , 2009, Cancer treatment reviews.

[5]  A. Quiñones‐Hinojosa,et al.  Applications of neural and mesenchymal stem cells in the treatment of gliomas , 2009, Expert review of anticancer therapy.

[6]  J. Kim,et al.  Overexpression of CXC chemokine receptors is required for the superior glioma-tracking property of umbilical cord blood-derived mesenchymal stem cells. , 2009, Stem cells and development.

[7]  Ralph Weissleder,et al.  Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy , 2009, Proceedings of the National Academy of Sciences.

[8]  M. McGirt,et al.  Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. , 2009, Journal of neurosurgery.

[9]  Y. Sung,et al.  Gene therapy using TRAIL-secreting human umbilical cord blood-derived mesenchymal stem cells against intracranial glioma. , 2008, Cancer research.

[10]  A. Ashkenazi,et al.  Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/Tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  S. Goldenberg,et al.  Dissimilar Differentiation of Mesenchymal Stem Cells from Bone Marrow, Umbilical Cord Blood, and Adipose Tissue , 2008, Experimental biology and medicine.

[12]  J. Fiveash,et al.  Enhancement of glioma radiotherapy and chemotherapy response with targeted antibody therapy against death receptor 5. , 2004, International journal of radiation oncology, biology, physics.

[13]  W. Woodward,et al.  Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. , 2007, Cancer research.

[14]  G. Cohen,et al.  Barriers to effective TRAIL-targeted therapy of malignancy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  B. Scheithauer,et al.  The 2007 WHO classification of tumours of the central nervous system , 2007, Acta Neuropathologica.

[16]  H. Neumann,et al.  Bystander killing of malignant glioma by bone marrow-derived tumor-infiltrating progenitor cells expressing a suicide gene. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[17]  P. Neth,et al.  Scientific category: Stem cells in hematology MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines , 2006 .

[18]  M. Endres,et al.  Towards in situ tissue repair: Human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2 , 2007, Journal of cellular biochemistry.

[19]  A. Uccelli,et al.  Mesenchymal stem cells: a new strategy for immunosuppression? , 2007, Trends in immunology.

[20]  W. Cavenee,et al.  Synergistic cytotoxicity through the activation of multiple apoptosis pathways in human glioma cells induced by combined treatment with ionizing radiation and tumor necrosis factor-related apoptosis-inducing ligand. , 2007, Journal of neurosurgery.

[21]  Christian Schichor,et al.  Malignant gliomas actively recruit bone marrow stromal cells by secreting angiogenic cytokines , 2007, Journal of Neuro-Oncology.

[22]  C. Belka,et al.  The role of PDGF in radiation oncology , 2007, Radiation oncology.

[23]  Miao-Fen Chen,et al.  The sensitivity of human mesenchymal stem cells to ionizing radiation. , 2006, International journal of radiation oncology, biology, physics.

[24]  Hermann Eichler,et al.  Comparative Analysis of Mesenchymal Stem Cells from Bone Marrow, Umbilical Cord Blood, or Adipose Tissue , 2006, Stem cells.

[25]  S. Donaldson,et al.  Advances toward an understanding of brainstem gliomas. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  E. Chiocca,et al.  Genetic strategies for brain tumor therapy , 2006, Cancer Gene Therapy.

[27]  P. Robbins,et al.  Cancer gene therapy using a novel secretable trimeric TRAIL , 2006, Gene Therapy.

[28]  W. Ansorge,et al.  Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. , 2005, Experimental hematology.

[29]  Simon C Watkins,et al.  Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors , 2005, Cancer Gene Therapy.

[30]  M. Andreeff,et al.  Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. , 2005, Cancer research.

[31]  S. Hwang,et al.  Differential Gene Expression Profiling of Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells by DNA Microarray , 2005, Stem cells.

[32]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[33]  K. Houkin,et al.  Mesenchymal stem cells (MSC) as therapeutic cytoreagents for gene therapy , 2005, Cancer science.

[34]  C. Belka,et al.  Irradiation specifically sensitises solid tumour cell lines to TRAIL mediated apoptosis , 2005, BMC Cancer.

[35]  C. Ha,et al.  Mesenchymal stem/progenitor cells developed in cultures from UC blood. , 2004, Cytotherapy.

[36]  S. Shankar,et al.  Ionizing radiation enhances the therapeutic potential of TRAIL in prostate cancer in vitro and in vivo: Intracellular mechanisms , 2004, The Prostate.

[37]  H. Tsuda,et al.  Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model , 2004, Gene Therapy.

[38]  Ralph Weissleder,et al.  Real-time imaging of TRAIL-induced apoptosis of glioma tumors in vivo , 2003, Oncogene.

[39]  E. J. Friedman.  Immune modulation by ionizing radiation and its implications for cancer immunotherapy. , 2002, Current pharmaceutical design.

[40]  H. Fine,et al.  Antitumor activity and prolonged expression from a TRAIL-expressing adenoviral vector. , 2002, Neoplasia.

[41]  F. Tomaselli,et al.  DNA Microarray , 2002 .

[42]  I. Pollack,et al.  Direct stimulation of apoptotic signaling by soluble Apo2l/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[43]  A. Almasan,et al.  Apo2 ligand/TNF-related apoptosis-inducing ligand and death receptor 5 mediate the apoptotic signaling induced by ionizing radiation in leukemic cells. , 2000, Cancer research.

[44]  B. Davidson,et al.  Adenoviral-Mediated Transfer of the TNF-Related Apoptosis-Inducing Ligand/Apo-2 Ligand Gene Induces Tumor Cell Apoptosis1 , 2000, The Journal of Immunology.

[45]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[46]  R. Barnard,et al.  The classification of tumours of the central nervous system. , 1982, Neuropathology and applied neurobiology.