Human Bone Marrow-Derived Mesenchymal Stem Cells Suppress Human Glioma Growth Through Inhibition of Angiogenesis§

Authors

  • Ivy A.W. Ho,

    1. Laboratory of Cancer Gene TherapyHumphrey Oei Institute of Cancer Research, National Cancer Center, Singapore
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  • Han C Toh,

    1. Laboratory of Cell Therapy and Cancer VaccineHumphrey Oei Institute of Cancer Research, National Cancer Center, Singapore
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  • Wai H. Ng,

    1. Department of Neurosurgery, National Neuroscience Institute, Singapore
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  • Yuan L. Teo,

    1. Laboratory of Cancer Gene TherapyHumphrey Oei Institute of Cancer Research, National Cancer Center, Singapore
    2. National Institute of Education, Singapore
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  • Chang M. Guo,

    1. Department of Orthopedic, Singapore General Hospital, Singapore
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  • Kam M. Hui,

    1. Bek Chai Heah Laboratory of Cancer Genomics, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore
    2. Cancer and Stem Cells Biology Program, Duke-NUS Graduate Medical School, Singapore
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  • Paula Y.P. Lam

    Corresponding author
    1. Laboratory of Cancer Gene TherapyHumphrey Oei Institute of Cancer Research, National Cancer Center, Singapore
    2. Department of Physiology, National University of Singapore, Singapore
    3. Cancer and Stem Cells Biology Program, Duke-NUS Graduate Medical School, Singapore
    • Laboratory of Cancer Gene Therapy, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11, Hospital Drive, Singapore 169610, Singapore
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    • Telephone: 65-64368357; Fax: 65-62265694


  • Author contributions: I.A.W.H.: conception and design, data analysis and interpretation, and manuscript writing; H.C.T., C.M.G., and W.H.N: provision of study material; Y.L.T.: collection and assembly of data; K.M.H.: administrative support; P.Y.P.L.: conception and design, data analysis and interpretation, manuscript writing, financial support, and final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS October 3, 2012.

Abstract

Tumor tropism of human bone marrow-derived mesenchymal stem cells (MSC) has been exploited for the delivery of therapeutic genes for anticancer therapy. However, the exact contribution of these cells in the tumor microenvironment remains unknown. In this study, we examined the biological effect of MSC on tumor cells. The results showed that MSC inhibited the growth of human glioma cell lines and patient-derived primary glioma cells in vitro. Coadministration of MSC and glioma cells resulted in significant reduction in tumor volume and vascular density, which was not observed when glioma was injected with immortalized normal human astrocytes. Using endothelial progenitor cells (EPC) from healthy donors and HUVEC endothelial cells, the extent of EPC recruitment and capacity to form endothelial tubes was significantly impaired in conditioned media derived from MSC/glioma coculture, suggesting that MSC suppressed tumor angiogenesis through the release of antiangiogenic factors. Further studies using antibody array showed reduced expression of platelet-derived growth factor (PDGF)-BB and interleukin (IL)-1β in MSC/glioma coculture when compared with controls. In MSC/glioma coculture, PDGF-BB mRNA and the corresponding proteins (soluble and membrane bound forms) as well as the receptors were found to be significantly downregulated when compared with that of glioma cocultured with normal human astrocytes or glioma monoculture. Furthermore, IL-1β, phosphorylated Akt, and cathepsin B proteins were also reduced in MSC/glioma. Taken together, these data indicated that the antitumor effect of MSC may be mediated through downregulation of PDGF/PDGFR axis, which is known to play a key role in glioma angiogenesis. STEM Cells2013;31:146–155

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