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Laminin alpha 2 enables glioblastoma stem cell growth

Authors

  • Justin D. Lathia PhD,

    Corresponding author
    1. Departments of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
    2. Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
    3. Department of Molecular Medicine, University Hospital–Case Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
    • Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, NC 10, Cleveland, OH 44195
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  • Meizhang Li PhD,

    1. Departments of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
    2. Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • Peter E. Hall MBBS, PhD,

    1. Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • Joseph Gallagher BS,

    1. Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • James S. Hale PhD,

    1. Departments of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • Qiulian Wu DDS,

    1. Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • Monica Venere PhD,

    1. Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • Emily Levy BS,

    1. Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • M.R. Sandhya Rani PhD,

    1. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • Ping Huang PhD,

    1. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • Eunnyung Bae PhD,

    1. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • Julia Selfridge BS,

    1. Department of Neurology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA
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  • Lin Cheng PhD,

    1. Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • Hacer Guvenc MD,

    1. Department of Neurological Surgery, James Comprehensive Cancer Center, Ohio State University, Columbus, OH
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  • Roger E. McLendon MD,

    1. Department of Pathology, Duke University Medical Center, Durham, NC
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  • Ichiro Nakano MD, PhD,

    1. Department of Neurological Surgery, James Comprehensive Cancer Center, Ohio State University, Columbus, OH
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  • Andrew E. Sloan MD,

    1. Department of Molecular Medicine, University Hospital–Case Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
    2. Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
    3. Departments of Neurological Surgery, Pathology, and Translational Neuroscience, University Hospital–Case Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
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  • Heidi S. Phillips PhD,

    1. Genetech, South San Francisco, CA
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  • Albert Lai MD, PhD,

    1. Department of Neurology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA
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  • Candece L. Gladson MD,

    1. Department of Molecular Medicine, University Hospital–Case Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
    2. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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  • Markus Bredel MD, PhD,

    1. Department of Radiation Oncology, University of Alabama Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL
    2. Department of Neurosurgery, Neurocenter and Comprehensive Cancer Center, University of Freiburg, Freiburg, Germany
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  • Shideng Bao PhD,

    1. Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
    2. Department of Molecular Medicine, University Hospital–Case Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
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  • Anita B. Hjelmeland PhD,

    1. Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
    2. Department of Molecular Medicine, University Hospital–Case Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
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  • Jeremy N. Rich MD, MHSc

    Corresponding author
    1. Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
    2. Department of Molecular Medicine, University Hospital–Case Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH
    • Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, NE 30, Cleveland, OH 44195
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Abstract

Objective:

Glioblastomas (GBMs) are lethal cancers that display cellular hierarchies parallel to normal brain. At the apex are GBM stem cells (GSCs), which are relatively resistant to conventional therapy. Interactions with the adjacent perivascular niche are an important driver of malignancy and self-renewal in GSCs. Extracellular matrix (ECM) cues instruct neural stem/progenitor cell–niche interactions, and the objective of our study was to elucidate its composition and contribution to GSC maintenance in the perivascular niche.

Methods:

We interrogated human tumor tissue for immunofluorescence analysis and derived GSCs from tumor tissues for functional studies. Bioinformatics analyses were conducted by mining publicly available databases.

Results:

We find that laminin ECM proteins are localized to the perivascular GBM niche and inform negative patient prognosis. To identify the source of laminins, we characterized cellular elements within the niche and found that laminin α chains were expressed by nonstem tumor cells and tumor-associated endothelial cells (ECs). RNA interference targeting laminin α2 inhibited GSC growth and self-renewal. In co-culture studies of GSCs and ECs, laminin α2 knockdown in ECs resulted in decreased tumor growth.

Interpretation:

Our studies highlight the contribution of nonstem tumor cell-derived laminin juxtracrine signaling. As laminin α2 has recently been identified as a molecular marker of aggressive ependymoma, we propose that the brain vascular ECM promotes tumor malignancy through maintenance of the GSC compartment, providing not only a molecular fingerprint but also a possible therapeutic target. ANN NEUROL 2012;72:766–778

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