Cellular Plasticity Confers Migratory and Invasive Advantages to a Population of Glioblastoma-Initiating Cells that Infiltrate Peritumoral Tissue§

Authors

  • Patricia Ruiz-Ontañon,

    1. Molecular Genetics Unit, Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación Marques de Valdecilla (IFIMAV), Av. Cardenal Herrera Oria s/n, Santander, Spain
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  • Jose L. Orgaz,

    1. Randall Division of Cell and Molecular Biophysics, School of Biomedical and Health Sciences, King's College London, London, United Kingdom
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  • Beatriz Aldaz,

    1. Division of Oncology, Centro para la Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain
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  • Alberto Elosegui-Artola,

    1. Centro de Estudios e Investigaciones Técnicas de Gipuzkoa (CEIT), Paseo Manuel Lardizabal 15, San Sebastián, Spain
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  • Juan Martino,

    1. Neurosurgery Service, Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación Marques de Valdecilla (IFIMAV), Av. Cardenal Herrera Oria s/n, Santander, Spain
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  • Maria T. Berciano,

    1. Department of Anatomy and Cell Biology and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), University of Cantabria-IFIMAV, Santander, Spain
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  • Juan A. Montero,

    1. Department of Anatomy and Cell Biology and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), University of Cantabria-IFIMAV, Santander, Spain
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  • Lara Grande,

    1. Molecular Genetics Unit, Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación Marques de Valdecilla (IFIMAV), Av. Cardenal Herrera Oria s/n, Santander, Spain
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  • Lorena Nogueira,

    1. Molecular Genetics Unit, Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación Marques de Valdecilla (IFIMAV), Av. Cardenal Herrera Oria s/n, Santander, Spain
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  • Santiago Diaz-Moralli,

    1. Department of Biochemistry and Molecular Biology, School of Biology, University of Barcelona, Av. Diagonal 645, Barcelona, Spain
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  • Azucena Esparís-Ogando,

    1. Centro de Investigación del Cáncer (CIC), Campus Miguel de Unamuno, Salamanca, Spain
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  • Alfonso Vazquez-Barquero,

    1. Neurosurgery Service, Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación Marques de Valdecilla (IFIMAV), Av. Cardenal Herrera Oria s/n, Santander, Spain
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  • Miguel Lafarga,

    1. Department of Anatomy and Cell Biology and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), University of Cantabria-IFIMAV, Santander, Spain
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  • Atanasio Pandiella,

    1. Centro de Investigación del Cáncer (CIC), Campus Miguel de Unamuno, Salamanca, Spain
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  • Marta Cascante,

    1. Department of Biochemistry and Molecular Biology, School of Biology, University of Barcelona, Av. Diagonal 645, Barcelona, Spain
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  • Victor Segura,

    1. Bioinformatics Unit, Centro para la Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain
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  • Jose A. Martinez-Climent,

    1. Division of Oncology, Centro para la Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain
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  • Victoria Sanz-Moreno,

    1. Randall Division of Cell and Molecular Biophysics, School of Biomedical and Health Sciences, King's College London, London, United Kingdom
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  • Jose L. Fernandez-Luna

    Corresponding author
    1. Molecular Genetics Unit, Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación Marques de Valdecilla (IFIMAV), Av. Cardenal Herrera Oria s/n, Santander, Spain
    • Molecular Genetics Unit, Hospital Valdecilla-IFIMAV, Av Cardenal Herrera Oria s/n, Santander 39011, Spain
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    • Telephone: +34-942-315271


  • Author contributions: P.R.-O.: collection of data and data analysis and interpretation; J.L.O.: collection of data and provision of study material; B.A., A.E.-A., M.T.B., J.A.M., L.G., L.N., S.D., and A.E.-O.: collection of data; J.M. and A.V.-B.: collection of data and provision of study patients; M.L., A.P., J.A.M.-C., and M.C.: data analysis and interpretation; V.S.: assembly of data; V.S.-M.: conception and design and data analysis and interpretation; J.L.F.-L.: conception and design, data analysis and interpretation, and manuscript writing.

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

  • §

    first published online in STEM CELLS EXPRESS February 8, 2013.

Abstract

Glioblastoma (GBM) is associated with infiltration of peritumoral (PT) parenchyma by isolated tumor cells that leads to tumor regrowth. Recently, GBM stem-like or initiating cells (GICs) have been identified in the PT area, but whether these GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass (TM) is presently unknown. We isolated GICs from the infiltrated PT tissue and the TM of three patients and found that PT cells have an advantage over TM cells in two-dimensional and three-dimensional migration and invasion assays. Interestingly, PT cells display a high plasticity in protrusion formation and cell shape and their migration is insensitive to substrate stiffness, which represent advantages to infiltrate microenvironments of different rigidity. Furthermore, mouse and chicken embryo xenografts revealed that only PT cells showed a dispersed distribution pattern, closely associated to blood vessels. Consistent with cellular plasticity, simultaneous Rac and RhoA activation are required for the enhanced invasive capacity of PT cells. Moreover, Rho GTPase signaling modulators αVβ3 and p27 play key roles in GIC invasiveness. Of note, p27 is upregulated in TM cells and inhibits RhoA activity. Gene silencing of p27 increased the invasive capacity of TM GICs. Additionally, β3 integrin is upregulated in PT cells. Blockade of dimeric integrin αVβ3, a Rac activator, reduced the invasive capacity of PT GICs in vitro and abrogated the spreading of PT cells into chicken embryos. Thus, our results describe the invasive features acquired by a unique subpopulation of GICs that infiltrate neighboring tissue. STEM Cells 2013;31:1075–1085

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