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PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo

Oncogene volume 35, pages 3817–3828 (2016)Cite this article

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Abstract

Glioblastoma (GBM) remains the most common and lethal intracranial tumor. In a comparison of gene expression by A2B5-defined tumor-initiating progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain, we found that the F2R gene encoding PAR1 was differentially overexpressed by A2B5-sorted TPCs isolated from gliomas at all stages of malignant development. In this study, we asked if PAR1 is causally associated with glioma progression. Lentiviral knockdown of PAR1 inhibited the expansion and self-renewal of human GBM-derived A2B5+ TPCs in vitro, while pharmacological inhibition of PAR 1 similarly slowed both the growth and migration of A2B5+ TPCs in culture. In addition, PAR1 silencing potently suppressed tumor expansion in vivo, and significantly prolonged the survival of mice following intracranial transplantation of human TPCs. These data strongly suggest the importance of PAR1 to the self-renewal and tumorigenicity of A2B5-defined glioma TPCs; as such, the abrogation of PAR1-dependent signaling pathways may prove a promising strategy for gliomas.

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Acknowledgements

We thank Dr Mahlon Johnson for the histopathological validation of tumor stage, Dr Kevin Walter for arranging tissue donation and Shengtao Qu and Eric Franklin for technical assistance. This work was supported by the Dr Miriam and Sheldon G Adelson Medical Research Foundation, and by the New York State Stem Cell Research Program. Tissue collection, processing and studies on human tissue derived from Johns Hopkins University were supported by NIH R01NS070024.

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Authors and Affiliations

  1. Department of Neurology, Neurology University of Rochester Medical Center, Center for Translational Neuromedicine, Rochester, NY, USA

    R Auvergne, C Wu, A Connell, S Au, A Cornwell, M Osipovitch, A Benraiss & S A Goldman

  2. Center for Translational Neuromedicine, Neurology University of Rochester Medical Center, Rochester, NY, USA

    R Auvergne, C Wu, A Connell, S Au, A Cornwell, M Osipovitch, A Benraiss & S A Goldman

  3. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    S Dangelmajer, H Guerrero-Cazares & A Quinones-Hinojosa

  4. Center for Basic and Translational Neuroscience, University of Copenhagen, Copenhagen, Denmark

    S A Goldman

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Auvergne, R., Wu, C., Connell, A. et al. PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo. Oncogene 35, 3817–3828 (2016). https://doi.org/10.1038/onc.2015.452

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