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

R. Auvergne, C. Wu, A. Connell, S. Au, A. Cornwell, M. Osipovitch, A. Benraiss, S. Dangelmajer, H. Guerrero-Cazares, A. Quinones-Hinojosa, S. A. Goldman

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3817-3828
Number of pages12
JournalOncogene
Volume35
Issue number29
DOIs
StatePublished - Jul 21 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Auvergne, R., Wu, C., Connell, A., Au, S., Cornwell, A., Osipovitch, M., Benraiss, A., Dangelmajer, S., Guerrero-Cazares, H., Quinones-Hinojosa, A., & Goldman, S. A. (2016). PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo. Oncogene, 35(29), 3817-3828. https://doi.org/10.1038/onc.2015.452