Cancer stem cell-specific scavenger receptor 36 drives glioblastoma progression

James S. Hale, Balint Otvos, Maksim Sinyuk, Alvaro G. Alvarado, Masahiro Hitomi, Kevin Stoltz, Qiulian Wu, William Flavahan, Bruce Levison, Mette L. Johansen, David Schmitt, Janna M. Neltner, Ping Huang, Bin Ren, Andrew E. Sloan, Roy L. Silverstein, Candece L. Gladson, Joseph A. Didonato, J. Mark Brown, Thomas McIntyreStanley L. Hazen, Craig Horbinski, Jeremy N. Rich, Justin D. Lathia*

*Corresponding author for this work

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Glioblastoma (GBM) contains a self-renewing, tumorigenic cancer stem cell (CSC) population which contributes to tumor propagation and therapeutic resistance. While the tumor microenvironment is essential to CSC self-renewal, the mechanisms by which CSCs sense and respond to microenvironmental conditions are poorly understood. Scavenger receptors are a broad class of membrane receptors well characterized on immune cells and instrumental in sensing apoptotic cellular debris and modified lipids. Here, we provide evidence that CSCs selectively use the scavenger receptor CD36 to promote their maintenance using patient-derived CSCs and in vivo xenograft models. CD36 expression was observed in GBM cells in addition to previously described cell types including endothelial cells, macrophages, and microglia. CD36 was enriched in CSCs and was able to functionally distinguish self-renewing cells. CD36 was coexpressed with integrin alpha 6 and CD133, previously described CSC markers, and CD36 reduction resulted in concomitant loss of integrin alpha 6 expression, self-renewal, and tumor initiation capacity. We confirmed oxidized phospholipids, ligands of CD36, were present in GBM and found that the proliferation of CSCs, but not non-CSCs, increased with exposure to oxidized low-density lipoprotein. CD36 was an informative biomarker of malignancy and negatively correlated to patient prognosis. These results provide a paradigm for CSCs to thrive by the selective enhanced expression of scavenger receptors, providing survival, and metabolic advantages. Stem Cells 2014;32:1746-1758

Original languageEnglish (US)
Pages (from-to)1746-1758
Number of pages13
JournalStem Cells
Volume32
Issue number7
DOIs
StatePublished - Jul 2014

Keywords

  • Cancer stem cells
  • Glioma
  • Self-renewal
  • Stem cell-microenvironment interactions

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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    Hale, J. S., Otvos, B., Sinyuk, M., Alvarado, A. G., Hitomi, M., Stoltz, K., Wu, Q., Flavahan, W., Levison, B., Johansen, M. L., Schmitt, D., Neltner, J. M., Huang, P., Ren, B., Sloan, A. E., Silverstein, R. L., Gladson, C. L., Didonato, J. A., Brown, J. M., ... Lathia, J. D. (2014). Cancer stem cell-specific scavenger receptor 36 drives glioblastoma progression. Stem Cells, 32(7), 1746-1758. https://doi.org/10.1002/stem.1716