Cancer Stem Cell-Specific Scavenger Receptor CD36 Drives Glioblastoma Progression

Author:

Hale James S.1,Otvos Balint1,Sinyuk Maksim1,Alvarado Alvaro G.12,Hitomi Masahiro12,Stoltz Kevin1,Wu Qiulian3,Flavahan William3,Levison Bruce1,Johansen Mette L.1,Schmitt David1,Neltner Janna M.4,Huang Ping5,Ren Bin6,Sloan Andrew E.78,Silverstein Roy L.6,Gladson Candece L.248,DiDonato Joseph A.1,Brown J. Mark12,McIntyre Thomas12,Hazen Stanley L.12,Horbinski Craig4,Rich Jeremy N.238,Lathia Justin D.128

Affiliation:

1. Department of Cellular and Molecular Medicine Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA

2. Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA

3. Department of Stem Cell Biology and Regenerative Medicine Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA

4. Department of Pathology University of Kentucky, Lexington, Kentucky, USA

5. Department of Cancer Biology Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA

6. Department of Medicine Medical College of Wisconsin, Milwaukee, Wisconsin, USA

7. Department of Neurological Surgery University Hospitals, Cleveland, Ohio, USA

8. Case Comprehensive Cancer Center, Cleveland, Ohio, USA

Abstract

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

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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