title: Cancer stem cell-specific scavenger receptor CD36 drives glioblastoma progression.
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.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Hale
authors.forename: Balint
authors.initials: B
authors.lastname: Otvos
authors.forename: Maksim
authors.initials: M
authors.lastname: Sinyuk
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Alvarado
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hitomi
authors.forename: Kevin
authors.initials: K
authors.lastname: Stoltz
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Wu
authors.forename: William
authors.initials: W
authors.lastname: Flavahan
authors.forename: Bruce
authors.initials: B
authors.lastname: Levison
authors.forename: Mette L
authors.initials: ML
authors.lastname: Johansen
authors.forename: David
authors.initials: D
authors.lastname: Schmitt
authors.forename: Janna M
authors.initials: JM
authors.lastname: Neltner
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.forename: Bin
authors.initials: B
authors.lastname: Ren
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Sloan
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
authors.forename: Candece L
authors.initials: CL
authors.lastname: Gladson
authors.forename: Joseph A
authors.initials: JA
authors.lastname: DiDonato
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown
authors.forename: Thomas
authors.initials: T
authors.lastname: McIntyre
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008077:Lipoproteins, LDL / Q000502:physiology; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D018955:CD36 Antigens; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein
keywords: Cancer stem cells; Glioma; Self-renewal; Stem cell-microenvironment interactions
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