title: Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression.
abstract: Tumors contain hostile inflammatory signals generated by aberrant proliferation, necrosis, and hypoxia. These signals are sensed and acted upon acutely by the Toll-like receptors (TLRs) to halt proliferation and activate an immune response. Despite the presence of TLR ligands within the microenvironment, tumors progress, and the mechanisms that permit this growth remain largely unknown. We report that self-renewing cancer stem cells (CSCs) in glioblastoma have low TLR4 expression that allows them to survive by disregarding inflammatory signals. Non-CSCs express high levels of TLR4 and respond to ligands. TLR4 signaling suppresses CSC properties by reducing retinoblastoma binding protein 5 (RBBP5), which is elevated in CSCs. RBBP5 activates core stem cell transcription factors, is necessary and sufficient for self-renewal, and is suppressed by TLR4 overexpression in CSCs. Our findings provide a mechanism through which CSCs persist in hostile environments because of an inability to respond to inflammatory signals.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Alvarado
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Praveena S
authors.initials: PS
authors.lastname: Thiagarajan
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Mulkearns-Hubert
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Silver
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Hale
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Alban
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Soumya M
authors.initials: SM
authors.lastname: Turaga
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Awad
authors.initials: A
authors.lastname: Jarrar
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
authors.forename: Ofer
authors.initials: O
authors.lastname: Reizes
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Longworth
authors.affiliation: Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Vogelbaum
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA; Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA. Electronic address: lathiaj@ccf.org.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000066673:Cell Self Renewal / Q000276:immunology*; D004268:DNA-Binding Proteins; D005260:Female; D005909:Glioblastoma / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D051379:Mice; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C470552:RBBP5 protein, human; D051197:Toll-Like Receptor 4; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human
keywords: RBBP5; TLR4; cancer stem cells; glioblastoma; innate immunity; pluripotency transcription factors