title: TLR9 is critical for glioma stem cell maintenance and targeting.
abstract: Understanding supports for cancer stem-like cells in malignant glioma may suggest therapeutic strategies for their elimination. Here, we show that the Toll-like receptor TLR9 is elevated in glioma stem-like cells (GSC) in which it contributes to glioma growth. TLR9 overexpression is regulated by STAT3, which is required for GSC maintenance. Stimulation of TLR9 with a CpG ligand (CpG ODN) promoted GSC growth, whereas silencing TLR9 expression abrogated GSC development. CpG-ODN treatment induced Frizzled4-dependent activation of JAK2, thereby activating STAT3. Targeted delivery of siRNA into GSC was achieved via TLR9 using CpG-siRNA conjugates. Through local or systemic treatment, administration of CpG-Stat3 siRNA to silence STAT3 in vivo reduced GSC along with glioma growth. Our findings identify TLR9 as a functional marker for GSC and a target for the delivery of efficacious therapeutics for glioma treatment. Cancer Res; 74(18); 5218-28. ©2014 AACR.
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
authors.forename: Gregory
authors.initials: G
authors.lastname: Cherryholmes
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
authors.forename: Anne
authors.initials: A
authors.lastname: Schroeder
authors.affiliation: Department of Neurosurgery at the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jillian
authors.initials: J
authors.lastname: Phallen
authors.affiliation: Division of Neurosurgery, City of Hope Medical Center, Duarte, California.
authors.forename: Darya
authors.initials: D
authors.lastname: Alizadeh
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
authors.forename: Heehyoung
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lahtz
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
authors.forename: Piotr
authors.initials: P
authors.lastname: Swiderski
authors.affiliation: Department of Neuroscience, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
authors.forename: Brian
authors.initials: B
authors.lastname: Armstrong
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kowolik
authors.affiliation: Department of Neurosurgery at the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Gallia
authors.affiliation: Department of Neurosurgery at the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: Lim
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, California.
authors.forename: Christine
authors.initials: C
authors.lastname: Brown
authors.affiliation: Division of Neurosurgery, City of Hope Medical Center, Duarte, California.
authors.forename: Behnam
authors.initials: B
authors.lastname: Badie
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, California.
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope Medical Center, Duarte, California. Center for Translational Medicine, Shanghai Zhangjiang High-Tech Park, Shanghai, China. hyu@coh.org.
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9