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Cancer Res. 2014 Sep 15;74(18):5218-28. doi: 10.1158/0008-5472.CAN-14-1151. Epub 2014 Jul 21.

TLR9 is critical for glioma stem cell maintenance and targeting.

Author information

1
Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
2
Department of Molecular Medicine, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
3
Department of Neurosurgery at the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Division of Neurosurgery, City of Hope Medical Center, Duarte, California.
5
Department of Neuroscience, Beckman Research Institute at City of Hope Medical Center, Duarte, California.
6
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, California.
7
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.

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.

PMID:
25047528
PMCID:
PMC4167470
DOI:
10.1158/0008-5472.CAN-14-1151
[Indexed for MEDLINE]
Free PMC Article
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