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TLR9 Is Critical for Glioma Stem Cell Maintenance and Targeting

TLR9 Is Critical for Glioma Stem Cell Maintenance and Targeting CANCER RESEARCH Herrmann, A., Cherryholmes, G., Schroeder, A., Phallen, J., Alizadeh, D., Xin, H., Wang, T., Lee, H., Lahtz, C., Swiderski, P., Armstrong, B., Kowolik, C., Gallia, G. L., Lim, M., Brown, C., Badie, B., Forman, S., Kortylewski, M., Jove, R., Yu, H. 2014; 74 (18): 5218–28

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.

View details for DOI 10.1158/0008-5472.CAN-14-1151

View details for Web of Science ID 000342358300024

View details for PubMedID 25047528

View details for PubMedCentralID PMC4167470