Merck

TLR9 is critical for glioma stem cell maintenance and targeting.

Cancer research (2014-07-23)
Andreas Herrmann, Gregory Cherryholmes, Anne Schroeder, Jillian Phallen, Darya Alizadeh, Hong Xin, Tianyi Wang, Heehyoung Lee, Christoph Lahtz, Piotr Swiderski, Brian Armstrong, Claudia Kowolik, Gary L Gallia, Michael Lim, Christine Brown, Behnam Badie, Stephen Forman, Marcin Kortylewski, Richard Jove, Hua Yu
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.

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