TLR9 is critical for glioma stem cell maintenance and targeting
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 STA...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2014-09, Vol.74 (18), p.5218-5228 |
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| creator | Herrmann, Andreas Cherryholmes, Gregory Schroeder, Anne Phallen, Jillian Alizadeh, Darya Xin, Hong Wang, Tianyi Lee, Heehyoung Lahtz, Christoph Swiderski, Piotr Armstrong, Brian Kowolik, Claudia Gallia, Gary L Lim, Michael Brown, Christine Badie, Behnam Forman, Stephen Kortylewski, Marcin Jove, Richard Yu, Hua |
| description | 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. |
| doi_str_mv | 10.1158/0008-5472.CAN-14-1151 |
| format | Article |
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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. 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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.</description><subject>Animals</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Glioma - metabolism</subject><subject>Glioma - pathology</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Toll-Like Receptor 9 - metabolism</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkV1LwzAUhoMobk5_gpJLbzrz2bQ3yhh-wVCQeR3SNJ2RNp1JJvjvTdkceiUEDjnnPW_y8gBwjtEUY15cIYSKjDNBpvPZU4ZZlrr4AIwxp0UmGOOHYLzXjMBJCO_pyjHix2BEOGKCk2IMbpaLlxLaALW30WrVwqb3cNXavlMwRNNBbdoWdsq6aJxy2kDlahiVX5lo3eoUHDWqDeZsVyfg9e52OX_IFs_3j_PZItPpyZjlFRWspgYLWjaa5LmpEVFVhRUqUTp1JUxBBKWYI14TYWheVIqWiiBDClbRCbje-q43VWdqbVz0qpVrbzvlv2SvrPw7cfZNrvpPyXAumEDJ4HJn4PuPjQlRdjYM2ZQz_SZIXFBCmBA5_V_K85QAi5IkKd9Kte9D8KbZ_wgjOXCSAwM5MJCJk8Rs6OK0d_E7zn7rBwz9BpkijTw</recordid><startdate>20140915</startdate><enddate>20140915</enddate><creator>Herrmann, Andreas</creator><creator>Cherryholmes, Gregory</creator><creator>Schroeder, Anne</creator><creator>Phallen, Jillian</creator><creator>Alizadeh, Darya</creator><creator>Xin, Hong</creator><creator>Wang, Tianyi</creator><creator>Lee, Heehyoung</creator><creator>Lahtz, Christoph</creator><creator>Swiderski, Piotr</creator><creator>Armstrong, Brian</creator><creator>Kowolik, Claudia</creator><creator>Gallia, Gary L</creator><creator>Lim, Michael</creator><creator>Brown, Christine</creator><creator>Badie, Behnam</creator><creator>Forman, Stephen</creator><creator>Kortylewski, Marcin</creator><creator>Jove, Richard</creator><creator>Yu, Hua</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20140915</creationdate><title>TLR9 is critical for glioma stem cell maintenance and targeting</title><author>Herrmann, Andreas ; 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | Animals Brain Neoplasms - metabolism Brain Neoplasms - pathology Cell Line, Tumor Cell Proliferation Glioma - metabolism Glioma - pathology Humans Mice Mice, Inbred C57BL Mice, Inbred NOD Mice, SCID Toll-Like Receptor 9 - metabolism |
| title | TLR9 is critical for glioma stem cell maintenance and targeting |
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