TLR4 interaction with LPS in glioma CD133+ cancer stem cells induces cell proliferation, resistance to chemotherapy and evasion from cytotoxic T lymphocyte-induced cytolysis
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Fengyuan Che1,2,3, Jiawei Yin2, Yanchun Quan2, Xiaoli Xie2, Xueyuan Heng4, Yifeng Du1 and Lijuan Wang2,5
1Department of Neurology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong Province, China
2Central Laboratory, Linyi People’s Hospital, Shandong University, Linyi, Shandong Province, China
3Department of Neurology, Linyi People’s Hospital, Shandong University, Linyi, Shandong Province, China
4Department of Neurosurgery, Linyi People’s Hospital, Shandong University, Linyi, Shandong Province, China
5Department of Hematology, Linyi People’s Hospital, Shandong University, Linyi, Shandong Province, China
Lijuan Wang, email: email@example.com
Yifeng Du, email: firstname.lastname@example.org
Keywords: glioma cancer stem cells, CD133-positive, toll-like receptor 4, cytotoxic T lymphocyte, immune evasion
Received: March 04, 2017 Accepted: May 22, 2017 Published: June 21, 2017
Despite advances in treatment modalities, 5-year survival among glioma patients remains poor. Glioma cancer stem cells (CSCs) exhibit high tumorigenic activity and are associated with resistance to treatment and tumor recurrence. Because overexpression of toll-like receptor 4 (TLR4) correlated with cancer development, we investigated LPS-induced TLR4 signaling in glioma CD133-positive (CD133+) CSCs. The proliferation of CD133+ CSCs isolated from CSCs derived from the U251 and SF295 glioma cell lines and from human glioma samples was upregulated on a time- and concentration-dependent basis by LPS stimulation, with increases in CD133, NANOG, and NESTIN mRNA and protein levels. Also elevated was cytokine expression, which was coupled to phosphorylation of mitogen-activated protein kinase, and activation of cyclins and cyclin-dependent kinase complexes. TLR4 knockdown reduced LPS-induced CD133+ CSC proliferation, whereas Adriamycin-induced CD133+ CSC apoptosis was moderately inhibited by treatment with LPS, implying a protective effect of LPS. The capacity of glioma CD133+ CSC-reactive cytotoxic T lymphocyte to selectively kill CD133+ CSCs was reduced by LPS, and this effect was not apparent after TLR4 knockdown in CD133+ CSCs. These data suggest TLR4 signaling is a factor in CD133+ CSC immune evasion, and thus disruption of TLR4 signaling is a potential therapeutic strategy in glioma.
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