TLR4 interaction with LPS in glioma CD133+ cancer stem cells induces cell proliferation, resistance to chemotherapy and evasion from cytotoxic T lymphocyte-induced cytolysis.

Fengyuan Che,Yifeng Du,Xiaoli Xie,Yanchun Quan,Xueyuan Heng,Jiawei Yin,Lijuan Wang

doi:10.18632/oncotarget.18586

Fengyuan Che, Yifeng Du + Show 5 more

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https://doi.org/10.18632/oncotarget.18586

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Abstract

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.

Highlights

Gliomas account for approximately 80% of all malignant primary central nervous system tumors [1, 2]
Because overexpression of toll-like receptor 4 (TLR4) correlated with cancer development, we investigated LPS-induced TLR4 signaling in glioma CD133-positive (CD133+) cancer stem cells (CSCs)
We investigated the expression of TLR4 in human glioma CD133+ CSCs isolated from six CSCs derived from two glioma cell lines, SF295 and U251, and four fresh human surgical glioma tissues, patient 1 to pT4

Summary

Introduction

Gliomas account for approximately 80% of all malignant primary central nervous system tumors [1, 2]. Progress has been made in treatment modalities such as surgery, chemotherapy, and radiotherapy, recurrence after standard therapies is inevitable, and the median survival of patients with high-grade gliomas is no more than 14 months [5, 6]. CSCs are www.impactjournals.com/oncotarget undifferentiated cells within tumors that possess high tumorigenic activity and the capacity to self-renew and undergo multilineage differentiation [9,10,11]. Evidence indicates that malignant glioma CSCs induce cancer and promote cancer development [16, 17]. Glioma CSCs promote cancer resistance to treatment and recurrence, leading to high mortality [18]. Most reports define CD133positivity (CD133+) as a marker of glioma CSCs [19,20,21]

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