Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression.
Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression.
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DOI：
10.1016/j.stem.2016.12.001
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发表时间：
2017-04-06
期刊：
影响因子：
23.9
通讯作者：
Lathia JD
中科院分区：
文献类型：
--
作者：
Alvarado AG;Thiagarajan PS;Mulkearns-Hubert EE;Silver DJ;Hale JS;Alban TJ;Turaga SM;Jarrar A;Reizes O;Longworth MS;Vogelbaum MA;Lathia JD
肿瘤含有由异常增殖、坏死和缺氧产生的敌意炎症信号。这些信号被Toll样受体(TLRs)敏锐地感知并作用于这些信号，以阻止增殖并激活免疫反应。尽管在微环境中存在TLR配体，但肿瘤的进展，以及允许这种生长的机制在很大程度上仍不清楚。我们报道，在胶质母细胞瘤中，自我更新的癌症干细胞(CSCs)具有低TLR4的表达，这使得它们能够在不考虑炎症信号的情况下存活。非CSCs表达高水平的TLR4，并对配体作出反应。TLR4信号通过减少视网膜母细胞瘤结合蛋白5(RBBP5)而抑制CSC的特性，RBBP5在CSCs中升高。RBBP5激活核心干细胞转录因子，是自我更新的必要条件和充分条件，并被CSCs中TLR4的过表达抑制。我们的发现提供了一种机制，通过这种机制，由于无法对炎症信号做出反应，CSCs在恶劣的环境中持续存在。Alvarado等人。证明胶质母细胞瘤癌症干细胞比周围细胞表达更低水平的天然免疫受体TLR4，这使它们能够避免抑制本来会抑制自我更新的天然免疫信号。
Tumors contain hostile inflammatory signals generated by aberrant proliferation, necrosis, and hypoxia. These signals are sensed and acted upon acutely by the Toll-like receptors (TLRs) to halt proliferation and activate an immune response. Despite the presence of TLR ligands within the microenvironment, tumors progress, and the mechanisms that permit this growth remain largely unknown. We report that self-renewing cancer stem cells (CSCs) in glioblastoma have low TLR4 expression that allows them to survive by disregarding inflammatory signals. Non-CSCs express high levels of TLR4 and respond to ligands. TLR4 signaling suppresses CSC properties by reducing retinoblastoma binding protein 5 (RBBP5), which is elevated in CSCs. RBBP5 activates core stem cell transcription factors, is necessary and sufficient for self-renewal, and is suppressed by TLR4 overexpression in CSCs. Our findings provide a mechanism through which CSCs persist in hostile environments because of an inability to respond to inflammatory signals. Alvarado et al. demonstrate that glioblastoma cancer stem cells express a lower level of the innate immune receptor TLR4 than surrounding cells, which allows them to avoid inhibitory innate immune signaling that would otherwise suppress self-renewal.
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影响因子：
4
作者：
Hess, J;Angel, P;Schorpp-Kistner, M
通讯作者：
Schorpp-Kistner, M
影响因子：
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Yu H
影响因子：
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影响因子：
50.3
作者：
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通讯作者：
Schwabe RF