Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy.
Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy.
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DOI：
10.1101/gad.235515.113
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发表时间：
2014-05-15
影响因子：
10.5
通讯作者：
Rich JN
中科院分区：
文献类型：
--
作者：
Yan K;Wu Q;Yan DH;Lee CH;Rahim N;Tritschler I;DeVecchio J;Kalady MF;Hjelmeland AB;Rich JN
In glioblastomas, cancer stem cells (CSCs) reside in functional niches that provide essential cues to maintain the cellular hierarchy. Bone morphogenetic proteins (BMPs) are proposed as anti-CSC therapies to induce differentiation, but, paradoxically, tumors express high levels of BMPs. Yan et al. demonstrate that the BMP antagonist Gremlin1 is specifically expressed by CSCs as protection from endogenous BMPs. Gremlin1-overexpressing cells display increased growth and tumor formation, while targeting Gremlin1 in CSCs impairs growth and self-renewal associated with inhibition of p21WAF1/CIP1, a key CSC signaling node. Glioblastomas are the most prevalent and lethal primary brain tumor and are comprised of hierarchies with self-renewing cancer stem cells (CSCs) at the apex. Like neural stem cells (NSCs), CSCs reside in functional niches that provide essential cues to maintain the cellular hierarchy. Bone morphogenetic proteins (BMPs) instruct NSCs to adopt an astrocyte fate and are proposed as anti-CSC therapies to induce differentiation, but, paradoxically, tumors express high levels of BMPs. Here we demonstrate that the BMP antagonist Gremlin1 is specifically expressed by CSCs as protection from endogenous BMPs. Gremlin1 colocalizes with CSCs in vitro and in vivo. Furthermore, Gremlin1 blocks prodifferentiation effects of BMPs, and overexpression of Gremlin1 in non-CSCs decreases their endogenous BMP signaling to promote stem-like features. Consequently, Gremlin1-overexpressing cells display increased growth and tumor formation abilities. Targeting Gremlin1 in CSCs results in impaired growth and self-renewal. Transcriptional profiling demonstrated that Gremlin1 effects were associated with inhibition of p21WAF1/CIP1, a key CSC signaling node. This study establishes CSC-derived Gremlin1 as a driving force in maintaining glioblastoma tumor proliferation and glioblastoma hierarchies through the modulation of endogenous prodifferentiation signals.
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影响因子：
64.5
作者：
Eyler CE;Wu Q;Yan K;MacSwords JM;Chandler-Militello D;Misuraca KL;Lathia JD;Forrester MT;Lee J;Stamler JS;Goldman SA;Bredel M;McLendon RE;Sloan AE;Hjelmeland AB;Rich JN
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影响因子：
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影响因子：
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