Endothelial secreted factors suppress mitogen deprivation-induced autophagy and apoptosis in glioblastoma stem-like cells.
Endothelial secreted factors suppress mitogen deprivation-induced autophagy and apoptosis in glioblastoma stem-like cells.
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DOI：
10.1371/journal.pone.0093505
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Gavard J
中科院分区：
文献类型：
--
作者：
Galan-Moya EM;Treps L;Oliver L;Chneiweiss H;Vallette FM;Bidère N;Gavard J
快速生长和高度血管化的肿瘤，如多形性胶质母细胞瘤，在肿瘤块内含有异质区域，其中一些区域不能有效地供应营养和氧气。虽然在这些区域中细胞死亡率升高，但仍怀疑肿瘤细胞独立于细胞外生长因子生长和存活。与此一致，胶质母细胞瘤干细胞样细胞（GSC）被发现与原位脑血管系统密切相关，因此最有可能处于受保护的微环境中。然而，在剥夺条件下的GSC的行为还没有详细探讨。使用一组14例患者来源的GSC，我们报告说，离体有丝分裂原剥夺损害自我更新能力，废除组成性激活的mTor通路，并通过自噬和凋亡级联的参与影响GSC的生存。此外，mTor途径的药理学抑制重演了有丝分裂原剥夺的情况。相反，阻断细胞凋亡或自噬，或与内皮分泌因子一起培养GSC，部分恢复了mTor通路激活并挽救了GSC存活。总的来说，我们的数据表明GSC对mTor上瘾，因为它们的生存和自我更新深深依赖于这个信号轴。因此，由于mTor在剥夺条件下和存在内皮因子的情况下控制GSC的命运，因此它可能是治疗目的的关键靶标。
Rapidly growing and highly vascularized tumors, such as glioblastoma multiforme, contain heterogeneous areas within the tumor mass, some of which are inefficiently supplied with nutrients and oxygen. While the cell death rate is elevated in such zones, tumor cells are still suspected to grow and survive independently of extracellular growth factors. In line with this, glioblastoma stem-like cells (GSCs) are found closely associated with brain vasculature in situ, and as such are most likely in a protected microenvironment. However, the behavior of GSCs under deprived conditions has not been explored in detail. Using a panel of 14 patient-derived GSCs, we report that ex vivo mitogen deprivation impaired self-renewal capability, abolished constitutive activation of the mTor pathway, and impinged on GSC survival via the engagement of autophagic and apoptotic cascades. Moreover, pharmacological inhibition of the mTor pathway recapitulated the mitogen deprivation scenario. In contrast, blocking either apoptosis or autophagy, or culturing GSCs with endothelial-secreted factors partly restored mTor pathway activation and rescued GSC survival. Overall, our data suggest that GSCs are addicted to mTor, as their survival and self-renewal are profoundly dependent on this signaling axis. Thus, as mTor governs the fate of GSCs under both deprivation conditions and in the presence of endothelial factors, it could be a key target for therapeutic purposes.
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DOI：
10.1126/science.1171643
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Discher DE;Mooney DJ;Zandstra PW
通讯作者：
Zandstra PW
影响因子：
3.7
作者：
Oliver L;Hue E;Rossignol J;Bougras G;Hulin P;Naveilhan P;Heymann D;Lescaudron L;Vallette FM
通讯作者：
Vallette FM
影响因子：
12.4
作者：
Eramo, A.;Ricci-Vitiani, L.;De Maria, R.
通讯作者：
De Maria, R.
影响因子：
3.7
作者：
Priault M;Hue E;Marhuenda F;Pilet P;Oliver L;Vallette FM
通讯作者：
Vallette FM
DOI：
10.1084/jem.20100951
发表时间：
2011-07-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Naik E;O'Reilly LA;Asselin-Labat ML;Merino D;Lin A;Cook M;Coultas L;Bouillet P;Adams JM;Strasser A
通讯作者：
Strasser A