Autocrine/Paracrine Sphingosine-1-Phosphate Fuels Proliferative and Stemness Qualities of Glioblastoma Stem Cells
Autocrine/Paracrine Sphingosine-1-Phosphate Fuels Proliferative and Stemness Qualities of Glioblastoma Stem Cells
复制标题
DOI：
10.1002/glia.22718
复制
发表时间：
2014-12-01
期刊：
影响因子：
6.2
通讯作者：
Riboni, Laura
中科院分区：
文献类型：
--
作者：
Marfia, Giovanni;Campanella, Rolando;Riboni, Laura
越来越多的报道表明，人类胶质母细胞瘤含有胶质瘤干细胞(GSCs)，GSCs是驱动肿瘤生长、血管生成和治疗耐药的关键决定因素。参与GSC增殖和进展的增殖信号尚不清楚。使用不同增殖指数和干细胞标记物表达的人脑胶质母细胞瘤GSC系，我们评估了神经鞘氨醇-1-磷酸(S1P)影响神经干细胞增殖和干性的假说。代谢研究结果表明，GSC迅速消耗新合成的神经酰胺，并在细胞外环境中输出S1P，这两个过程在表现出高增殖指数和茎标记的细胞中都得到增强。胞外S1P水平达到NM浓度是对胞外鞘氨醇增加的反应。此外，EGF和bFGF的存在增强了GSCs快速分泌新合成S1P的构成能力，提示S1P与这些生长因子之间的协同作用在GSCs的维持和增殖中起着核心作用。我们还首次报道了S1P能够作为GSCs的增殖和促干性自分泌因子，促进其细胞周期进程和干性表型。这些结果首次表明，GSC种群受到微环境S1P的关键调控，这种生物活性脂质充当自分泌信号，维持亲茎环境，有利于GSC的增殖、存活和茎的特性。Glia 2014；62：1968-1981主要观点GSC可以快速有效地在细胞外释放S1P。这种输出与GSC的增殖和干性有关，并受到EGF和bFGF的促进。反过来，S1P作为自分泌信号促进GSC的生长和茎的生长。
Accumulating reports suggest that human glioblastoma contains glioma stem-like cells (GSCs) which act as key determinants driving tumor growth, angiogenesis, and contributing to therapeutic resistance. The proliferative signals involved in GSC proliferation and progression remain unclear. Using GSC lines derived from human glioblastoma specimens with different proliferative index and stemness marker expression, we assessed the hypothesis that sphingosine-1-phosphate (S1P) affects the proliferative and stemness properties of GSCs. The results of metabolic studies demonstrated that GSCs rapidly consume newly synthesized ceramide, and export S1P in the extracellular environment, both processes being enhanced in the cells exhibiting high proliferative index and stemness markers. Extracellular S1P levels reached nM concentrations in response to increased extracellular sphingosine. In addition, the presence of EGF and bFGF potentiated the constitutive capacity of GSCs to rapidly secrete newly synthesized S1P, suggesting that cooperation between S1P and these growth factors is of central importance in the maintenance and proliferation of GSCs. We also report for the first time that S1P is able to act as a proliferative and pro-stemness autocrine factor for GSCs, promoting both their cell cycle progression and stemness phenotypic profile. These results suggest for the first time that the GSC population is critically modulated by microenvironmental S1P, this bioactive lipid acting as an autocrine signal to maintain a pro-stemness environment and favoring GSC proliferation, survival and stem properties. GLIA 2014;62:1968-1981Main Points GSCs can release S1P extracellularly in a rapid and efficient fashion. This export is related to GSC proliferation and stemness, and promoted by EGF and bFGF. On its turn, S1P acts as autocrine signal to increase GSC growth and stemness.