PI3K activation in neural stem cells drives tumorigenesis which can be ameliorated by targeting the cAMP response element binding protein
PI3K activation in neural stem cells drives tumorigenesis which can be ameliorated by targeting the cAMP response element binding protein
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DOI：
10.1093/neuonc/noy068
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发表时间：
2018-10-01
期刊：
影响因子：
15.9
通讯作者：
Mantamadiotis, Theo
中科院分区：
文献类型：
--
作者：
Daniel, Paul M.;Filiz, Gulay;Mantamadiotis, Theo
背景。磷酸肌醇 3 激酶 (PI3K) 信号传导过度激活在癌症中很常见，但该通路在神经胶质瘤生物学中的确切作用仍有待确定。对脑癌中 PI3K 信号传导机制的一些理解来自于对神经干/祖细胞 (NSPC) 的研究，其中通过 PI3K 通路传递的信号与其他细胞内通路和下游转录因子配合来调节关键的细胞功能。为了研究 PI3K 通路在神经胶质瘤发生和发展中的作用，我们构建了一个小鼠模型，该模型针对 NSPCs 的 PIK3CAH1047A 致癌突变体的诱导表达和 PI3K 负调节因子、磷酸酶和张力蛋白同源物 (PTEN) 的缺失。结果。 Pik3caH1047A 的表达足以产生具有少突胶质细胞特征的肿瘤，但同时 PTEN 的缺失是侵袭性高级神经胶质瘤的发展所必需的。 Pik3caH1047A-PTEN 突变型 NSPC 表现出神经球形成增强，这与 Wnt 信号传导增强相关，而 Pik3caH1047A-Pten 突变型肿瘤中 cAMP 反应元件结合蛋白 (CREB) 的缺失导致小鼠无症状生存期更长。结论。总而言之，我们的研究结果提出了一种新的神经胶质瘤小鼠模型，证明 PI3K 通路对于肿瘤发生的启动非常重要，并且下游 CREB 信号传导的破坏可以减弱肿瘤的扩张。
Background. Hyperactivation of phosphoinositide 3-kinase (PI3K) signaling is common in cancers, but the precise role of the pathway in glioma biology remains to be determined. Some understanding of PI3K signaling mechanisms in brain cancer comes from studies on neural stem/progenitor cells (NSPCs), where signals transmitted via the PI3K pathway cooperate with other intracellular pathways and downstream transcription factors to regulate critical cell functions.Methods. To investigate the role of the PI3K pathway in glioma initiation and development, we generated a mouse model targeting the inducible expression of a PIK3CAH1047A oncogenic mutant and deletion of the PI3K negative regulator, phosphatase and tensin homolog (PTEN), to NSPCs.Results. Expression of a Pik3caH1047A was sufficient to generate tumors with oligodendroglial features, but simultaneous loss of PTEN was required for the development of invasive, high-grade glioma. Pik3caH1047A-PTEN mutant NSPCs exhibited enhanced neurosphere formation which correlated with increased Wnt signaling, while loss of cAMP response element binding protein (CREB) in Pik3caH1047A-Pten mutant tumors led to longer symptom-free survival in mice.Conclusion. Taken together, our findings present a novel mouse model for glioma demonstrating that the PI3K pathway is important for initiation of tumorigenesis and that disruption of downstream CREB signaling attenuates tumor expansion.