Glutamate and the biology of gliomas.
Glutamate and the biology of gliomas.
复制标题
DOI：
10.1002/glia.21113
复制
发表时间：
2011-08
期刊：
影响因子：
6.2
通讯作者：
Sontheimer, Harald
中科院分区：
文献类型：
--
作者：
de Groot, John;Sontheimer, Harald
神经递质谷氨酸在原发性脑肿瘤生物学中的几个重要的和以前未被认识的作用最近已经被阐明。谷氨酸作为谷胱甘肽合成的副产物，通过系统XC-胱氨酸谷氨酸转运体从胶质瘤细胞中产生和释放。谷氨酸似乎通过多种机制在胶质瘤的恶性表型中发挥核心作用。通过与肿瘤周围的神经元谷氨酸受体结合，谷氨酸负责癫痫发作诱导，并且类似地引起兴奋性毒性，这有助于肿瘤细胞扩展到被破坏的组织空出的空间中。谷氨酸还以旁分泌和自分泌方式激活胶质瘤细胞上的亲离子型和亲代谢型谷氨酸受体。AMPA谷氨酸受体缺乏GluR 2亚基，使其具有Ca 2+渗透性并能够激活AKT和MAPK途径。此外，这些受体在帮助神经胶质瘤细胞侵入正常脑中是至关重要的。AMPA-R聚集在粘着斑位点，在粘着斑位点AMPA-R可间接介导ECM与整联蛋白之间的相互作用。谷氨酸受体刺激导致粘着斑激酶（FAK）的活化，粘着斑激酶（FAK）对于调节生长因子和整合素刺激的细胞运动和侵袭是关键的。谷氨酸对神经胶质瘤生物学的多种作用支持谷氨酸受体和转运蛋白的药理学靶向的基本原理。一些正在进行和最近完成的临床试验正在探索中断谷氨酸介导的脑肿瘤生长的治疗潜力。
Several important and previously unrecognized roles for the neurotransmitter glutamate in the biology of primary brain tumors have recently been elucidated. Glutamate is produced and released from glioma cells via the system xc- cystine glutamate transporter as a byproduct of glutathione synthesis. Glutamate appears to play a central role in the malignant phenotype of glioma via multiple mechanisms. By binding to peritumoral neuronal glutamate receptors, glutamate is responsible for seizure induction and similarly causes excitotoxicity which aids the expansion of tumor cells into the space vacated by destroyed tissue. Glutamate also activates ionotropic and metabotropic glutamate receptors on glioma cells in a paracrine and autocrine manner. AMPA glutamate receptors lack the GluR2 subunit rendering them Ca2+ permeable and capable of activating the AKT and MAPK pathways. Furthermore, these receptors are critical in aiding the invasion of glioma cells into normal brain. AMPA-Rs accumulate at focal adhesion sites where they may indirectly mediate interactions between the ECM and integrins. Glutamate receptor stimulation results in activation of focal adhesion kinase (FAK) which is critical to the regulation of growth factor and integrin-stimulated cell motility and invasion. The multitude of effects of glutamate on glioma biology supports the rationale for pharmacological targeting of glutamate receptors and transporters. Several ongoing and recently completed clinical trials are exploring the therapeutic potential of interrupting glutamate-mediated brain tumor growth.
登录
查看更多内容
影响因子：
45.3
作者：
Grossman, Stuart A.;Ye, Xiaobu;Fine, Howard A.
通讯作者：
Fine, Howard A.
影响因子：
3.4
作者：
Beretta, Francesca;Bassani, Silvia;Passafaro, Maria
通讯作者：
Passafaro, Maria
影响因子：
3.9
作者：
Behrens, PF;Langemann, H;Henning, J
通讯作者：
Henning, J
talampanel（一种谷氨酸受体抑制剂）治疗成人复发性恶性神经胶质瘤的 2 期试验。
影响因子：
6.2
作者：
Iwamoto, Fabio M.;Kreisl, Teri N.;Kim, Lyndon;Duic, J. Paul;Butman, John A.;Albert, Paul S.;Fine, Howard A.
通讯作者：
Fine, Howard A.
影响因子：
4.4
作者：
Condorelli, DF;DellAlbani, P;Stella, AMG
通讯作者：
Stella, AMG