Increased expression of glutamate transporter GLT-1 in peritumoral tissue associated with prolonged survival and decreases in tumor growth in a rat model of experimental malignant glioma.
Increased expression of glutamate transporter GLT-1 in peritumoral tissue associated with prolonged survival and decreases in tumor growth in a rat model of experimental malignant glioma.
复制标题
在实验性恶性神经胶质瘤大鼠模型中，瘤周组织中谷氨酸转运蛋白 GLT-1 的表达增加与生存期延长和肿瘤生长减少相关。
作者：
R. Sattler;B. Tyler;Benjamin Hoover;Luke T. Coddington;V. Recinos;Lee S. Hwang;H. Brem;J. Rothstein
对象
已知神经胶质瘤释放过量的谷氨酸，诱导肿瘤周围区域的谷氨酸兴奋毒性细胞死亡，并允许肿瘤生长和扩张。谷氨酸转运蛋白上调已被证明是神经保护，通过去除细胞外谷氨酸在神经退行性疾病，包括肌萎缩性侧索硬化症和帕金森病以及精神疾病，如抑郁症的临床前动物模型。因此，作者假设谷氨酸转运蛋白上调的保护机制也可用于治疗胶质瘤。
方法
在这项研究中，9 L胶质肉瘤细胞用谷氨酸转运蛋白上调剂甲砜霉素处理，甲砜霉素是一种在欧洲批准的抗生素，以前已显示可增加谷氨酸转运蛋白表达，最近已在谷氨酸转运蛋白上调的人类I期生物标志物试验中得到验证。在体外监测细胞的谷氨酸转运蛋白水平和细胞增殖。在体内，大鼠颅内注射9 L细胞，并与甲砜霉素剂量增加治疗。监测动物的存活情况。此外，还分析了死后脑组织的肿瘤大小、谷氨酸转运蛋白水平和神经元计数。
结果
甲砜霉素在体外对9 L胶质肉瘤细胞的增殖几乎没有影响，并且不改变这些细胞中谷氨酸转运体的水平。然而，当在大鼠实验性胶质瘤模型中局部给药时，与未治疗对照组相比，甲砜霉素剂量依赖性（10-5000 μM）显著增加了长达7天的存活率，同时肿瘤大小从46.2 mm（2）降至10.2 mm（2）。此外，肿瘤周围组织的免疫组织化学和生物化学分析证实，谷氨酸转运蛋白水平增加了84%，肿瘤附近组织中神经元细胞数量增加了72%。
结论
这些结果表明，增加肿瘤周围组织中谷氨酸转运蛋白的表达具有神经保护作用。这表明谷氨酸转运蛋白上调治疗胶质瘤应进一步研究，并可能成为标准化疗药物联合治疗的一部分。
OBJECT
Gliomas are known to release excessive amounts of glutamate, inducing glutamate excitotoxic cell death in the peritumoral region and allowing the tumor to grow and to expand. Glutamate transporter upregulation has been shown to be neuroprotective by removing extracellular glutamate in a number of preclinical animal models of neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson disease as well as psychiatric disorders such as depression. The authors therefore hypothesized that the protective mechanism of glutamate transporter upregulation would be useful for the treatment of gliomas as well.
METHODS
In this study 9L gliosarcoma cells were treated with a glutamate transporter upregulating agent, thiamphenicol, an antibiotic approved in Europe, which has been shown previously to increase glutamate transporter expression and has recently been validated in a human Phase I biomarker trial for glutamate transporter upregulation. Cells were monitored in vitro for glutamate transporter levels and cell proliferation. In vivo, rats were injected intracranially with 9L cells and were treated with increasing doses of thiamphenicol. Animals were monitored for survival. In addition, postmortem brain tissue was analyzed for tumor size, glutamate transporter levels, and neuron count.
RESULTS
Thiamphenicol showed little effects on proliferation of 9L gliosarcoma cells in vitro and did not change glutamate transporter levels in these cells. However, when delivered locally in an experimental glioma model in rats, thiamphenicol dose dependently (10-5000 μM) significantly increased survival up to 7 days and concomitantly decreased tumor size from 46.2 mm(2) to 10.2 mm(2) when compared with lesions in nontreated controls. Furthermore, immunohistochemical and biochemical analysis of peritumoral tissue confirmed an 84% increase in levels of glutamate transporter protein and a 72% increase in the number of neuronal cells in the tissue adjacent to the tumor.
CONCLUSIONS
These results show that increasing glutamate transporter expression in peritumoral tissue is neuroprotective. It suggests that glutamate transporter upregulation for the treatment of gliomas should be further investigated and potentially be part of a combination therapy with standard chemotherapeutic agents.
影响因子：
4.1
作者：
B. Tyler;K. Fowers;Khan W. Li;V. Recinos;J. Caplan;Alia M. Hdeib;R. Grossman;L. Basaldella;K. Bekelis;G. Pradilla;F. Legnani;H. Brem
通讯作者：
B. Tyler;K. Fowers;Khan W. Li;V. Recinos;J. Caplan;Alia M. Hdeib;R. Grossman;L. Basaldella;K. Bekelis;G. Pradilla;F. Legnani;H. Brem
癌基因 AEG-1 通过增加谷氨酸兴奋毒性来促进神经胶质瘤诱导的神经变性。
影响因子：
11.2
作者：
Lee SG;Kim K;Kegelman TP;Dash R;Das SK;Choi JK;Emdad L;Howlett EL;Jeon HY;Su ZZ;Yoo BK;Sarkar D;Kim SH;Kang DC;Fisher PB
通讯作者：
Fisher PB