The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas
The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas
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DOI：
10.1200/jco.2004.07.193
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发表时间：
2004-05-15
影响因子：
45.3
通讯作者：
Loeffler, JS
中科院分区：
文献类型：
--
作者：
Chakravarti, A;Zhai, G;Loeffler, JS
本研究的目的是检测PI3K通路在胶质瘤中的激活模式，并利用速冻临床标本检测PI3K通路激活对预后的意义。材料与方法通过使用PI3K、Akt和p70(S6K)的总抗体和磷酸化特异性抗体，对92例前瞻性收集的胶质瘤进行PI3K通路成员的定量Western分析。这些PI3K通路成员的表达和表达水平与组织学、细胞凋亡标志物(裂解的caspase3)和临床预后(如总生存期)相关。磷酸化PI3K、磷酸化Akt和磷酸化p70(S6K)水平均与caspase 3裂解水平呈负相关，提示PI3K途径激活与细胞凋亡水平降低有关。也许最重要的是，当综合考虑所有胶质瘤病例时，发现PI3K通路成员的激活与生存时间的减少显著相关。当单独考虑胶质母细胞瘤患者时，PI3K激活的预后价值仍然显著，提示PI3K激活可能与放射抵抗直接相关，因为这是对这一亚群患者进行的唯一辅助治疗。结论PI3K通路的激活与人脑胶质瘤肿瘤分级的增加、细胞凋亡水平的降低以及不良的临床结局显著相关。调控PI3K激活的分子通路有望成为胶质瘤患者临床治疗的靶点。(C)2004年，由美国临床肿瘤学会提供。
PurposeThe objectives of this study were to examine activation patterns of the phosphatidylinositol 3-kinase (PI3K) pathway in gliomas and to examine the prognostic significance of PI3K pathway activation using snap-frozen clinical specimens.Materials and MethodsLevels of expression of PI3K pathway members were assessed in 92 prospectively collected gliomas through quantitative Western analysis using total and phospho-specific antibodies for PI3K, Akt, and p70(s6k). Both expression and expression levels of these PI3K pathway members were correlated with histology, markers of apoptosis (cleaved caspase 3), and with clinical outcome (eg, overall survival).ResultsIt was determined that activation of all three PI3K pathway members were significantly more frequent in glioblastoma multiforme than in non-glioblastoma multiforme tumors. Levels of phospho-PI3K, phospho-Akt, and phospho-p70(s6k) were all found to be inversely associated with cleaved caspase 3 levels, suggesting PI3K pathway activation is associated with reduced levels of apoptosis. Perhaps most importantly, activation of PI3K pathway members was found to be significantly associated with reduced survival times when all glioma cases were considered in aggregate. When glioblastoma cases were considered separately, the prognostic value of PI3K activation remained significant, suggesting that PI3K activation may directly be associated with radiation resistance, given that this was the only adjuvant therapy administered to this subset of patients.ConclusionActivation of the PI3K pathway is significantly associated with increasing tumor grade, decreased levels of apoptosis, and with adverse clinical outcome in human gliomas. Molecular pathways regulating PI3K activation would appear to be promising targets in the clinical management of glioma patients. (C) 2004 by American Society of Clinical Oncology.