Department of Pediatrics, University of California, San Francisco, CA, USA.
Neuro Oncol. 2012 Sep;14(9):1146-52. doi: 10.1093/neuonc/nos140. Epub 2012 Jun 29.
The signaling pathways that underlie the pathogenesis of pediatric gliomas are poorly understood. We characterized the PI3K/Akt/mTOR pathway in pediatric gliomas of all grades. Using immunohistochemistry, we assessed activation of the PI3K/Akt/mTOR pathway by evaluating the downstream signaling molecules phospho(p)-S6, phospho(p)-4BP1, and phospho(p)-PRAS40; PTEN; and PTEN promoter methylation, as well as the MIB labeling index. We correlated these findings with the clinical outcomes of 48 children with gliomas. Eighty percent of high-grade gliomas (12/15) showed activation of the PI3K/Akt/mTOR pathway based on p-S6 and p-4EBP1 expression. The majority of high-grade gliomas were negative for PTEN expression (10/15), and 50% had PTEN promoter methylation (grade III: 2/4; grade IV: 3/6). Low-grade gliomas demonstrated PI3K/Akt/mTOR pathway activation in 14/32 (43.8%) by p-S6 and 16/32 (50%) by p-4EBP1. Over 50% of grade I (6/11) and almost all grade II tumors (6/7) showed PTEN promoter methylation. Tumor grade correlated negatively with PTEN expression and positively with expression of p-S6 and p-4EBP1 (PTEN: P = .0025; pS6: P = .0075; p-4EBP1: P = .0066). There was a trend toward inverse correlation of methylation of the PTEN promoter with expression of PTEN protein (P= .0990) and direct correlation of expression of p-S6 and p-4EBP1 with poorer clinical outcome, as measured by progression-free survival (p-S6: P= .0874; p-4EBP1: P= .0475). Tumors with no PTEN expression had a higher MIB labeling index (P= .007). The majority of pediatric gliomas show activation of the PI3K/Akt/mTOR pathway, with methylation of the PTEN promoter occurring commonly in these tumors.
小儿脑胶质瘤的发病机制相关信号通路尚未完全阐明。我们对各等级小儿脑胶质瘤的 PI3K/Akt/mTOR 通路进行了特征描述。通过免疫组化，我们通过评估下游信号分子磷酸化(p)-S6、磷酸化(p)-4BP1 和磷酸化(p)-PRAS40；PTEN；以及 PTEN 启动子甲基化，以及 MIB 标记指数，来评估 PI3K/Akt/mTOR 通路的激活情况。我们将这些发现与 48 名脑胶质瘤患儿的临床结果进行了关联。80%的高级别胶质瘤（12/15）基于 p-S6 和 p-4EBP1 的表达显示出 PI3K/Akt/mTOR 通路的激活。大多数高级别胶质瘤的 PTEN 表达呈阴性（10/15），且 50%的肿瘤存在 PTEN 启动子甲基化（III 级：2/4；IV 级：3/6）。32 例低级别胶质瘤中（43.8%）通过 p-S6 和 16/32（50%）通过 p-4EBP1 显示出 PI3K/Akt/mTOR 通路的激活。超过 50%的 I 级（6/11）和几乎所有的 II 级肿瘤（6/7）均存在 PTEN 启动子甲基化。肿瘤分级与 PTEN 表达呈负相关，与 p-S6 和 p-4EBP1 的表达呈正相关（PTEN：P=.0025；pS6：P=.0075；p-4EBP1：P=.0066）。PTEN 启动子甲基化与 PTEN 蛋白表达呈负相关（P=.0990），p-S6 和 p-4EBP1 的表达与无进展生存期（p-S6：P=.0874；p-4EBP1：P=.0475）呈负相关。无 PTEN 表达的肿瘤具有更高的 MIB 标记指数（P=.007）。大多数小儿脑胶质瘤显示出 PI3K/Akt/mTOR 通路的激活，PTEN 启动子的甲基化在这些肿瘤中较为常见。
