Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach.
Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach.
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DOI：
10.1038/cddis.2013.157
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发表时间：
2013-05-16
影响因子：
9
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中科院分区：
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胶质母细胞瘤（GBM）是成人中最常见和最具侵袭性的原发性脑肿瘤。GBM细胞对由抗肿瘤药物和放疗诱导的凋亡具有高度抗性，从而导致癌症进展。我们评估了系统医学方法，分析肿瘤细胞执行凋亡的能力是否可以用来预测GBM患者对治疗的反应。在一组GBM细胞系和GBM患者肿瘤切除物中测定关键促凋亡蛋白半胱天冬酶原-3、半胱天冬酶原-9、Smac和Apaf-1以及抗凋亡蛋白XIAP的浓度。这些值用作APOPTO-CELL的输入，APOPTO-CELL是一种基于系统生物学的数学模型，用于预测细胞对半胱天冬酶活化的敏感性。该建模能够准确区分GBM细胞之间的死亡或存活的治疗与替莫唑胺在10的11个分析线。重要的是，使用GBM患者样本获得的结果表明，APOPTO-CELL能够根据患者的无进展生存时间对患者进行分层，并预测肿瘤细胞支持分析的21名GBM患者中的16名中的半胱天冬酶激活的能力。计算对细胞凋亡执行的敏感性可能是预测GBM患者治疗反应性的有效工具，并且可以允许在临床环境中使用APOPTO-CELL。
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting.