Analysis of CD95L and TRAIL apoptotic pathways in glioma.

大多数患有脑癌恶性胶质瘤的患者在确诊后两年内死亡，因此迫切需要创新的治疗方法。阻止癌前细胞对自杀(凋亡)信号做出反应的突变可能有助于肿瘤的发生。由于标准治疗机制通过诱导这种细胞自杀机制发挥作用，具有凋亡途径改变的肿瘤细胞可能对传统治疗具有抵抗力。恶性胶质瘤通常对化疗和放射治疗有抵抗力，因此可能改变了细胞凋亡的途径。通过确定胶质瘤细胞中凋亡途径的组成部分，合理设计新药或治疗方法将是可行的，从而恢复肿瘤细胞对目前可用的治疗方法的敏感性。在这里，我们将重点介绍CD95L和TRAIL分子引发的自杀途径。我们将表征胶质瘤细胞对CD95L和TRAIL、化疗药物和放射的敏感性。然后，我们将在其他细胞类型研究的基础上，系统地研究CD95L和TRAIL介导的细胞死亡所涉及的分子，以确定CD95L-TRAIL暴露后导致细胞凋亡的分子通路的相关组成部分。我们还将评估已知的抑制剂在确定对CD95L和-或TRAIL的耐药性方面所起的作用，并将筛选这些途径的新抑制剂。这项研究将阐明CD95L-TRAIL介导的一些胶质瘤细胞凋亡的分子，以及在另一些胶质瘤细胞中对这些治疗产生耐药性的分子。我们还将了解在胶质瘤中观察到的典型的化疗和放射耐药是否与CD95和-或TRAIL耐药有机械联系。这些知识将对合理设计脑胶质瘤的诊断和治疗药物有价值，并有可能用于其他疾病。

Most patients with the brain cancer malignant glioma die within two years of diagnosis, thus innovative approaches to treatment are desperately needed. Mutations which prevent the precancerous cells from responding to suicide (apoptotic) signals can contribute to tumourigenesis. As standard treatment regimes act by inducing this cellular suicide machinery, tumour cells with apoptotic pathway alterations can be resistant to conventional therapies. Malignant gliomas are typically resistant to chemo- and radiotherapy, and therefore may have altered apoptotic pathways. By identifying the components of apoptotic pathways in glioma cells, rational design of either novel drugs, or treatments which will restore-enable susceptibility of the tumour cells to currently available therapies will be feasible. Here we will focus on the suicide pathways triggered by the molecules CD95L and TRAIL. We will characterise the sensitivity of glioma cells to CD95L and TRAIL, chemotherapeutic drugs and irradiation. We will then systematically survey the molecules implicated in CD95L and TRAIL-mediated cell death, based on studies in other cell types, to determine the relevant components of the molecular pathways which lead to apoptosis following CD95L-TRAIL exposure. We will also assess the roles played by known inhibitors, in determining resistance to CD95L and-or TRAIL, and will perform screens for novel inhibitors of these pathways. This study will elucidate the molecules responsible for the CD95L-TRAIL-mediated apoptosis seen in some glioma cells, and the molecules which confer resistance to these treatments in others. We will also learn whether the typical resistance to chemo- and radiotherapy observed in gliomas is mechanistically linked to resistance to CD95 and-or TRAIL resistance. This knowledge will be valuable for the rational design of diagnostic and therapeutic agents for glioma, and potentially for other diseases.