Molecular mechanisms of death in cells with defective apoptotic pathways

身体通过杀死任何可能成为肿瘤的细胞来保护自己免受癌症的侵害。身体通过精心策划的事件序列（或途径）杀死这些细胞，然而，许多癌细胞在细胞死亡途径中存在缺陷，即使它们被告知死亡，也允许它们存活。在这个提案中，我们提出了一个研究计划，研究如何杀死不想死的癌细胞。各种肿瘤细胞已被证明具有增加的Bcl-2水平，Bcl-2是一种原癌基因，其阻断由各种刺激诱导的细胞死亡。过度表达Bcl-2的细胞也对细胞毒性药物具有抗性。了解如何绕过Bcl-2（或阻止肿瘤细胞死亡的蛋白质）将有助于更好地了解细胞死亡-细胞存活，并使我们能够探索为患者量身定制治疗的可能性，其中死亡途径的特定缺陷已在他们的癌细胞中被确定。细胞毒性淋巴细胞（CL）是免疫系统的细胞，通过特异性攻击和杀死肿瘤细胞来保护身体免受癌症的侵害。我们一直在开拓CL：肿瘤相互作用的研究，其中我们可以定义细胞死亡中关键事件的形态学和动力学，并表明CL有能力杀死过表达Bcl-2的靶细胞。根据本提案的目标，我们将了解细胞毒性淋巴细胞杀死经典细胞死亡途径中存在缺陷的靶细胞的机制。因此，这些研究将确定细胞死亡的替代途径，如果细胞死亡的优先途径的一个关键组成部分是细胞死亡。由于细胞毒性淋巴细胞使用多种方式杀死其靶标，并且肿瘤可能包含细胞死亡途径中的多种缺陷，因此我们将探索细胞死亡途径中的哪些是关键缺陷或多种缺陷的组合，这些缺陷可防止细胞毒性淋巴细胞介导的细胞死亡并允许肿瘤在体内存活。

The body protects itself from cancer by killing any cell that poses a risk of becoming a tumour. The body kills these cells via a carefully orchestrated sequence (or pathway) of events, however many cancer cells have defects in cell death pathways that has permitted them to survive even though they have been told to die. In this proposal we set out a research program to investigate how to kill cancer cells that don't want to die. Various tumour cells have been shown to have increased levels of Bcl-2, a proto-oncogene that blocks cell death induced by diverse stimuli. Cells that over-express Bcl-2 are also resistant to cytotoxic drugs. Understanding how to bypass Bcl-2 (or proteins that block cell death in tumours) will lead to a better understanding of cell death-cell survival and allow us to explore the possibility of tailoring treatment for patients in which specific defects in death pathways have been identified in their cancer cells. Cytotoxic lymphocytes (CL) are cells of the immune system that defend the body from cancer by specifically attacking and killing tumor cells. We have been pioneering studies of CL:tumour interactions in which we can define the morphology and kinetics of critical events in cell death and have shown that CL have the ability to kill target cells that over-express Bcl-2. Following the aims in this proposal, we will understand the mechanisms by which cytotoxic lymphocytes kill target cells that have defects in classical cell death pathways. These studies will therefore define alternative pathways to cell death in the event that a key component of the preferential pathway to cell death is inoperative. Since cytotoxic lymphocytes use a variety of ways to kill their targets and tumors may contain multiple defects in cell death pathways, we will explore which are the key defects, or the combination of multiple defects, in cell death pathways that prevent cytotoxic lymphocyte mediated cell death and permit tumour survival in vivo.