Integrins and Caspase 8 in Neuroblastoma Progression

整合素和 Caspase 8 在神经母细胞瘤进展中的作用

• 批准号: 6873379
• 负责人: Dwayne G Stupack
• 金额: $ 13.84万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-06 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6873379
• 关键词: apoptosis; athymic mouse; cell adhesion; cell migration; cysteine endopeptidases; enzyme induction /repression; integrins; laboratory rabbit; neoplastic process; neuroblastoma; tissue /cell culture

DESCRIPTION (provided by applicant): The overall goal of this proposal is to understand the mechanisms regulating the malignant phenotype of neuroblastoma. Neuroblastoma (NB) is the most common pediatric solid tumor, accounting for 7-10 percent of all childhood cancer. NB progresses to an aggressive, disseminated disease, termed stage IV NB, characterized by widespread dissemination of the tumor, and colonization of privileged sites, including bone marrow. Current treatments have limited success, and mortality associated with late stage disease is high (approximately 70%). One hallmark of the most malignant form of NB (stage IV) is the complete loss of caspase 8 expression. We show here that this loss of caspase 8 is associated with resistance to a form of apoptosis termed "Integrin-mediated Death," in which apoptosis is triggered by unligated cell-surface integrins. Loss of caspase 8 is associated with other alterations in integrin function, including decreased adhesion of malignant NB to ECM and increased migration/invasion. Importantly, as we show in the Preliminary Results, stable reconstitution of physiological levels of caspase 8 expression reverses each of these properties of stage IV NB in vitro. Moreover, initial studies suggest that caspase 8 re-expression blocks the metastasis of stage IV NB in vivo. We therefore propose to examine the molecular mechanisms by which caspase 8 may regulate these malignant characteristics of advanced NB. In the initial Aim, we will perform molecular mapping studies to determine how unligated integrins can recruit and activate caspase 8, promoting apoptosis among NB tumor cells in vitro. Studies outlined in Aim 2 will focus on the mechanisms by which caspase 8 increase ECM adhesion and influence the migration of NB cells. Finally, in the third Aim we will examine the impact of these events on NB progression and dissemination in vivo. An understanding of these molecular mechanisms will be crucial for the design of future therapies that target the malignant properties of NB.

描述（由申请人提供）：该提案的总体目标是了解调节神经母细胞瘤恶性表型的机制。 神经母细胞瘤（NB）是最常见的小儿实体瘤，占所有儿童癌症的7-10％。 NB发展为一种侵略性的，传播的疾病，称为IV期NB，其特征是肿瘤的广泛传播和包括骨髓在内的特权部位的定殖。 当前的治疗方法的成功有限，与晚期疾病有关的死亡率很高（约70％）。 NB最恶性形式的标志（IV阶段）是caspase 8表达的完全损失。 我们在这里表明，caspase 8的这种丧失与称为“整联蛋白介导的死亡”的凋亡形式的抗性有关，其中凋亡是由无原始的细胞表面整合蛋白触发的。 caspase 8的丧失与整联蛋白功能的其他改变有关，包括恶性NB对ECM的粘附降低以及增加的迁移/侵袭。 重要的是，正如我们在初步结果中所显示的那样，caspase 8表达的生理水平的稳定重建逆转了体外IV期NB的这些特性中的每一个。 此外，初步研究表明，caspase 8的重新表达阻止了体内IV期NB的转移。 因此，我们建议检查caspase 8可以调节晚期NB的这些恶性特征的分子机制。 在最初的目标中，我们将进行分子映射研究，以确定无凝结素可以如何募集和激活caspase 8，从而在体外促进NB肿瘤细胞之间的凋亡。 AIM 2中概述的研究将重点放在caspase 8增加ECM粘附并影响NB细胞迁移的机制上。 最后，在第三个目标中，我们将研究这些事件对体内NB进展和传播的影响。 对这些分子机制的理解对于针对NB的恶性特性的未来疗法的设计至关重要。