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: 7540471
• 负责人: Dwayne G Stupack
• 金额: $ 30.03万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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 2010-06-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7540471
• 关键词: Accounting; Adhesions; Affinity; Apoptosis; Birds; Bone Marrow; Caspase; Cell Adhesion; Cell Death; Cell Survival; Cell surface; Cells; Cellular biology; Cessation of life; Characteristics; Childhood Solid Neoplasm; Critical Pathways; Disease; Environment; Event; Extracellular Matrix; Future; Genetic; Goals; Growth; HRAS gene; Image; In Vitro; Integrins; Link; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Mediating; Modeling; Molecular; Mus; Nature; Neoplasm Metastasis; Neuroblastoma; Oncogenes; PTEN gene; Physiological; Principal Investigator; Process; Property; Recruitment Activity; Reporting; Research Design; Resistance; Role; Site; Staging; Testing; Tissues; Tumor Suppressor Genes; Tumorigenicity; advanced disease; caspase-8; cell motility; design; in vivo; malignant phenotype; migration; mortality; neoplastic cell; novel; programs; reconstitution; research study; success; tumor

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）：本提案的总体目标是了解神经母细胞瘤恶性表型的调节机制。 神经母细胞瘤（NB）是最常见的儿科实体瘤，占所有儿童癌症的7- 10%。 NB进展为侵袭性、播散性疾病，称为IV期NB，其特征在于肿瘤的广泛播散和特权部位（包括骨髓）的定殖。 目前的治疗成功率有限，与晚期疾病相关的死亡率很高（约70%）。 NB最恶性形式（IV期）的一个标志是半胱天冬酶8表达的完全丧失。 我们在这里表明，这种caspase 8的损失与称为“整合素介导的死亡”，其中细胞凋亡是由未连接的细胞表面整合素触发的一种形式的细胞凋亡的抗性。 半胱天冬酶8的缺失与整合素功能的其他改变相关，包括恶性NB与ECM的粘附减少和迁移/侵袭增加。 重要的是，正如我们在初步结果中所显示的，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的再表达阻断了体内IV期NB的转移。 因此，我们建议检查的分子机制，半胱天冬酶8可以调节这些恶性特征的先进NB。 在最初的目标中，我们将进行分子定位研究，以确定未连接的整合素如何招募和激活caspase 8，促进NB肿瘤细胞在体外的凋亡。 目标2中概述的研究将集中在caspase 8增加ECM粘附和影响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NB进展和体内传播的影响。 了解这些分子机制对于设计针对NB恶性特性的未来疗法至关重要。