The Role of Caspase-8 in Neuroblastoma Tumorigenesis

Caspase-8 在神经母细胞瘤肿瘤发生中的作用

基本信息

批准号：
8321652
负责人：
GERARD PAUL ZAMBETTI
金额：
$ 38.34万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-07-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321652
关键词：
15 year old Accounting Apoptosis Apoptotic Biological Biological Models Biology Cell Death Cell Line Cell physiology Cells Cessation of life Child Childhood Children&apos s Oncology Group Complex Cultured Cells Data Death Rate Decitabine Deoxycytidine Diagnosis Disease Epigenetic Process Event Exhibits Frequencies Funding Gene Deletion Glioblastoma Goals Healed Human Immigration Induction of Apoptosis Integrins Interferons Laboratories MYCN gene Malignant Childhood Neoplasm Mediating Modeling Molecular Abnormality Mus Mutation Nature Neoplasm Metastasis Neuroblastoma Other Genetics Pathway interactions Patients Personal Communication Phase I Clinical Trials Phosphorylation Play Post-Translational Protein Processing Prevention Proteins Protocols documentation Publishing Relapse Role SCID Mice Signal Transduction Skin Solid Neoplasm Staging Stimulus System Testing Therapeutic Time Tretinoin Work base caspase-8 cell motility chemotherapeutic agent design healing improved in vivo insight medulloblastoma mouse model neoplastic cell neuroblastoma cell outcome forecast overexpression public health relevance response tissue culture tumor tumor initiation tumorigenesis wound

项目摘要

DESCRIPTION (provided by applicant): Neuroblastoma (NB), the most frequent extracranial solid tumor in children, causes 15% of pediatric cancer deaths. Greater than 50% of all NB patients present with aggressive metastatic disease. Significantly, the death rate for patients that have metastatic disease at the time of diagnosis remains at ~30-50%, despite aggressive treatment and significant increases in our understanding of the disease. Several genetic abnormalities have been identified in this disease. However, little is known about how these genetic alterations contribute to tumor formation and metastasis, although N-myc amplification correlates with aggressive metastatic disease. Our laboratory discovered that NB cell lines and patients frequently exhibit loss of caspase-8 (C8) expression either by epigenetic mechanisms or in a few cases through gene deletion. We have also shown that the loss of caspase-8 facilitates tumor initiation and enhances metastasis via the prevention of integrin mediated cell death and decreases the responsiveness of tumors to apoptotic stimuli. The studies in this proposal are designed to test the t the hypothesis that caspase-8 plays an important modifier role in N-myc induced NB. We further hypothesize that C8 has both apoptotic and nonapoptotic roles in neuroblastoma formation and metastasis and that modulation of caspase-8 expression and/or activity cooperate with other genetic changes, such as MYCN over-expression in tumor formation. To test this hypothesis we plan to: 1.) develop a mouse model system that recapitulated the increase in MYCN expression and the decrease in caspase-8 expression that is seen in most human patients and to use this system to determine how reducing C8 expression alters the effects of MYCN over-expression on apoptosis, proliferation and survival and 2.) To determine whether caspase-8 plays nonapoptotic roles in tumorigenesis and metastasis in NB tumors that retain C8 expression. These studies will examine whether the apoptotic functions of C8 are abrogated in these cells, by reducing C8 levels below the threshold needed for induction of apoptosis and/or by posttranslational modification that decrease enzymatic activity or alter subcellular localization. We will also delineate that pathways involved in the nonapoptotic functions of C8 in survival and proliferation and determine whether similar decreases in C8 expression or posttranslational modifications are seen in human NB patients. Upon completion of these studies we will have obtained significant new insight into the biology of this complex disease that can be used to develop more targeted treatments and ideally improve the prognosis of NB patients diagnosed with aggressive metastatic disease. In addition, since loss of C8 has been correlated with poor prognosis in medulloblastoma and with relapsed aggressive glioblastoma, which also exhibit N-myc amplification and/or overexpression, the data from these studies may provide insight into the biology of other human tumors. PUBLIC HEALTH RELEVANCE: Neuroblastoma is the most common extracranial solid tumor in childhood, accounting for approximately 7% to10% of pediatric cancers and 15% of all pediatric cancer deaths in patients less than 15 years old. Importantly, >50% of all neuroblastoma patients present with metastatic disease. Despite aggressive treatment 30% to 50% of these patients die. The studies in this proposal are designed to determine the role of caspase-8 and N-myc, two proteins whose expression is altered in neuroblastoma, in tumorigenesis, metastasis and chemotherapeutic responsiveness.

描述（由申请人提供）：神经母细胞瘤 (NB) 是儿童中最常见的颅外实体瘤，导致 15% 的儿童癌症死亡。超过 50% 的 NB 患者患有侵袭性转移性疾病。值得注意的是，尽管采取了积极的治疗并且我们对该疾病的了解显着增加，但诊断时患有转移性疾病的患者的死亡率仍保持在 30-50% 左右。在这种疾病中已经发现了几种遗传异常。然而，尽管 N-myc 扩增与侵袭性转移性疾病相关，但人们对这些基因改变如何促进肿瘤形成和转移知之甚少。我们的实验室发现，NB 细胞系和患者经常表现出 caspase-8 (C8) 表达缺失，这可能是由于表观遗传机制造成的，也有少数情况下是由于基因缺失造成的。我们还表明，caspase-8 的缺失可通过预防整合素介导的细胞死亡促进肿瘤发生并增强转移，并降低肿瘤对细胞凋亡刺激的反应性。本提案中的研究旨在检验 caspase-8 在 N-myc 诱导的 NB 中发挥重要修饰作用的假设。我们进一步假设 C8 在神经母细胞瘤形成和转移中具有凋亡和非凋亡作用，并且 caspase-8 表达和/或活性的调节与其他遗传变化协同作用，例如肿瘤形成中的 MYCN 过表达。为了检验这一假设，我们计划：1.) 开发一个小鼠模型系统，重现大多数人类患者中观察到的 MYCN 表达增加和 caspase-8 表达减少，并使用该系统来确定减少 C8 表达如何改变MYCN 过表达对细胞凋亡、增殖和存活的影响；2.) 确定 caspase-8 是否在保留 C8 表达的 NB 肿瘤的肿瘤发生和转移中发挥非细胞凋亡作用。这些研究将通过将 C8 水平降低到诱导细胞凋亡所需的阈值以下和/或通过降低酶活性或改变亚细胞定位的翻译后修饰来检查这些细胞中 C8 的凋亡功能是否被消除。我们还将描述与 C8 在存活和增殖中的非凋亡功能相关的途径，并确定在人类 NB 患者中是否观察到 C8 表达或翻译后修饰的类似降低。完成这些研究后，我们将对这种复杂疾病的生物学获得重要的新见解，可用于开发更有针对性的治疗方法，并理想地改善诊断为侵袭性转移性疾病的 NB 患者的预后。此外，由于 C8 缺失与髓母细胞瘤和复发性侵袭性胶质母细胞瘤的不良预后相关，这些肿瘤也表现出 N-myc 扩增和/或过度表达，因此这些研究的数据可能有助于深入了解其他人类肿瘤的生物学。公共卫生相关性：神经母细胞瘤是儿童期最常见的颅外实体瘤，约占儿科癌症的 7% 至 10%，占 15 岁以下患者所有儿科癌症死亡的 15%。重要的是，>50% 的神经母细胞瘤患者出现转移性疾病。尽管积极治疗，仍有 30% 至 50% 的患者死亡。本提案中的研究旨在确定 caspase-8 和 N-myc 这两种蛋白在肿瘤发生、转移和化疗反应中的作用，这两种蛋白的表达在神经母细胞瘤中发生改变。