Intermittent hypoxia on the progression of neuroblastoma

间歇性缺氧对神经母细胞瘤进展的影响

基本信息

批准号：
8011200
负责人：
SANJEEVA MOHANAM
金额：
$ 31.6万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011200
关键词：
1 year old Accounting Acute Adhesions Adolescent Apoptosis Apoptotic Area Behavior Binding Biologic Characteristic Biological Biological Assay Biological Factors Bone Marrow Cell Communication Cell Line Cell Survival Cells Chick Embryo Child Childhood Solid Neoplasm Chronic Clinical Diagnosis Diploidy Disease Evaluation Exhibits Experimental Neoplasms Genetic Growth Heterogeneity Histologic Histology Human Human Characteristics Hypoxia Immune response In Vitro Invaded MYCN gene Malignant - descriptor Malignant Neoplasms Mediating Modality Modeling Molecular Neoplasm Metastasis Neural Crest Cell Neuroblastoma Neurons Osteolysis Oxygen Consumption Pathogenesis Pathway interactions Patients Proliferating Proteins Radiation therapy Refractory Relapse Resistance Site Solid Neoplasm Staging Stromal Cells Sympathetic Nervous System Therapeutic Therapeutic Intervention Treatment Protocols Vascular blood supply Xenograft procedure YC-1 angiogenesis bone cancer cell chemotherapy chorioallantoic membrane high risk improved in vivo inhibitor/antagonist insight matrigel mouse model mutant neoplastic cell neuroblastoma cell novel novel strategies osteoclastogenesis outcome forecast overexpression public health relevance response tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Intermittent hypoxia on the progression of neuroblastoma Neuroblastoma is the most common pediatric solid tumor that arises from the sympathetic nervous system. Neuroblastoma tumors exhibit clinical and biological heterogeneity associated with certain genetic aberrations. Advanced stage IV neuroblastoma is refractory to all conventional therapeutic modalities and is associated with a dismal prognosis. The cure rate of children with high-risk stage IV neuroblastoma remains at <20%, providing a compelling reason to better understand the molecular mechanisms that can be targeted to treat this disease. The irregular vasculature of tumors creates regions of acute, chronic or intermittent hypoxia as a result of the inefficient vascular supply and high oxygen consumption of rapidly proliferating malignant cells. Hypoxia induces a multitude of biological responses in cells. Tumor cells adapt to these changes, survive and grow. Neuroblastoma tumors present hypoxic areas and metastasize to sites such as bone and bone marrow. Hypoxia alters neuronal characteristics of human neuroblastoma cells. Transient hypoxia and subsequent reoxygenation are common phenomena occurring within most solid tumors. This intermittent hypoxia has the potential to influence the response to therapy. Our central hypothesis is that intermittent hypoxia enhances survival of human neuroblastoma cells and promotes tumor growth that correlates with aggressiveness of the disease. In this proposal, we plan to study the effects of intermittent hypoxia on neuroblastoma cells. In the first aim we will analyze the intermittent hypoxia-induced alterations in molecules which are involved in angiogenesis and apoptosis, thereby altering the response of tumor cells to chemotherapy and radiotherapy. Second, we will study the effects of intermittent hypoxia on cellular and molecular interactions of neuroblastoma cells with bone marrow stromal cells. Third, we will determine the effects of intermittent hypoxia on the growth and metastasis of human neuroblastoma cells in xenograft mouse models. The proposed studies should generate major insights into the pathogenesis of intermittent hypoxia-induced alterations in neuroblastoma tumors and, in turn, should suggest novel targets for therapeutic interventions. PUBLIC HEALTH RELEVANCE: Neuroblastoma accounts for 10% of all juvenile cancers. Advanced-stage neuroblastoma in children over 1-year old is largely incurable using current treatment protocols. Tumors exhibit hypoxic regions and cause resistance to therapeutic applications. This study will likely provide novel approaches for an improved neuroblastoma therapy.

描述（由申请人提供）：神经母细胞瘤进展过程中的间歇性缺氧神经母细胞瘤是最常见的儿科实体瘤，起源于交感神经系统。神经母细胞瘤表现出与某些遗传畸变相关的临床和生物学异质性。晚期 IV 期神经母细胞瘤对所有常规治疗方式均无效，并且预后不佳。高危 IV 期神经母细胞瘤儿童的治愈率保持在 <20%，这为更好地了解可靶向治疗该疾病的分子机制提供了令人信服的理由。由于血管供应效率低下和快速增殖的恶性细胞耗氧量高，肿瘤的不规则脉管系统会产生急性、慢性或间歇性缺氧区域。缺氧会引起细胞内多种生物反应。肿瘤细胞适应这些变化、生存和生长。神经母细胞瘤肿瘤呈现缺氧区域并转移至骨和骨髓等部位。缺氧会改变人神经母细胞瘤细胞的神经元特征。短暂缺氧和随后的复氧是大多数实体瘤中发生的常见现象。这种间歇性缺氧可能会影响对治疗的反应。我们的中心假设是，间歇性缺氧可以增强人类神经母细胞瘤细胞的存活率，并促进与疾病侵袭性相关的肿瘤生长。在本提案中，我们计划研究间歇性缺氧对神经母细胞瘤细胞的影响。第一个目标是分析间歇性缺氧引起的参与血管生成和细胞凋亡的分子变化，从而改变肿瘤细胞对化疗和放疗的反应。其次，我们将研究间歇性缺氧对神经母细胞瘤细胞与骨髓基质细胞的细胞和分子相互作用的影响。第三，我们将确定间歇性缺氧对异种移植小鼠模型中人神经母细胞瘤细胞生长和转移的影响。拟议的研究应该对间歇性缺氧引起的神经母细胞瘤肿瘤改变的发病机制产生重要的见解，反过来，应该提出治疗干预的新目标。公共卫生相关性：神经母细胞瘤占所有青少年癌症的 10%。使用目前的治疗方案，一岁以上儿童的晚期神经母细胞瘤基本上无法治愈。肿瘤表现出缺氧区域并导致对治疗应用的抵抗。这项研究可能会为改进神经母细胞瘤治疗提供新方法。