Apical-basal polarity signaling in glioblastoma

胶质母细胞瘤中的顶端-基底极性信号传导

• 批准号: 8649817
• 负责人: Sourav Ghosh
• 金额: $ 6.56万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649817
• 关键词: Adjuvant; Apical; Biological Assay; Brain; Brain Neoplasms; Cell Proliferation; Cell Separation; Cell-Cell Adhesion; Cells; Cessation of life; Characteristics; Child; Clinical; Clinical Management; Clinical Treatment; Complement; Data; Defect; Development; Diagnosis; Disease; Drug Design; Elements; Embryo; Epidermal Growth Factor Receptor; Excision; Exhibits; Genes; Glioblastoma; Glioma; Gliomagenesis; Goals; Growth; Hour; Immunocompromised Host; In Vitro; Indium; Invaded; Lateral; Lead; Light; Malignant Childhood Neoplasm; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mitosis; Modeling; Molecular; Molecular Target; Mus; NIH Program Announcements; Nature; Neuraxis; Oncogenic; Operative Surgical Procedures; Outcome; Pathology; Pathway interactions; Patients; Play; Primary Neoplasm; Property; Radiation therapy; Recurrence; Regimen; Relapse; Resistance; Role; Seeds; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Slice; Solid Neoplasm; Stem cells; Survival Rate; System; Testing; Therapeutic; Treatment Protocols; Tumor Cell Invasion; Tumor-Derived; Undifferentiated; United States; Vertebral column; Xenograft Model; Xenograft procedure; base; brain tissue; cell growth; cell motility; chemotherapy; design; drug discovery; glioma cell line; implantation; improved; in vivo; innovation; migration; mortality; neoplastic cell; nerve stem cell; novel; novel strategies; novel therapeutics; outcome forecast; pre-clinical; prevent; research study; self-renewal; stem; stem cell population; subcutaneous; therapeutic target; tumor; tumor growth; white matter

Over 44,500 people in the United States are diagnosed with a primary tumor in the brain or spine each year. Of this group, approximately 20,500 are diagnosed with primary malignant brain tumors. Brain tumors are also the second most common cancer of childhood comprising approximately 25% of all pediatric cancers. It is the leading cause of solid tumor cancer death in children. Mortality rates from brain tumors are extremely high, with a median survival of approximately 12 months. Notably, mortality rates have remained unchanged over the last two decades as malignant gliomas continue to present significant problems for successful clinical treatment with the current regimen of surgery, radiotherapy or chemotherapy. The highly aggressive nature of malignant gliomas - glioblastoma cells rapidly invade the surrounding brain parenchyma - stems from defects in genes that control cell motility. Invasive tumor cells remaining after surgical resection confound clinical management and significantly contribute to the lethality of this disease. Additionally, a chemotherapy and radiotherapy resistant subpopulation of glioma cells retain stem cell-like properties to re-seed the tumor. This leads to recurrence with even poorer prognosis. The glioma stem cell population may harbor defects in genes that control self-renewal, proliferation and differentiation. Effective targeting of these invasive cells and the stem cell population is critical for the improved management and positive clinical outcome in malignant gliomas. The objective of this proposal is to determine if apical-basal polarity signaling is an important molecular element in the invasive pathology and recurrence of gliomas. We have observed that altered apical- basal polarity signaling causes the rapid proliferation and abnormal migration of undifferentiated cells bearing markers of embryonic neural stem cells in the developing chick central nervous system. Based on this previous study, we hypothesize that aberrant function of apical-basal polarity signaling pathway may play a central role in the invasive progression and growth of glioblastoma. The specific aims of this proposal are: (i) to validate our preliminary observation of a positive association between elevated apical-basal polarity signaling pathway components and clinical glioblastoma, and to investigate the function of this pathway in glioma pathology. This study is likely to elucidate the molecular function of apical-basal polarity signaling pathway in glioma invasion, growth and progression, and provide the proof-of-concept for targeting this pathway as a novel strategy for glioblastoma therapy. Our long-term goal is the rational targeting of this pathway in an improved therapeutic paradigm for gliomas.

在美国，每年有超过 44,500 人被诊断患有脑部或脊柱原发性肿瘤。的 在这一群体中，大约有 20,500 人被诊断患有原发性恶性脑肿瘤。脑肿瘤也是 儿童第二常见癌症，约占所有儿科癌症的 25%。它是 儿童实体瘤癌症死亡的主要原因。脑肿瘤的死亡率极高， 中位生存期约为 12 个月。值得注意的是，死亡率多年来一直保持不变 在过去的二十年里，恶性神经胶质瘤继续给成功的临床带来重大问题 目前的治疗方案包括手术、放疗或化疗。高度攻击性的本质 恶性胶质瘤 - 胶质母细胞瘤细胞迅速侵入周围的脑实质 - 源于缺陷 控制细胞运动的基因。手术切除后残留的侵袭性肿瘤细胞混淆了临床 管理并极大地促进了这种疾病的致死率。此外，化疗和 放射治疗耐药的神经胶质瘤细胞亚群保留了干细胞样特性，可以重新播种肿瘤。这 导致复发，预后更差。神经胶质瘤干细胞群可能存在基因缺陷 控制自我更新、增殖和分化。有效靶向这些侵袭细胞和 干细胞群对于改善恶性疾病的治疗和积极的临床结果至关重要 神经胶质瘤。该提案的目的是确定顶端-基底极性信号传导是否是重要的 神经胶质瘤侵袭性病理学和复发中的分子因素。我们观察到改变了心尖- 基底极性信号导致未分化细胞快速增殖和异常迁移 发育中的雏鸡中枢神经系统中胚胎神经干细胞的标记。在此基础上 研究中，我们假设顶端-基底极性信号通路的异常功能可能发挥核心作用 胶质母细胞瘤的侵袭性进展和生长。该提案的具体目标是： (i) 验证 我们初步观察到顶端-基底极性信号通路升高之间存在正相关 成分和临床胶质母细胞瘤，并研究该通路在胶质瘤病理学中的功能。这 研究可能会阐明顶端-基底极性信号通路在神经胶质瘤侵袭中的分子功能， 生长和进展，并提供了将该途径作为一种新策略的概念验证 胶质母细胞瘤治疗。我们的长期目标是在改进的治疗中合理靶向该途径 神经胶质瘤的范例。