Apical-basal polarity signaling in glioblastoma

胶质母细胞瘤中的顶底极性信号传导

• 批准号: 8817344
• 负责人: Sourav Ghosh
• 金额: $ 6.77万
• 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 2014-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8817344
• 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人被诊断出患有脑部或脊柱的原发肿瘤。的 这一群体约有20,500人被诊断出患有原发恶性脑瘤。脑瘤也是 第二常见的儿童癌症，约占所有儿童癌症的25%。它是 儿童实体瘤癌症死亡的主要原因。脑瘤的死亡率非常高， 中位生存期约12个月。值得注意的是，死亡率保持不变。 在过去的二十年里，恶性胶质瘤继续成为临床成功的重要问题 采用目前的手术、放疗或化疗方案进行治疗。具有极强攻击性的 恶性胶质瘤--胶质母细胞瘤细胞迅速侵袭周围脑实质--源于缺陷 在控制细胞运动的基因中。手术切除后残留的侵袭性肿瘤细胞令临床困惑 管理，并在很大程度上促成这种疾病的致命性。此外，化疗和 对放射治疗耐药的胶质瘤细胞亚群保留干细胞样特性以重新种植肿瘤。这 导致复发，预后更差。胶质瘤干细胞群体可能存在基因缺陷 它们控制着自我更新、增殖和分化。有效地靶向这些侵袭细胞和 干细胞群对改善恶性肿瘤的治疗和积极的临床结果至关重要 神经胶质瘤。这一建议的目的是确定心尖-基底极性信号是否是一种重要的 分子在胶质瘤侵袭病理和复发中的作用我们观察到改变后的根尖- 基础极性信号导致未分化细胞的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志物。基于此之前的 研究中，我们假设心尖-基底极性信号通路的异常功能可能起着中心作用 在胶质母细胞瘤的侵袭性进展和生长中起重要作用。这项建议的具体目的是：(一)验证 心尖-基底极性信号通路升高正相关的初步观察 成分和临床胶质母细胞瘤，并探讨该通路在胶质瘤病理中的作用。这 研究可能阐明顶端-基底极信号通路在脑胶质瘤侵袭中的分子功能。 生长和进展，并为将这一途径作为一种新的战略提供了概念验证 胶质母细胞瘤治疗。我们的长期目标是在一种改进的治疗方法中合理地靶向这一途径 神经胶质瘤的范例。