Apical-basal polarity signaling in glioblastoma

胶质母细胞瘤中的顶端-基底极性信号传导

基本信息

批准号：
8527897
负责人：
Sourav Ghosh
金额：
$ 5.46万
依托单位：
UNIVERSITY OF ARIZONA
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：
2010-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8527897
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

项目摘要

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.

每年，美国有44,500多人被诊断出大脑或脊柱的原发性肿瘤。的这组约有20,500个被诊断出患有原发性恶性脑肿瘤。脑肿瘤也是第二个最常见的儿童期癌症，约占所有儿科癌症的25％。是儿童实体癌死亡的主要原因。脑肿瘤的死亡率极高，中位存活约为12个月。值得注意的是，死亡率保持不变过去二十年，由于恶性神经胶质瘤继续为成功的临床带来重大问题用手术，放疗或化学疗法的当前方案进行治疗。高度侵略性的本质恶性神经胶质瘤 - 胶质母细胞瘤细胞迅速侵袭周围的脑实质 - 源于缺陷在控制细胞运动的基因中。手术切除后仍保持侵入性肿瘤细胞混淆临床管理和显着促进了这种疾病的致命性。此外，一种化学疗法和神经胶质瘤细胞的放射疗法抗性亚群保留了干细胞样特性，以重新播种肿瘤。这导致复发，预后较差。神经胶质瘤干细胞种群可能存在基因缺陷控制自我更新，增殖和分化。这些侵入性细胞的有效靶向干细胞种群对于改善管理和恶性的阳性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质极性信号是否重要神经胶质瘤的侵入性病理和复发中的分子元素。我们已经观察到了顶端的改变基础极性信号传导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记。基于此之前研究，我们假设顶端基质极性信号通路的异常功能可能起着核心作用在胶质母细胞瘤的侵入性进展和生长中。该提案的具体目的是：（i）验证我们对升高的顶碱极性信号通路之间正相关的初步观察成分和临床胶质母细胞瘤，并研究该途径在神经胶质瘤病理学中的功能。这研究可能会阐明神经瘤侵袭中顶端基质极性信号通路的分子功能，生长和进步，并提供概念概念，以将这一途径作为一种新的策略胶质母细胞瘤疗法。我们的长期目标是在改进的治疗方面的合理靶向这一途径神经胶质瘤的范式。