Molecular Mechanisms Underlying Glioma Invasion of the Human Subventricular Zone

神经胶质瘤侵袭人类脑室下区的分子机制

• 批准号: 9338333
• 负责人: Nader Sanai
• 金额: $ 36.73万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9338333
• 关键词: Adult; Affinity; Aminolevulinic Acid; Animal Model; Antimitotic Agents; Automobile Driving; Behavior; Biological Assay; Brain; CXCL12 gene; Cell Culture Techniques; Cell physiology; Cells; Chemotaxis; Clinical; Coculture Techniques; Cytarabine; Data; Development; Diagnostic Imaging; Diagnostic radiologic examination; Distant; Dose; EGF gene; Ependyma; Excision; Fluorescence-Activated Cell Sorting; Future; Glioma; Growth; Home environment; Homing; Human; Imagery; Immunohistochemistry; Infiltration; Integrins; Intraventricular; Invaded; Label; Ligands; Measures; Modality; Molecular; Molecular Target; Neurons; No Evidence of Disease; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Population; Primary Neoplasm; Prodrugs; Proteins; Radiation; Recurrence; Relapse; Reporting; Route; Signal Pathway; Slice; Source; Specimen; Stem cells; System; Testing; The Cancer Genome Atlas; Tissues; Tumor Cell Invasion; Tumor Initiators; Ventricular; Work; Xenograft procedure; brain tissue; cancer invasiveness; chemotherapy; cytokine; human adult stem cell; in vivo; infancy; irradiation; migration; nerve stem cell; newborn neuron; platelet-derived growth factor BB; prognostic; protoporphyrin IX; public health relevance; radioresistant; response; stem cell niche; subventricular zone; targeted treatment; tumor

DESCRIPTION (provided by applicant): The clinical inefficacy of glioma therapy can be, in part, attributed to the persistence of a disseminated subpopulation of glioma cells that survive treatment, only to disperse and repopulate the brain. These glioma stem cells (GSCs) are potent and resilient - capable of propagating the tumor from a very low titer, but also more resistant to radiation and chemotherapy. Mounting evidence suggests a facilitative relationship between gliomas and the subventricular zone (SVZ), a stem cell niche that supports migration of newborn neurons in humans. Although glioma contact with the SVZ has been offered as evidence for a stem cell origin of the tumor, this proposal will test an alternative interpretation- that the SVZ is a preferred migratory route for tumor invasion and a reservoir for GSCs. In previous work, we identified the human SVZ 'gap' layer that lies under the ependyma and demonstrated this to be a major corridor for migrating young neurons during infancy. Preliminary data suggests that the human gap layer is hypocellular in adults, but retains high levels of pro-migratory ligands potentially co-opted by gliomas during subventricular spread. Using a glioma cell labeling agent, 5-aminolevulinic acid (5-ALA), that is administered to patients prior to tumor resection, we have determined that the human SVZ is highly-enriched for infiltrating GSCs, even when diagnostic imaging shows no evidence of disease. We hypothesize that GSCs preferentially home to the human SVZ from the primary tumor mass and are vulnerable to SVZ-directed therapy. Using intraoperative tissue, we propose to characterize human glioma and GSC homing to the SVZ, determine the effects of SVZ-directed radiation and chemotherapy, and identify new, targetable signaling pathways to disrupt this niche. In adapting our system for human SVZ analysis to investigate 5-ALA-treated glioma patients, the proposed work will define patterns of glioma and GSC infiltration of the human SVZ, evaluate how existing therapies disrupt this migratory corridor and GSC reservoir, and identify molecular targets that drive subventricular spread and GSC homing.

描述（由申请人提供）：神经胶质瘤疗法的临床效率低下，部分原因是由于胶质瘤细胞的传播亚群的持续存在，而胶质瘤细胞幸存下来，仅是为了分散和重新填充大脑。这些神经胶质瘤干细胞（GSC）具有有效且具有弹性 - 能够从非常低的滴度中传播肿瘤，但对放射和化学疗法的耐药性也更具耐药性。越来越多的证据表明，神经胶质瘤与室心（SVZ）之间存在促进关系，这是一种支持人类新生神经元迁移的干细胞生态位。尽管已提供与SVZ的神经胶质瘤作为肿瘤干细胞起源的证据，但该提案将测试另一种解释 - SVZ是肿瘤侵袭的首选迁移途径和GSC的储层。在先前的工作中，我们确定了位于室内室下的人类SVZ“间隙”层，并证明这是婴儿期迁移年轻神经元的主要走廊。初步数据表明，人体间隙层在成年人中是低细胞的，但是保留了室室室散布期间神经胶质瘤可能采用的高水平的迁移配体。使用神经瘤细胞标记剂，5-氨基乙烯酸（5-ALA），该剂在肿瘤之前对患者施用 切除，我们已经确定，即使诊断成像没有疾病的迹象，人类SVZ也高度渗透了GSC。我们假设GSC优先从原发性肿瘤质量中归于人类SVZ，并且容易受到SVZ定向治疗的影响。我们建议使用术中组织来表征人神经胶质瘤和GSC归位为SVZ，确定SVZ定向放射和化学疗法的影响，并确定破坏这种利基市场的新的，可靶向的信号传导途径。在调整我们的人类SVZ分析系统以研究5-ALA治疗的神经胶质瘤患者时，拟议的工作将定义人类SVZ的神经胶质瘤和GSC浸润模式，评估现有疗法如何破坏这种迁移的走廊和GSC储存剂，并确定驱动亚ventricular spribcular spristribular spersebsbss的分子靶标。