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

基本信息

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
项目类别：
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

项目摘要

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）：神经胶质瘤治疗的临床无效部分归因于治疗后存活下来的播散性神经胶质瘤细胞亚群的持续存在，只是为了分散和重新填充大脑。这些神经胶质瘤干细胞（GSC）强大而有弹性，能够以非常低的滴度繁殖肿瘤，但对放射和化疗也更具抵抗力。越来越多的证据表明，神经胶质瘤和脑室下区（SVZ）之间存在促进关系，SVZ 是支持人类新生神经元迁移的干细胞生态位。尽管神经胶质瘤与 SVZ 的接触已被作为肿瘤干细胞起源的证据，但该提议将测试另一种解释——SVZ 是肿瘤侵袭的首选迁移途径和 GSC 的储存库。在之前的工作中，我们确定了位于室管膜下方的人类 SVZ“间隙”层，并证明这是婴儿期年轻神经元迁移的主要走廊。初步数据表明，成人间隙层细胞减少，但保留高水平的促迁移配体，在脑室下扩散过程中可能被神经胶质瘤吸收。使用神经胶质瘤细胞标记剂 5-氨基乙酰丙酸 (5-ALA)，在肿瘤治疗前给予患者切除后，我们确定人类 SVZ 高度富集浸润性 GSC，即使诊断成像没有显示疾病证据。我们假设 GSC 优先归巢于原发肿瘤块的人类 SVZ，并且容易受到 SVZ 定向治疗的影响。我们建议利用术中组织来表征人类胶质瘤和 GSC 归巢到 SVZ 的特征，确定 SVZ 定向放疗和化疗的效果，并确定新的、可靶向的信号通路来破坏这一生态位。在调整我们的系统进行人类 SVZ 分析以研究 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走廊和 GSC 库，并确定分子靶点驱动室下扩散和 GSC 归巢。