Non-neoplastic cell types dictate gliomagenesis and

非肿瘤细胞类型决定神经胶质瘤的发生和

• 批准号: 8353539
• 负责人: ERIC C. HOLLAND
• 金额: $ 59.15万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353539
• 关键词: Ablation; Astrocytes; Autologous Expanded Mesenchymal Stem Cells; Behavior; Brain; Brain Neoplasms; Cells; Complex; Data; Development; Drug Design; Ecosystem; Gene Expression Profile; Generations; Genetic; Genetically Engineered Mouse; Glioma; Gliomagenesis; Growth; In Vitro; Individual; Laboratories; Maintenance; Malignant neoplasm of brain; Messenger RNA; Methodology; Microglia; Modality; Modeling; Molecular; Mus; Nature; Neuroglia; Pattern; Physicians; Platelet-Derived Growth Factor; Polyribosomes; Population; Population Growth; Radiation; Reagent; Recruitment Activity; Regulation; Research Personnel; Resistance; Role; Scientist; Senior Scientist; Signal Transduction; Sorting - Cell Movement; Staging; Stem cells; Therapeutic; Tissues; Transcript; Tumor Biology; Validation; base; cancer stem cell; cell growth; cell type; conventional therapy; improved; in vivo; mouse model; neoplastic; neoplastic cell; new therapeutic target; novel; outcome forecast; response; stem cell population; temozolomide; therapeutic target; therapy design; translational medicine; tumor; tumor initiation

DESCRIPTION (provided by applicant): Converging data from our individual laboratories support the notion that brain cancers (gliomas) are complex and dynamic ecosystems composed of several non-neoplastic cell types critical for glioma formation and maintenance. Specifically, we have shown that one of these non-neoplastic cell types (microglia) in the tumor microenvironment is a critical determinant of glioma cell growth and invasion. To more completely define the molecular mechanisms underlying tumor microenvironment regulation of glioma behavior, we have assembled a highly interactive team of researchers, including one early stage investigator focused on the tumor microenvironment (Dolores Hambardzumyan), one senior scientist expert in microglia-glioma interactions (Helmut Kettenmann), and two established physician-scientists (Eric Holland and David Gutmann) whose laboratories employ genetically engineered mouse models (GEMMs) to evaluate the dynamic interactions between non-neoplastic and neoplastic cells in glioma. Based on experimental findings from each of our individual laboratories, we hypothesize neoplastic glia (glioma cells) recruit and alter the function of resident brain microglia to create specialized tumor-associated microglia, that elaborate molecules that both create a permissive stroma ("stromagenesis") (Aim 1) and activate astrocytes (Aim 2). These "reactive" astrocytes support the creation and maintenance of the perivascular niche (gliomagens) (Aim 3), which provides the proper microenvironment for cancer stem cells - the treatment-resistant population of glioma cells (Aim 4). Collectively, this cross-disciplinary initiative capitalizes on converging lines of evidence that conceptualize gliomas as dynamic ecosystems composed of neoplastic and non-neoplastic cells and leverages expertise in mouse modeling, glioma biology, tumor microenvironment, microglia function, and translational medicine to identify new therapeutic targets for treating these deadly brain cancers.

描述（由申请人提供）：来自我们各个实验室的汇总数据支持脑癌（神经胶质瘤）是由几种对神经胶质瘤形成和维持至关重要的非肿瘤细胞类型组成的复杂动态生态系统的概念。 具体来说，我们已经证明肿瘤微环境中的一种非肿瘤细胞类型（小胶质细胞）是胶质瘤细胞生长和侵袭的关键决定因素。 为了更完整地定义肿瘤微环境调控胶质瘤行为的分子机制，我们组建了一个高度互动的研究团队，其中包括一名专注于肿瘤微环境的早期研究人员（Dolores Hambardzumyan），一位研究小胶质细胞-胶质瘤相互作用的资深科学家专家（赫尔穆特·凯滕曼），和两个著名的医学科学家（Eric Holland和大卫古特曼），他们的实验室采用基因工程小鼠模型（GEMM）来评估神经胶质瘤中非肿瘤细胞和肿瘤细胞之间的动态相互作用。 基于我们每个实验室的实验结果，我们假设肿瘤性胶质细胞（胶质瘤细胞）招募并改变常驻脑小胶质细胞的功能，以产生专门的肿瘤相关小胶质细胞，这些小胶质细胞精心制作分子，既产生允许的基质（“基质形成”）（目标1）又激活星形胶质细胞（目标2）。 这些“反应性”星形胶质细胞支持血管周围小生境（胶质瘤原）的产生和维持（Aim 3），其为癌症干细胞-胶质瘤细胞的治疗抗性群体（Aim 4）提供适当的微环境。 总的来说，这 跨学科的倡议利用汇聚线的证据，概念化神经胶质瘤作为动态生态系统组成的肿瘤和非肿瘤细胞，并利用专门知识在小鼠建模，神经胶质瘤生物学，肿瘤微环境，小胶质细胞功能，和转化医学，以确定新的治疗目标，治疗这些致命的脑癌。