Interplay between intrinsic and extrinsic force and glioma aggression

内在和外在力量与神经胶质瘤攻击之间的相互作用

基本信息

批准号：
8457931
负责人：
James Matthew Barnes
金额：
$ 5.39万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8457931
关键词：
Address Adult Affect Aggressive behavior Alkylating Agents Animals Area Astrocytes Atomic Force Microscopy Attenuated Behavior Biochemical Biochemistry Blood Vessels Brain Brain Neoplasms Brain imaging Breast Breast Carcinoma Cancer Patient Caring Cell Communication Cell Proliferation Cell Survival Cells Cephalic Characteristics Clinical Cues Cytoskeleton Deposition Disease Disease Progression Edema Epithelial Event Excision Exhibits Extracellular Matrix Focal Adhesion Kinase 1 Focal Adhesions Genetic Glial Fibrillary Acidic Protein Glioblastoma Glioma Histologic Histology Hypoxia Image Imagery Imaging Techniques Immune Implant Infiltration Inflammatory Integrins Intracranial Hypertension Intracranial Pressure Knockout Mice Label Lead Life MAP Kinase Gene Maintenance Malignant Neoplasms Malignant neoplasm of brain Measurement Measures Mechanics Microscopy Modeling Modification Molecular Target Monitor Mus Oncogenic Operative Surgical Procedures Pancreas Pancreatic carcinoma Paracrine Communication Patients Photons Primary Brain Neoplasms Procedures Property Radiation therapy Regulation Relative (related person)Research Resistance Rho-associated kinase Role Signal Pathway Signal Transduction Skin Squamous cell carcinoma Survival Rate Tail Testing Therapeutic Time Tissues Transgenes Transgenic Mice Tumor Stem Cells Tumor Tissue Tumor-Associated Vasculature Veins Work brain tissue cancer type cell behavior cellular imaging chemotherapeutic agent chemotherapy cranium crosslink driving force malignant phenotype mammary epithelium migration molecular imaging mouse model mutant neoplastic cell nerve stem cell novel outcome forecast promoter public health relevance recombinase research study response self-renewal stem subventricular zone temozolomide tomato lectin tumor tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Gliomas represent over half of all brain cancers and are by far the most common type of primary brain tumor in adults. Glioblastoma multiforme (GBM), the most common form of glioma, is associated with dismal clinical prognosis. GBM patients presenting with GBM often have survival rates as low as one year, even after surgical resection of the tumor and combined chemo and radiotherapy. As an example of the unmet therapeutic need for this tumor type, the alkylating agent temozolomide is one of the only chemotherapeutic agents with a proven survival benefit, only extending life by approximately three months. To date, most brain tumor research has focused on the genetics and biochemical signaling pathways unique to tumor cells. In all cancer types, however, it is becoming greatly appreciated how microenvironmental factors contribute to tumor cell behavior. During GBM progression, many changes occur in the tumor microenvironment, including recruitment and remodeling of tumor-associated vasculature, extensive hypoxia, and immune cell infiltration, all of which likely drive the robust invasive and treatment-resistant characteristics of GBM cells. The recent discovery of a vascular niche that not only harbors tumor stem cells but also provides essential signals for self-renewal and maintenance provides evidence that tumor cell propagation and aggressiveness is strongly influenced by contextual signals emanating from the tumor microenvironment. In addition, brain tissue of GBM patients is associated with large changes in mechanical forces. This includes dramatic increases in intracranial pressure as well as stiffening of tumor tissue. The latter is likely a result of increased tumor cell contractility, extracellular matrix deposition and modifications. Perturbations in such cell- intrinsic and extrinsic forces have been shown to drive the malignant phenotype in several epithelial cancers; however the role of mechanical forces in brain cancer progression has largely been overlooked. My proposed studies intend to reveal how the vascular niche, its inflammatory cell constituents, and its associated ECM affect tumor stem cell survival, migration, and proliferation. Further, this proposed work will directly test the effect of perturbed microenvironmental force on tumor cell aggressiveness and GBM progression. This will be done systematically by closely monitoring tumor cell behavior and tumor progression in novel mouse modes of glioma exhibiting either augmented or attenuated integrin signaling, focal adhesion formation, or cell contractility. Furthermore, this work aims to address the question of whether GBM arises from a neural stem cell precursor, as is often debated. These mouse studies will make use of histology, biochemistry, molecular imaging techniques, as well as quantitative measurements of the mechanical properties of cells and tissues. To reveal cell-cell interactions important in GBM progression, I aim to establish a live animal imaging technique allowing real time visualization of tumor and vascular cells. Ultimately, these studies aim to elucidate the relative contributions of the mechanically challenged brain microenvironment to tumor cell aggressiveness and survival during glioma progression. Progress in this underdeveloped area will be important to reveal new and more successful avenues for brain tumor therapy.

描述（由申请人提供）：神经胶质瘤占所有脑癌的一半以上，是迄今为止成人中最常见的原发性脑肿瘤类型。多形性胶质母细胞瘤（GBM）是最常见的胶质瘤形式，与不良的临床预后相关。即使手术切除肿瘤并联合化疗和放疗后，患有 GBM 的 GBM 患者的生存率通常低至一年。作为这种肿瘤类型未得到满足的治疗需求的一个例子，烷化剂替莫唑胺是唯一被证明具有生存益处的化疗药物之一，只能将生命延长约三个月。迄今为止，大多数脑肿瘤研究都集中在肿瘤细胞特有的遗传学和生化信号通路上。然而，在所有癌症类型中，人们越来越认识到微环境因素如何影响肿瘤细胞的行为。在GBM进展过程中，肿瘤微环境发生许多变化，包括肿瘤相关脉管系统的募集和重塑、广泛缺氧和免疫细胞浸润，所有这些都可能驱动GBM细胞强大的侵袭性和治疗抵抗特性。最近发现的血管生态位不仅包含肿瘤干细胞，而且还提供自我更新和维持的重要信号，这提供了证据表明肿瘤细胞的增殖和侵袭性受到肿瘤微环境发出的背景信号的强烈影响。此外，GBM患者的脑组织与机械力的较大变化有关。这包括颅内压急剧增加以及肿瘤组织变硬。后者可能是肿瘤细胞收缩力增加的结果，细胞外基质沉积和修饰。这种细胞内在和外在力量的扰动已被证明可驱动多种上皮癌的恶性表型。然而，机械力在脑癌进展中的作用在很大程度上被忽视了。我提出的研究旨在揭示血管生态位、其炎症细胞成分及其相关的 ECM 如何影响肿瘤干细胞的存活、迁移和增殖。此外，这拟议的工作将直接测试微环境扰动对肿瘤细胞侵袭性和 GBM 进展的影响。这将通过密切监测新的神经胶质瘤小鼠模型中的肿瘤细胞行为和肿瘤进展来系统地完成，这些神经胶质瘤表现出增强或减弱的整合素信号传导、粘着斑形成或细胞收缩性。此外，这项工作旨在解决经常争论的 GBM 是否源自神经干细胞前体的问题。这些小鼠研究将利用组织学、生物化学、分子成像技术以及细胞和组织机械特性的定量测量。为了揭示 GBM 进展中重要的细胞间相互作用，我的目标是建立一种活体动物成像技术，允许实时可视化肿瘤和血管细胞。最终，这些研究旨在阐明以下方面的相对贡献：在神经胶质瘤进展过程中，机械挑战的大脑微环境对肿瘤细胞的侵袭性和存活率产生影响。这一欠发达领域的进展对于揭示脑肿瘤治疗新的、更成功的途径非常重要。