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：
8895756
负责人：
James Matthew Barnes
金额：
$ 0.81万
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 2015-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8895756
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 Health 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 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 animal imaging brain tissue cancer type cell behavior cellular imaging chemotherapeutic agent chemotherapy cranium crosslink driving force intravital imaging malignant phenotype mammary epithelium migration molecular imaging mouse model mutant neoplastic cell nerve stem cell novel outcome forecast promoter recombinase research study response self-renewal stem subventricular zone temozolomide tomato lectin tumor tumor microenvironment tumor progression two-photon

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）：神经胶质瘤代表了所有大脑癌的一半以上，并且是迄今为止成人原发性脑肿瘤的类型。胶质瘤胶质母细胞瘤（GBM）是最常见的神经胶质瘤形式，与衰减的临床预后有关。即使在肿瘤进行手术切除，化学疗法和放射疗法的手术切除后，出现的GBM患者的存活率也通常低至一年。作为对这种肿瘤类型的未满足治疗需求的一个例子，烷基化剂Temozolomide是唯一具有可靠生存益处的化学治疗剂之一，仅将寿命延长了大约三个月。迄今为止，大多数脑肿瘤研究都集中在肿瘤细胞独有的遗传学和生化信号通路上。然而，在所有癌症类型中，微环境因素如何促进肿瘤细胞行为。在GBM进展过程中，肿瘤微环境中发生了许多变化，包括募集和重塑肿瘤相关的脉管系统，广泛的缺氧和免疫细胞浸润，所有这些都可能促进GBM细胞的稳健侵入性和耐药性特征。最近发现的血管生态位不仅含有肿瘤干细胞，而且还为自我更新和维持提供了必不可少的信号，这证明了肿瘤细胞传播和侵略性受到肿瘤微环境散发的上下文信号的强烈影响。此外，GBM患者的脑组织与机械力的巨大变化有关。这包括颅内压的急剧增加以及肿瘤组织的僵硬。后者可能是肿瘤细胞收缩性增加的结果，细胞外基质沉积和修饰。这种细胞内在和外在力中的扰动已被证明可以驱动几种上皮癌中的恶性表型。但是，机械力在脑癌进展中的作用在很大程度上被忽略了。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扰动的微环境对肿瘤细胞侵袭性和GBM进展的影响。这将通过密切监测新颖的胶质瘤小鼠模式中的肿瘤细胞行为和肿瘤进展来系统地完成，该模式表现出增强或减弱的整联蛋白信号传导，局灶性粘附形成或细胞收缩力。此外，这项工作旨在解决GBM是否来自神经干细胞前体引起的问题，这是经常进行辩论的。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的机械性能的定量测量。为了揭示在GBM进展中重要的细胞 - 细胞相互作用，我旨在建立一种活动物成像技术，以实时可视化肿瘤和血管细胞。最终，这些研究旨在阐明机械挑战脑微环境在肿瘤细胞侵袭性和胶质瘤进展过程中的存活率。在这个欠发达地区的进展对于揭示新的和更成功的脑肿瘤治疗途径至关重要。