Interstitial Fluid Flow Regulates Glioma Cell Invasion

间质液流动调节神经胶质瘤细胞侵袭

• 批准号: 10443221
• 负责人: Jennifer M Munson
• 金额: $ 52.53万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443221
• 关键词: 3-Dimensional; Affect; Algorithmic Analysis; Angiogenesis Inhibitors; Area; Astrocytes; Autologous; Automobile Driving; Brain; Brain Neoplasms; Brain region; CCL21 gene; CXCL5 gene; CXCR4 gene; Cell Line; Cells; Chemotaxis; Coculture Techniques; Computer Models; Contrast Media; Correlative Study; Disease; Extracellular Matrix; Fibroblasts; Gene Expression; Genetic Engineering; Glioblastoma; Glioma; Grant; Image; Imaging Device; Implant; In Vitro; Intercellular Fluid; Invaded; Knock-out; Liquid substance; Magnetic Resonance Imaging; Malignant neoplasm of brain; Maps; Measurement; Measures; Mediating; Methodology; Methods; Microarray Analysis; Microfluidics; Microglia; Modality; Modeling; Mus; Nature; Neuroglia; Outcome; Pathway interactions; Patients; Pattern; Physiological; Population; Prevalence; Prognosis; Radiation therapy; Recurrence; Reporter; Reporting; Role; Route; Signal Transduction; Sphingosine-1-Phosphate Receptor; Stromal Cell-Derived Factor 1; Stromal Cells; System; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Up-Regulation; Work; Xenograft procedure; brain parenchyma; brain tissue; cancer cell; chemokine; chemokine receptor; clinically relevant; computerized tools; contrast enhanced; experimental study; fluid flow; in vitro Assay; in vivo; in vivo Model; inhibitor; interstitial; malignant breast neoplasm; mechanical force; mouse model; neoplastic cell; novel; overexpression; pressure; receptor; response; small molecule; stem cells; treatment response; tumor; tumor growth; tumor microenvironment

Project Summary Glioblastoma, the deadliest form of brain cancer, is defined by the invasive nature of its cells. Invasion in the brain follows distinctive routes that correlate with interstitial and bulk flow pathways. In brain cancer, increased interstitial fluid flow develops due to the increase in interstitial pressure in the tumor bulk interfacing with the relatively normal pressure of the surrounding brain tissue, or tumor microenvironment. This differential leads to fluid transport specifically across the invasive edge of the tumor where cells are prone to both interact with the surrounding brain tissue and to evade localized, transport-limited therapies. To examine how interstitial fluid flow affects the invasion of brain cancer cells, we have developed in vitro and in vivo methods to examine fluid flow responses. In vitro, we have found that interstitial flow enhances invasion of brain cancer cells using both cell lines and patient-derived glioma stem cells in tissue-engineered models of the brain-tumor interface via the chemokine/receptor pair CXCL12/CXCR4. In vivo, we have seen interstitial flow and increase invasion of implanted cancer cells through the brain in part through this same mechanism. By conducting in vivo measurements of interstitial flow using MRI we have correlated regions of interstitial fluid flow, glioma invasion, and glial gene expression of the receptor sphingosine-1-phosphate 3. In this proposal, we will examine the role of interstitial fluid flow as a driving factor of glioma invasion. To make a case for the importance of interstitial flow in regulating GBM invasion first, we will elucidate the true nature of interstitial flow in the in vivo GBM microenvironment. We will accomplish this utilizing clinically relevant imaging and computational tools to probe the prevalence of flow as the tumor develops, and determine regions in which flow is the highest. Second, we will determine the contributions of interstitial flow at the level of cancer cell invasion. We will observe invasion patterns of multiple patient-derived glioblastoma stem cells in the specifically interrogating the mechanism of CXCR4/CXCL12-mediated autologous chemotaxis, a novel mechanism of invasion only possible under flow. Finally, we will use our unique ability to tissue engineer the glioblastoma microenvironment to examine the role of glial-expressed S1PR3 under flow on glioma invasion. Altogether, these reports will advance the importance and strategies for mitigating interstitial flow and its effects in GBM and offer modalities by which to study further effects of flow on therapeutic response. Understanding the impact of interstitial flow will ultimately help predict areas of GBM progression and recurrence. .

项目摘要 胶质母细胞瘤是最致命的脑癌形式，其定义是其细胞的侵袭性。 脑内的侵袭遵循与间质流和整体流相关的独特路径 途径。在脑癌中，增加的间质液流量是由于增加的 肿瘤体积中的间质压力与相对正常的 周围的脑组织或肿瘤微环境。这种差异导致液体运输 特别是穿过肿瘤的侵袭性边缘，在那里细胞倾向于与肿瘤细胞相互作用。 周围的脑组织，并逃避局部，运输有限的治疗。审查如何 间质液流动影响脑癌细胞的侵袭，我们已经在体外和体内开发了 体内方法来检查流体流动反应。在体外，我们发现， 使用细胞系和患者来源的神经胶质瘤干细胞增强脑癌细胞的侵袭 在脑肿瘤界面的组织工程模型中， CXCL12/CXCR4。在体内，我们已经看到间质流动和增加的入侵植入癌 细胞在大脑中的流动也是通过同样的机制通过进行体内测量 使用MRI的间质液流，我们有相关的区域间质液流，胶质瘤浸润， 和受体鞘氨醇-1-磷酸3的神经胶质基因表达。在本提案中，我们将 研究间质液流动作为胶质瘤侵袭驱动因素的作用。要说 间质流在调节GBM侵袭中的重要性首先，我们将阐明GBM侵袭的真正本质。 在体内GBM微环境中的间质流。我们将在临床上利用 相关的成像和计算工具来探测肿瘤发展时血流的流行， 并确定流量最高的区域。第二，我们将确定捐款 在癌细胞侵袭水平上的间质流动。我们将观察到多种入侵模式 患者来源的胶质母细胞瘤干细胞在特异性地询问 CXCR 4/CXCL 12介导的自体趋化性，一种新的侵袭机制， 下流。最后，我们将利用我们独特的能力， 微环境，以检查胶质细胞表达的S1 PR 3在胶质瘤侵袭中的作用。 总之，这些报告将推进减轻间质流的重要性和策略 以及它在GBM中的作用，并提供了进一步研究血流对治疗的影响的模式。 反应了解间隙流的影响将最终有助于预测GBM的面积 进展和复发。 .