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. .

项目概要 胶质母细胞瘤是最致命的脑癌，其细胞具有侵袭性。 大脑的侵袭遵循与间质和整体血流相关的独特路线 途径。在脑癌中，间质液流量增加是由于 肿瘤体积内的间质压力与相对正常的压力相交 周围的脑组织或肿瘤微环境。这种差异导致流体输送 特别是跨越肿瘤的浸润边缘，细胞很容易与肿瘤细胞相互作用 周围的脑组织并逃避局部的、运输受限的治疗。检查如何 间质液流动影响脑癌细胞的侵袭，我们已经在体外和在 检查流体流动反应的体内方法。在体外，我们发现间质流 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 通过趋化因子/受体对在脑-肿瘤界面的组织工程模型中 CXCL12/CXCR4。在体内，我们看到了间质流动并增加了植入性癌症的侵袭 细胞通过大脑部分通过相同的机制。通过进行体内测量 使用 MRI 分析间质流，我们将间质液流区域、神经胶质瘤侵袭、 以及受体鞘氨醇-1-磷酸3的神经胶质基因表达。在本提案中，我们将 检查间质液流动作为神经胶质瘤侵袭驱动因素的作用。为了证明 首先，我们将阐明间质流在调节 GBM 侵袭中的重要性 体内 GBM 微环境中的间质流动。我们将利用临床来实现这一目标 相关的成像和计算工具来探测肿瘤发展过程中血流的普遍程度， 并确定流量最高的区域。其次，我们将确定捐款额 癌细胞侵袭水平的间质流动。我们将观察多种入侵模式 患者来源的胶质母细胞瘤干细胞在具体询问机制 CXCR4/CXCL12介导的自体趋化性，一种新的入侵机制才有可能 流动下。最后，我们将利用我们独特的能力对胶质母细胞瘤进行组织工程 微环境来检查神经胶质细胞表达的 S1PR3 在流动下对神经胶质瘤侵袭的作用。 总而言之，这些报告将提高缓解间隙流动的重要性和策略 及其对 GBM 的影响，并提供研究血流对治疗的进一步影响的模式 回复。了解间质流的影响最终将有助于预测 GBM 区域 进展和复发。 。