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: 10297833
• 负责人: Jennifer M Munson
• 金额: $ 48.68万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297833
• 关键词: 3-Dimensional; Affect; Algorithmic Analysis; Area; Astrocytes; Autologous; Automobile Driving; Brain; Brain Neoplasms; Brain region; CCL21 gene; CXCL12 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; 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; Radiation therapy; Recurrence; Reporter; Reporting; Role; Route; Signal Transduction; Sphingosine-1-Phosphate Receptor; 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; 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。入侵于 大脑遵循与间质和整体流动路径相关的独特路径。在脑癌中，增加 间质液流的发展是由于肿瘤体与肿瘤的界面间质压力的增加 周围脑组织或肿瘤微环境的相对正常压力。这种差异导致 液体运输特别穿过肿瘤的侵入边缘，其中细胞易于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。检查间质液如何流动 影响脑癌细胞的侵袭，我们开发了体外和体内方法来检查流体流动 回应。在体外，我们发现间质流利用两种细胞增强了脑癌细胞的侵袭 通过脑-肿瘤界面的组织工程模型中的细胞系和患者来源的神经胶质瘤干细胞 趋化因子/受体对 CXCL12/CXCR4。在体内，我们已经看到间质流动和增加的侵袭 部分通过相同的机制将癌细胞植入大脑。通过在体内进行 使用 MRI 测量间质流量，我们将间质液流量区域、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，我们将研究其作用 间质液流动作为神经胶质瘤侵袭的驱动因素。论证间隙流的重要性 首先，在调节 GBM 侵袭方面，我们将阐明体内 GBM 中间质流的真实性质 微环境。我们将利用临床相关的成像和计算工具来探测来实现这一目标 肿瘤发展时血流的普遍程度，并确定血流最高的区域。第二，我们 将确定间质流在癌细胞侵袭水平上的贡献。我们将观察入侵 多个患者来源的胶质母细胞瘤干细胞的模式在具体询问机制中 CXCR4/CXCL12 介导的自体趋化性，一种只有在流动下才有可能的新型入侵机制。 最后，我们将利用我们对胶质母细胞瘤微环境进行组织工程的独特能力来检查其作用 神经胶质瘤侵袭时神经胶质细胞表达的 S1PR3 在流动下的变化。总而言之，这些报告将提高重要性 以及减轻间质流动及其对 GBM 影响的策略，并提供进一步研究的模式 流量对治疗反应的影响。了解间隙流的影响最终将有助于预测 GBM 进展和复发的区域。