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: 9425498
• 负责人: Jennifer M Munson
• 金额: $ 57.51万
• 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/9425498
• 关键词: 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 Simulation; 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; Radiation; Radiation therapy; Recurrence; Reporter; Reporting; Role; Route; Signal Transduction; Sphingosine-1-Phosphate Receptor; Stem cells; 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/antagonist; interstitial; malignant breast neoplasm; mechanical force; mouse model; neoplastic cell; novel; outcome forecast; overexpression; pressure; response; small molecule; 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，其细胞的侵袭性是其定义。侵略者在 大脑遵循与间质和整体流动相关的不同路线。在脑癌方面，增加 间质液体流动是由于肿瘤块状组织中间质压力增加而形成的。 周围脑组织压力相对正常，或肿瘤微环境。这种差异导致了 液体转运特别是通过肿瘤的侵袭边缘，在那里细胞容易与 并避免局部的、运输受限的治疗。检查组织间流体如何流动 影响脑癌细胞的侵袭，我们已经开发出体外和体内检测液体流动的方法 回应。在体外，我们发现间质血流通过这两种细胞增强了脑癌细胞的侵袭力。 脑-肿瘤界面的组织工程模型中的细胞系和患者来源的胶质瘤干细胞 趋化因子/受体对CXCL12/CXCR4。在活体内，我们已经看到间质血流和增加的侵袭 通过大脑植入癌细胞，部分是通过同样的机制。通过在体内进行 用MRI测量间质血流我们得到了间质液体流动、胶质瘤侵袭、 和神经胶质细胞中神经鞘氨醇-1-磷酸3受体的基因表达。在这项建议中，我们将研究 间质液体流动是胶质瘤侵袭的驱动因素。为了证明组织间流动的重要性 在调控基底膜侵袭的过程中，我们首先要阐明体内基底膜间质流动的真实性质。 微环境。我们将利用临床相关的成像和计算工具来探测 随着肿瘤的发展，血流的患病率，并确定哪些区域的血流最高。第二，我们 将决定间质血流在癌细胞侵袭水平的贡献。我们将观察入侵 多个患者来源的胶质母细胞瘤干细胞在特异性询问胶质母细胞瘤机制中的模式 CXCR4/CXCL12介导的自体趋化，一种新的侵袭机制，只有在FLOW下才可能发生。 最后，我们将使用我们独特的能力来组织工程胶质母细胞瘤微环境来检查其作用 胶质细胞表达的S1PR3在脑胶质瘤侵袭中的作用总而言之，这些报告将提高 以及减轻基底膜间质血流及其影响的策略，并提供了进一步研究的模式 流动对治疗反应的影响。了解间质流动的影响最终将有助于预测 基底膜进展和复发的区域。