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Interstitial Fluid Flow Regulates Glioma Cell Invasion

间质液流动调节神经胶质瘤细胞侵袭

基本信息

批准号：
10057362
负责人：
Jennifer M Munson
金额：
$ 47.7万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
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/10057362
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/antagonist 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

项目摘要

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.

项目总结