Interstitial Fluid Flow Regulates Glioma Cell Invasion

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。 大脑的侵袭遵循与间质和大块血流相关的独特路线 小路。在脑癌中，间质液体流量增加是由于 肿瘤间质内的压力与肿瘤相对正常的压力 周围脑组织，或肿瘤微环境。这种差异导致了流体的运输 尤其是在肿瘤的侵袭边缘，在那里细胞容易与 并避免局部的、运输受限的治疗。要研究如何 间质液体流动影响脑癌细胞的侵袭，我们在体外和在 检查流体流动反应的活体方法。在体外，我们发现间质血流 同时使用细胞系和患者来源的胶质瘤干细胞增强脑癌细胞的侵袭性 在脑肿瘤界面的组织工程模型中，通过趋化因子/受体对 CXCL12/CXCR4。在活体中，我们已经看到了植入性癌症的间质流动和侵袭性增加。 细胞穿过大脑，部分是通过同样的机制。通过进行活体测量 通过核磁共振对间质血流的分析，我们发现了间质液体流动、胶质瘤侵犯、 和神经胶质细胞受体鞘氨醇-1-磷酸3的基因表达。在这个提案中，我们将 检查间质液体流动作为胶质瘤侵袭的驱动因素的作用。为……辩护 间质血流在调节基底膜侵袭中的重要性首先，我们将阐明其真实性质。 在活体基底膜微环境中的间质流动。我们将在临床上实现这一点。 相关的成像和计算工具，以探测肿瘤发展过程中血流的普遍性， 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血流。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询问机制中的作用 CXCR4/CXCL12介导的自体趋化作用--一种仅可能的侵袭新机制 在流下。最后，我们将使用我们独特的能力对胶质母细胞瘤进行组织工程 微环境检测Flow下胶质细胞表达的S1PR3在胶质瘤侵袭中的作用。 总之，这些报告将推进缓解组织间流动的重要性和策略 以及它在GBM中的作用，并提供了进一步研究Flow对治疗的影响的方法 回应。了解间质血流的影响最终将有助于预测基底膜的面积 进展性和复发性。 。

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. .