Interstitial Fluid Flow Regulates Glioma Cell Invasion

项目摘要 胶质母细胞瘤是脑癌中最致命的一种，它的定义是其细胞的侵袭性。侵入 脑遵循与间质和整体流动路径相关的独特路径。在脑癌中， 间质液流动的发展是由于肿瘤块中的间质压力增加， 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，特别是穿过肿瘤的侵入性边缘，在那里细胞倾向于与肿瘤细胞相互作用。 周围的脑组织，并逃避局部，运输有限的治疗。检查组织间液是如何流动的 影响脑癌细胞的侵袭，我们已经开发了体外和体内方法来检查流体流动 应答在体外，我们发现，间质流动增强了脑癌细胞的侵袭， 细胞系和患者来源的神经胶质瘤干细胞在脑肿瘤界面的组织工程模型中， 趋化因子/受体对CXCL 12/CXCR 4。在体内，我们已经看到间质流动和增加的侵袭， 通过同样的机制将癌细胞植入大脑。通过在体内进行 使用MRI测量间质液流，我们将间质液流的区域，胶质瘤侵袭， 和受体鞘氨醇-1-磷酸3的神经胶质基因表达。在本提案中，我们将研究 间质液流动作为胶质瘤侵袭的驱动因素。为了证明间质流的重要性 在调节GBM侵袭方面，我们将首先阐明体内GBM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 随着肿瘤的发展，血流的发生率，并确定血流最高的区域。二是 将决定癌细胞侵袭水平上间质流的贡献。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，特别是询问的机制， CXCR 4/CXCL 12介导的自体趋化性，一种仅在流动下可能的新型侵袭机制。 最后，我们将利用我们独特的能力，组织工程胶质母细胞瘤微环境，以检查的作用 流式细胞仪检测胶质细胞表达S1 PR 3对胶质瘤侵袭的影响。总之，这些报告将提高 和减轻GBM间质流及其影响的策略，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。

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.