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:10297833
- 负责人:
- 金额:$ 48.68万
- 依托单位:
- 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:
- 关键词:3-DimensionalAffectAlgorithmic AnalysisAreaAstrocytesAutologousAutomobile DrivingBrainBrain NeoplasmsBrain regionCCL21 geneCXCL12 geneCXCL5 geneCXCR4 geneCell LineCellsChemotaxisCoculture TechniquesComputer ModelsContrast MediaCorrelative StudyDiseaseExtracellular MatrixFibroblastsGene ExpressionGenetic EngineeringGlioblastomaGliomaGrantImageImaging DeviceImplantIn VitroIntercellular FluidKnock-outLiquid substanceMagnetic Resonance ImagingMalignant neoplasm of brainMapsMeasurementMeasuresMediatingMethodologyMethodsMicroarray AnalysisMicrofluidicsMicrogliaModalityModelingMusNatureNeurogliaOutcomePathway interactionsPatientsPatternPhysiologicalPopulationPrevalencePrognosisRadiationRadiation therapyRecurrenceReporterReportingRoleRouteSignal TransductionSphingosine-1-Phosphate ReceptorStromal CellsSystemTechniquesTestingTherapeuticTimeTissue EngineeringTissuesUp-RegulationWorkXenograft procedurebrain parenchymabrain tissuecancer cellchemokinechemokine receptorclinically relevantcomputerized toolscontrast enhancedexperimental studyfluid flowin vitro Assayin vivoin vivo Modelinhibitorinterstitialmalignant breast neoplasmmechanical forcemouse modelneoplastic cellnoveloverexpressionpressureresponsesmall moleculestem cellstreatment responsetumortumor growthtumor 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.
项目摘要
胶质母细胞瘤是脑癌的最致命形式,是由其细胞的侵入性特性定义的。入侵
大脑遵循与间隙和散装流道相关的独特路线。在脑癌中,增加
间质性流体流量由于与肿瘤大体接口的间隙式增大而发展
周围脑组织或肿瘤微环境的相对正常压力。这种差异导致
流体转运特定在肿瘤的侵入性边缘,细胞易于与
周围的脑组织并逃避局部的运输受限疗法。检查间质流体如何流动
影响脑癌细胞的侵袭,我们已经在体外和体内方法开发了研究流体流动
回答。在体外,我们发现使用两个细胞的间隙流可以增强脑癌细胞的侵袭
线条和患者衍生的神经胶质瘤干细胞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。在体内,我们看到了间隙流并增加了
通过这种相同的机制植入大脑的癌细胞。通过体内进行
使用MRI的间质流量测量我们具有间质流体流动的相关区域,神经胶质瘤入侵,
和受体鞘氨醇1-磷酸3的神经胶质基因表达3。在此提案中,我们将检查该作用
间质流体流作为神经胶质瘤侵袭的驱动因子。为了说明间隙流的重要性
在调节GBM入侵时,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这一问题
随着肿瘤的发展,流动率的流行率,并确定流量最高的区域。第二,我们
将确定癌细胞浸润水平上的间质流的贡献。我们将观察入侵
多个患者衍生的胶质母细胞瘤干细胞的模式在特殊询问的机制中
CXCR4/CXCL12介导的自体趋化性,这种新型侵袭机制仅在流动下。
最后,我们将利用我们独特的能力来组织胶质母细胞瘤微环境来检查角色
在神经胶质瘤侵袭下流动下的神经胶质表达的S1PR3。总之,这些报告将提高重要性
以及缓解间隙流及其在GBM中的影响的策略,并提供了进一步研究的方式
流动对治疗反应的影响。了解间质流的影响最终将有助于预测
GBM的进展和复发区域。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Jennifer M Munson其他文献
Jennifer M Munson的其他文献
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{{ truncateString('Jennifer M Munson', 18)}}的其他基金
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:
10443221 - 财政年份:2022
- 资助金额:
$ 48.68万 - 项目类别:
Interstitial fluid flow in Alzheimer's Disease Progression
阿尔茨海默病进展中的间质液流动
- 批准号:
10185070 - 财政年份:2021
- 资助金额:
$ 48.68万 - 项目类别:
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:
10057362 - 财政年份:2017
- 资助金额:
$ 48.68万 - 项目类别:
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 - 财政年份:2017
- 资助金额:
$ 48.68万 - 项目类别:
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