Microfluidic tumor models to analyze the role of physicochemical cues in the angi

微流控肿瘤模型分析理化信号在血管生成中的作用

• 批准号: 7943105
• 负责人: Claudia Fischbach
• 金额: $ 50万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943105
• 关键词: 3-Dimensional; Address; Angiogenic Switch; Behavior; Biological Process; Biomimetics; Blood Vessels; Bone Marrow; Cancer Biology; Cell Culture Techniques; Cells; Characteristics; Chemistry; Clinical; Communication; Computer Simulation; Coupled; Cues; D Cells; Data; Data Set; Diffusion; Dissection; Endothelial Cells; Engineering; Environment; Event; Exhibits; Experimental Designs; Gene Expression Profile; Goals; Growth; Hypoxia; Image Analysis; Intrinsic factor; Label; Lead; Liquid substance; Malignant Neoplasms; Mechanics; Mediating; Microfluidics; Modeling; Molecular; Molecular Target; Motion; Mus; Neoplasm Metastasis; Organism; Outcome; Oxygen; Oxygen measurement, partial pressure, arterial; Paracrine Communication; Pathway Analysis; Patients; Perfusion; Phenotype; Physics; Play; Process; Reaction; Recruitment Activity; Research; Research Design; Role; Signal Transduction; Solid Neoplasm; Stem cells; Stromal Cells; Stromal Neoplasm; System; Testing; Tissues; Transducers; Translating; Tube; Tumor Angiogenesis; Up-Regulation; Variant; Vascularization; Xenograft Model; angiogenesis; autocrine; base; clinical care; cytokine; design; improved; mathematical model; outcome forecast; paracrine; physical science; public health relevance; research study; response; spatiotemporal; tissue culture; tool; trafficking; tumor

DESCRIPTION (provided by applicant): The angiogenic switch plays a fundamental role in tumor vascularization and metastasis; however, the underlying cellular and molecular mechanisms by which microenvironmental conditions regulate this process are still unclear. This project will address the hypothesis that the creation of distinct tumor-like niches and crosstalk between cells residing within these niches up-regulates expression of pivotal tumor cytokines that contribute to the recruitment of bone marrow-derived endothelial progenitor cells (EPCs) and enhanced tumor angiogenesis. To address our hypothesis we will utilize a physical-sciences based cancer biology approach that combines 3-D cell culture, microfluidics, and mathematical modeling. Our study design is based on 4 aims: In aim 1, we will design 3-D microfluidic tumor cultures that will allow us to test the hypothesis that the signaling of soluble factors, as regulated by spatially resolved differences in oxygen tension, provides a paracrine mechanism that spans between niches to regulate the differential expression of cytokines by both tumor and stromal cells. In aim 2, we will evaluate whether the global and local dynamics of tumor and stromal cell signaling, as elucidated in aim 1, impact invasion angiogenesis. To this end, we will expand the microfluidic platform developed in aim 1 to integrate endothelialized microchannels. This system will be remodelable and can be adjusted to exhibit enhanced matrix stiffness as typical of the tumor stroma. In aim 3, we will determine whether physicochemically mediated changes in neovessel formation as defined in aim 2 lead to the formation of vascular niches that impact the phenotypic identity, spatial and temporal contribution, and biological function of EPCs and their role in tumor angiogenesis. Finally, in aim 4, we will conduct dynamic global transcriptome and epigenome analysis of EPCs that have incorporated in the microfluidic microvessels. The generated data will be incorporated into computational signal transduction network analysis to identify molecular targets that may be responsible for physicochemically mediated changes in the angiogenic switch. Our proposed studies have the potential to improve current strategies of anti-angiogenic therapies by enhancing our understanding of the tumor angiogenic switch and identifying molecular mechanisms that may be involved in this process and provide therapeutically relevant targets. PUBLIC HEALTH RELEVANCE: Tumor angiogenesis represents a critical event of cancer that involves the recruitment of bone marrow derived endothelial progenitor cells; however, the exact mechanisms and effects by which microenvironmental conditions regulate these processes are not well understood. Using micropathological 3-D tumor models and mathematical modeling approaches this research will address the hypothesis that the creation of oxygen dependent tumor niches, and paracrine cellular crosstalk between these niches, up-regulates expression of pivotal tumor cytokines that impact invasion angiogenesis and the recruitment of endothelial progenitor cells. This interdisciplinary strategy has the potential to revolutionize our understanding of tumor vascularization and elucidate fundamentally new mechanisms of pro-angiogenic activity in cancers that could form a basis for improved anti-angiogenic therapies and clinical outcomes.

描述（由申请人提供）：血管生成开关在肿瘤血管化和转移中起着基本作用；但是，微环境条件调节该过程的基本细胞和分子机制尚不清楚。该项目将解决以下假设：在这些壁ches中，居住在这些壁ches中的细胞之间形成不同的肿瘤样的壁ni和串扰，上调了关键性肿瘤细胞因子的表达，这有助于募集骨衍生的内皮祖细胞（EPC）和增强的肿瘤血管生成。为了解决我们的假设，我们将利用一种基于物理诊断的癌症生物学方法，该方法结合了3-D细胞培养，微流体和数学建模。 Our study design is based on 4 aims: In aim 1, we will design 3-D microfluidic tumor cultures that will allow us to test the hypothesis that the signaling of soluble factors, as regulated by spatially resolved differences in oxygen tension, provides a paracrine mechanism that spans between niches to regulate the differential expression of cytokines by both tumor and stromal cells.在AIM 2中，我们将评估肿瘤和基质细胞信号传导的全局和局部动力学是否在AIM 1中阐明，影响入侵血管生成。为此，我们将扩展AIM 1中开发的微流体平台，以整合内皮化的微通道。该系统将是可重塑的，可以调整以表现出肿瘤基质的典型基质刚度增强。在AIM 3中，我们将确定AIM 2中定义的Neovesle形成的物理化学介导的变化是否导致形成的血管壁细分市场会影响表型认同，空间和时间贡献以及EPC的生物学功能及其在肿瘤血管生成中的作用。最后，在AIM 4中，我们将对已掺入微流体微血管中的EPC进行动态全局转录组和表观基因组分析。生成的数据将纳入计算信号转导网络分析中，以确定可能导致物理化学介导的血管生成开关变化的分子靶标。我们提出的研究有可能通过增强我们对肿瘤血管生成转换的理解并确定可能参与此过程并提供治疗相关靶标的分子机制来改善抗血管生成疗法的当前策略。 公共卫生相关性：肿瘤血管生成代表了癌症的关键事件，涉及刺激骨髓衍生的内皮祖细胞的募集。但是，微环境条件调节这些过程的确切机制和影响尚不清楚。使用微病理学3-D肿瘤模型和数学建模方法，这项研究将解决以下假设：这些壁细分市场之间的氧气依赖性肿瘤壁ni的产生以及旁分泌细胞串扰，上调了关键的肿瘤细胞因子的表达，这些细胞会影响入侵血管生成和内皮细胞的侵袭血管生成和疾病。这种跨学科策略有可能彻底改变我们对肿瘤血管化的理解，并阐明癌症中促血管生成活性的新机制，这可能为改善抗血管生成疗法和临床结果提供基础。