Mechanical Regulation of Tumor Angiogenesis

肿瘤血管生成的机械调节

基本信息

批准号：
9471682
负责人：
Cynthia A. Reinhart-King
金额：
$ 54.81万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9471682
关键词：
Affect Area Attention Biological Assay Blood Circulation Blood Vessels Cell-Cell Adhesion Cells Chemicals Collagen Cues Data Drug Delivery Systems Endothelial Cells Exhibits Gene Expression Regulation Goals Growth Heterogeneity Hypoxia Imaging Techniques Impairment In Vitro Mammary Neoplasms Measures Mechanics Mediating Metastatic breast cancer Microvascular Permeability Neoplasm Metastasis Normal tissue morphology PTK2 gene Pathway interactions Perfusion Permeability Phenotype Physical environment Play Publishing Radiation therapy Regulation Research Personnel Role Signal Transduction Solid Neoplasm Structure Therapeutic Tissues Translational Research Tumor Angiogenesis Tumor Tissue Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Permeabilities Vascularization Work angiogenesis cancer therapy cancer type crosslink density differential expression improved in vitro Model in vivo in vivo Model in vivo imaging mechanical properties migration monolayer new therapeutic target novel prevent public health relevance response rho success synergism transcriptome sequencing translational medicine tumor tumor growth tumor microenvironment tumor progression

Affect Area Attention Biological Assay Blood Circulation Blood Vessels Cell-Cell Adhesion Cells Chemicals Collagen Cues Data Drug Delivery Systems Endothelial Cells Exhibits Gene Expression Regulation Goals Growth Heterogeneity Hypoxia Imaging Techniques Impairment In Vitro Mammary Neoplasms Measures Mechanics Mediating Metastatic breast cancer Microvascular Permeability Neoplasm Metastasis Normal tissue morphology PTK2 gene Pathway interactions Perfusion Permeability Phenotype Physical environment Play Publishing Radiation therapy Regulation Research Personnel Role Signal Transduction Solid Neoplasm Structure Therapeutic Tissues Translational Research Tumor Angiogenesis Tumor Tissue Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Permeabilities Vascularization Work angiogenesis cancer therapy cancer type crosslink density differential expression improved in vitro Model in vivo in vivo Model in vivo imaging mechanical properties migration monolayer new therapeutic target novel prevent public health relevance response rho success synergism transcriptome sequencing translational medicine tumor tumor growth tumor microenvironment tumor progression

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项目摘要

DESCRIPTION (provided by applicant): Angiogenesis is upregulated in solid tumors, but the microvasculature that forms is more tortuous and permeable than typical vasculature. Traditional cancer therapies have focused on inhibiting angiogenesis to starve tumors. However, more recent evidence suggests that this approach may have deleterious effects because minimizing angiogenesis increases hypoxia in the tumor which is associated with decreased efficacy of chemotherapeutic and radiation treatment. Moreover, incomplete or leaky vessels can facilitate the intravasation of metastatic cells into the vasculature. As such, stabilizing vasculature may be a promising therapeutic approach to minimizing metastasis, increasing chemotherapeutic efficacy and improving drug delivery to the tumor. Significant emphasis has been placed on targeting VEGF, as it is known to play a key role in promoting angiogenesis and causing increased vascular permeability. However, anti-VEGF therapeutics has met with limited success in several cancer types, including metastatic breast cancer. The researchers' exciting, new data indicates that matrix stiffness, mimicking the stiffening that occurs during breast tumor progression, causes increased angiogenic outgrowth and increased endothelial monolayer permeability- notably, these are the same endothelial phenotypes that are attributed primarily to the action of VEGF. Moreover, these data indicate that matrix stiffness augments endothelial permeability response to VEGF, suggesting a crosstalk between VEGF and matrix stiffness-mediated signaling. Given these findings, this project will investigate the hypothesis that matrix stiffening contributes to impaired microvascular integrity in tumors by disrupting endothelial cell-cell adhesion, and correspondingly, inhibition of stiffening and/or endothelial cell response to stiffening can minimize impaired vascular integrity. Here, 3D in vitro models of matrix stiffness, in vivo models of tumor stiffening, advanced in vivo imaging techniques and RNA-seq will be used to investigate the mechanism by which matrix stiffness alters microvascular permeability in the tumor microenvironment. In Aim 1, the synergies between matrix stiffness and VEGF-mediated permeability will be defined. In Aim 2, the effects of mechanical heterogeneities in the matrix on vessel outgrowth and integrity will be investigated. In Aim 3, approaches to inhibit stiffness-induced vascular barrier disruption will be explored. Together, this work will lead to the identification of novel therapeutic targets to normalize tumor vasculature.

描述（由适用提供）：血管生成在实体瘤中进行了更新，但是形成的微脉管系统比典型的脉管系统更曲折，更可渗透。传统的癌症疗法的重点是抑制血管生成饥饿肿瘤。但是，最近的证据表明，这种方法可能已经删除了作用，因为最大程度地减少血管生成会增加肿瘤中缺氧，这与化学治疗和放射治疗效率降低有关。此外，不完全或泄漏的vissels可以促进转移细胞进入脉管系统。因此，稳定脉管系统可能是一种有希望的疗法，可以最大程度地减少转移，提高化学治疗效率并改善对肿瘤的药物递送。众所周知，这在促进血管生成和导致血管渗透性增加方面起着关键作用，这是靶向VEGF的重要重点。但是，抗VEGF疗法在包括转移性乳腺癌在内的几种癌症类型中取得了有限的成功。研究人员令人兴奋的新数据表明，基质刚度模仿乳腺肿瘤进展过程中发生的僵硬，导致血管生成的产物增加并增加了内皮单层渗透率，这些渗透性可能是相同的内皮表型，主要归因于VEGF的作用。此外，这些数据表明矩阵刚度增强对VEGF的内皮渗透性响应，表明VEGF和基质刚度介导的信号传导之间存在串扰。鉴于这些发现，该项目将通过破坏内皮细胞 - 细胞粘合剂的破坏，并相应地抑制僵硬和/或内皮细胞对僵硬的抑制作用可最大程度地减少血管完整性的抑制作用，从而调查基质僵硬的假说，从而有助于肿瘤中的微血管完整性受损。在这里，体外3D 基质刚度的模型，体内肿瘤僵硬，先进的体内成像技术和RNA-Seq的模型将用于研究基质刚度改变肿瘤微环境中微血管通透性的机制。在AIM 1中，将定义矩阵刚度和VEGF介导的渗透性之间的协同作用。在AIM 2中，将研究基质中机械异质性对血管生长和完整性的影响。 3，抑制刚度引起的血管屏障破坏的方法将是探索。总之，这项工作将导致鉴定新的治疗靶标，以使肿瘤脉管系统正常化。