Matrix stiffness mediated biglycan expression in the tumor vasculature

肿瘤脉管系统中基质刚度介导的双糖链蛋白聚糖表达

基本信息

批准号：
10319916
负责人：
Paul Taufalele
金额：
$ 4.3万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319916
关键词：
Abnormal Endothelial Cell Angiogenic Switch Automobile Driving Behavior Biochemical Biocompatible Materials Biological Assay Blood Blood Vessels Cell physiology Cells Characteristics Chemicals Communities Coupled Cues DNA Methylation Data Disease Drug Delivery Systems Endothelial Cells Endothelium Epigenetic Process Extracellular Matrix Extracellular Matrix Proteins Family Genes Goals Growth Hypoxia In Vitro Leucine Link Malignant Neoplasms Mechanics Mediating Molecular Normal tissue morphology Nutrient Oxygen Pathologic Pathologic Neovascularization Pathway interactions Perfusion Permeability Phenotype Process Prognosis Proteoglycan Regulation Role Signal Transduction Structure Testing Therapeutic Tissue Engineering Tissues Transgenic Mice Tumor Angiogenesis Work angiogenesis autocrine biglycan cancer therapy cell behavior combat crosslink in vivo insight interest malignant breast neoplasm mechanical properties novel strategies overexpression recruit response therapeutic target transcriptome sequencing tumor tumor growth tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY Angiogenesis refers to the process by which new blood vessels grow from pre-existing ones. Excessive angiogenesis is a hallmark of many cancers and contributes to cancer progression. During tumor growth, the angiogenic switch is deregulated resulting in an abnormal vasculature characterized by hyperpermeable, tortuous, and immature blood vessels. Consequences of the irregular tumor vasculature include poor tumor perfusion resulting in hypoxia and hindrance to therapeutic drug delivery. While it is well established that chemical cues are heavily involved in regulating tumor angiogenesis, the influence of mechanical cues are becoming more apparent. Notably, the extracellular matrix is significantly stiffer than normal tissue in many cancers, and elevated matrix stiffness has been shown to promote angiogenesis and disrupt barrier integrity. Prior work in our lab has shown both in vitro and in vivo that increased matrix crosslinking (resulting in a stiffer matrix) increases endothelial sprouting and causes more permeable blood vessels to form. However, the mechanisms governing the effects of matrix stiffness on endothelial cell function are still poorly understood. Uncovering the mechanisms driving stiffness-mediated effects on endothelial cells is critical for developing novel approaches to normalize tumor vasculature and promote normal vessel growth. Interestingly, our preliminary data obtained through RNA-sequencing indicate that endothelial biglycan expression is regulated by matrix stiffness in vitro and in vivo. Previously, biglycan has been identified as a tumor endothelial cell marker and biglycan overexpression is correlated to poor prognosis in several cancers. Notably, biglycan can promote angiogenesis as an autocrine agent. While it is established that biglycan is upregulated in disease and contributes to pathological endothelial signaling and behavior, our data indicates that ECM stiffness may drive these effects. Given these findings, we will use tailored biomaterials, transgenic mice, and state of the art biochemical assays to investigate the hypothesis that matrix stiffness increases cellular contractility to drive elevated endothelial biglycan expression and promote aberrant angiogenesis and hyperpermeability. In aim 1, the molecular mechanism governing matrix stiffness driven endothelial biglycan expression will be determined. In aim 2, the effects of matrix stiffness-mediated endothelial biglycan expression in promoting increased angiogenesis and a hyperpermeable phenotype will be investigated. This work will provide critical insight into how the mechanical properties of tumors regulate the structure and integrity of vasculature and uncover potential therapeutic targets for vasculature normalization with a focus on endothelial biglycan regulation.

项目概要血管生成是指新血管从已有血管生长的过程。过多的血管生成是许多癌症的标志，并有助于癌症进展。肿瘤期间生长过程中，血管生成开关失调，导致脉管系统异常，其特征为通透性高、曲折且不成熟的血管。不规则肿瘤的后果脉管系统包括肿瘤灌注不良，导致缺氧并阻碍治疗药物送货。虽然化学信号在肿瘤调节中发挥着重要作用，这一点已得到充分证实血管生成中，机械信号的影响变得越来越明显。值得注意的是，细胞外在许多癌症中，基质明显比正常组织坚硬，并且基质硬度升高显示可促进血管生成并破坏屏障完整性。我们实验室之前的工作已经表明体外和体内增加基质交联（导致更硬的基质）增加内皮细胞发芽并导致形成更具渗透性的血管。然而，管理机制基质硬度对内皮细胞功能的影响仍知之甚少。揭开驱动内皮细胞刚度介导效应的机制对于开发新的药物至关重要使肿瘤血管系统正常化并促进正常血管生长的方法。有趣的是，我们的通过RNA测序获得的初步数据表明内皮双糖链蛋白聚糖的表达是体外和体内受基质硬度调节。此前，双糖链蛋白聚糖已被确定为肿瘤内皮细胞标记物和双糖链蛋白聚糖过度表达与多种癌症的不良预后相关。值得注意的是，双糖链蛋白聚糖可以作为自分泌剂促进血管生成。虽然已经确定 biglycan 在疾病中上调并有助于病理性内皮信号传导和行为，我们的数据表明 ECM 刚度可能会导致这些影响。鉴于这些发现，我们将使用量身定制的生物材料、转基因小鼠和最先进的生化测定来研究以下假设：基质硬度增加细胞收缩性以驱动内皮双糖链蛋白聚糖表达升高促进异常血管生成和渗透性过高。在目标1中，控制的分子机制将确定基质硬度驱动的内皮双糖链蛋白聚糖表达。在目标 2 中，矩阵的影响硬度介导的内皮双糖链蛋白聚糖表达促进血管生成增加将研究高通透性表型。这项工作将为我们如何肿瘤的机械特性调节脉管系统的结构和完整性并揭示血管系统正常化的潜在治疗靶点，重点关注内皮双糖链蛋白聚糖规定。