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

• 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
• 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

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.

项目摘要 血管生成是指新血管从先前存在的血管生长的过程。过度 血管生成是许多癌症的标志，并且有助于癌症的进展。在肿瘤 生长时，血管生成开关失调，导致异常的脉管系统，其特征在于 高渗透性、曲折和不成熟的血管。不规则肿瘤的后果 血管系统包括不良的肿瘤灌注，导致缺氧和治疗药物的阻碍 交付.虽然已经很好地建立了化学信号在调节肿瘤中的重要作用， 在血管生成中，机械提示的影响变得越来越明显。值得注意的是， 在许多癌症中，基质比正常组织明显更硬，并且基质硬度升高已经被认为是癌症的主要原因。 显示促进血管生成和破坏屏障完整性。我们实验室先前的工作表明， 在体外和体内，增加的基质交联（导致更硬的基质）增加了内皮细胞的生长。 发芽并形成更具渗透性的血管。然而，管理 基质硬度对内皮细胞功能的影响仍然知之甚少。揭开 驱动对内皮细胞的刚性介导效应的机制对于开发新的 使肿瘤脉管系统正常化并促进正常血管生长的方法。有趣的是，我们 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 通过体外和体内基质硬度调节。此前，biglycan已被确定为肿瘤 内皮细胞标志物和双糖蛋白聚糖过表达与几种癌症的不良预后相关。 值得注意的是，双糖蛋白聚糖可以作为自分泌剂促进血管生成。虽然已经确定， 在疾病中上调，并导致病理性内皮信号传导和行为，我们的数据显示， 表明ECM刚度可能驱动这些效应。鉴于这些发现，我们将使用定制的 生物材料、转基因小鼠和最先进的生物化学测定来研究以下假设： 基质硬度增加细胞收缩性以驱动升高的内皮双糖蛋白聚糖表达， 促进异常的血管生成和高渗透性。在目标1中， 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， 刚性介导的内皮双糖蛋白聚糖表达促进血管生成增加， 将研究高渗透性表型。这项工作将提供关键的洞察力如何 肿瘤的机械性质调节血管的结构和完整性， 血管正常化的潜在治疗靶点，重点关注内皮双糖蛋白聚糖 调控