A microRNA mediating vascular directed fibrinolysis and tumor progression

介导血管定向纤溶和肿瘤进展的 microRNA

• 批准号: 9460134
• 负责人: James V McCann
• 金额: $ 3.33万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-13 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9460134
• 关键词: Blood Vessels; Cells; Cellular biology; Connective Tissue; Coupled; Data; Deposition; Drug Delivery Systems; Employee Strikes; Endothelial Cells; Endothelium; Equilibrium; Fibrin; Fibrinolysis; Fibroblasts; Fibrosis; Goals; Human; Hypoxia; Immune; Immunohistochemistry; Impairment; In Vitro; Inflammatory; Knockout Mice; Knowledge; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; MicroRNAs; Modeling; Morphology; Mus; Myofibroblast; Neoplasms in Vascular Tissue; Pathway interactions; Permeability; Pharmacology; Plasminogen Activator Inhibitor 1; Play; Process; Role; Science; Solid Neoplasm; Stromal Cells; Testing; Thrombosis; Transforming Growth Factor beta; Tumor Angiogenesis; Tumor Cell Invasion; Tumor-Associated Vasculature; Up-Regulation; angiogenesis; cancer cell; catalyst; cell growth; clinically relevant; dosage; experimental study; in vivo; inhibitor/antagonist; millimeter; nanoparticle; neoplastic cell; overexpression; response; scaffold; targeted treatment; tumor; tumor growth; tumor microenvironment; tumor progression; vascular contributions

Project Summary/Abstract Solid tumors cannot grow beyond a few millimeters in size without the support of co-opted stromal cells. The function of different stromal cells in the tumor microenvironment may be subverted in ways that are beneficial for tumor progression. Examples are the tumor-induced and specific polarization of immune/inflammatory cells, conversion of fibroblasts into tumor-supportive myofibroblasts, and dysfunctional tumor endothelial cells. Irregular and hyper-permeable vasculature occurs early when only a few hundred-tumor cells are present. Leaky tumor blood vessels deposit fibrin in a perivascular niche that forms scaffolds for tumor cell growth and invasion as well as sparks angiogenesis. Using a miRNA screen of freshly isolated TECs, I identified a TGFβ-regulated miRNA (miR-30c) that controls vascular-directed fibrinolysis in tumors. miR-30c is increased in TECs relative to normal endothelial cells (NECs) whereas its target PAI-1 (a fibrinolysis inhibitor) is strikingly decreased. TECs secrete less PAI-1 and they rapidly degrade fibrin scaffolds resulting in aberrant in vitro sprouting. However, TGFβ and miR-30c antagomiRs reduce miR-30c expression which re-instates PAI-1 secretion, diminishes fibrinolysis, and “normalizes” TEC sprouting in vitro. miR-30c antagomiRs coupled to vascular-tropic nanoparticles enforce vascular-specific PAI-1 expression and strikingly promote robust orthotopic mammary tumor growth in vivo. Thus, manipulation of vascular-specific expression of miR-30c in tumors promotes tumor growth likely due to enhanced fibrin-mediated angiogenesis. I propose an axis between TGFβ, miR-30c and PAI-1 in TECs controls the rate of perivascular fibrinolysis and is therefore an important effector of tumor angiogenesis and progression.

项目概要/摘要 如果没有增选基质细胞的支持，实体瘤的大小就无法生长超过几毫米。这 肿瘤微环境中不同基质细胞的功能可能会以有益的方式被颠覆 用于肿瘤进展。例子是肿瘤诱导的免疫/炎症细胞的特异性极化， 成纤维细胞转化为肿瘤支持性肌成纤维细胞和功能失调的肿瘤内皮细胞。 当仅存在几百个肿瘤细胞时，不规则和高渗透性脉管系统就出现在早期。 渗漏的肿瘤血管将纤维蛋白沉积在血管周围的微环境中，形成肿瘤细胞生长的支架 入侵并引发血管生成。 通过对新鲜分离的 TEC 进行 miRNA 筛选，我发现了一种 TGFβ 调节的 miRNA (miR-30c)，它控制 肿瘤中的血管定向纤溶。相对于正常内皮细胞，TEC 中 miR-30c 增加 (NECs)，而其目标 PAI-1（纤维蛋白溶解抑制剂）却显着减少。 TEC 分泌较少的 PAI-1 且 它们迅速降解纤维蛋白支架，导致异常的体外发芽。然而，TGFβ 和 miR-30c antagomiRs 降低 miR-30c 表达，从而恢复 PAI-1 分泌，减少纤维蛋白溶解，并 TEC 体外发芽“正常化”。 miR-30c antagomiRs 与血管亲和性纳米颗粒偶联增强 血管特异性 PAI-1 表达并显着促进体内原位乳腺肿瘤的强劲生长。 因此，操纵肿瘤中 miR-30c 的血管特异性表达可促进肿瘤生长，这可能是由于 增强纤维蛋白介导的血管生成。我提出 TEC 中 TGFβ、miR-30c 和 PAI-1 之间的轴 控制血管周围纤维蛋白溶解的速率，因此是肿瘤血管生成和 进展。