A microRNA mediating vascular directed fibrinolysis and tumor progression

项目总结/摘要 实体瘤在没有增选的基质细胞的支持下不能生长超过几毫米的大小。的 肿瘤微环境中不同基质细胞的功能可能以有益的方式被颠覆 for tumor肿瘤progression进展.实例是免疫/炎性细胞的肿瘤诱导和特异性极化， 成纤维细胞转化为肿瘤支持性肌成纤维细胞和功能障碍的肿瘤内皮细胞。 不规则和高渗透性的脉管系统在只有几百个肿瘤细胞存在的早期发生。 渗漏的肿瘤血管存款纤维蛋白在血管周围的小生境，形成肿瘤细胞生长的支架， 入侵以及引发血管生成。 使用新鲜分离的TEC的miRNA筛选，我鉴定了一种控制TGFβ调节的miRNA（miR-30 c） 肿瘤中的血管定向纤维蛋白溶解。miR-30 c在TEC中相对于正常内皮细胞增加 而其靶派-1（一种纤维蛋白溶解抑制剂）显著降低。TEC分泌较少的派-1， 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-30 c miR-30降低miR-30 c表达，其恢复派-1分泌，减少纤维蛋白溶解， 使TEC在体外发芽“正常化”。与亲血管性纳米颗粒偶联的miR-30 c miR-30 c微球增强 血管特异性派-1表达，并显著促进体内原位乳腺肿瘤生长。 因此，在肿瘤中操纵miR-30 c的血管特异性表达促进肿瘤生长可能是由于 增强纤维蛋白介导的血管生成。我提出了TEC中TGFβ、miR-30 c和派-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的重要效应物， 进展

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.