The influence of the extracellular RNA/RNase system on humoral and cellular reactions at the tumor-vessel interface

肿瘤-血管界面是一个脆弱的相互作用系统，与持续的组织重塑相关，包括细胞侵袭、增殖和凋亡，受体液和细胞介质的调节。患者的肿瘤负荷与高凝状态和血栓栓塞并发症相关，然而，缺乏对因果关系或分子机制的任何见解。我们最近发现细胞外RNA（eRNA）作为一种新的丝氨酸蛋白酶促凝血辅助因子和eRNA促进体内血液凝固的启动和进展。另一方面，核糖核酸酶给药在血栓形成动物模型中具有有效的抗血栓形成作用。此外，天然和人工eRNA都导致内皮细胞的活化。基于这些发现，我们假设eRNA在肿瘤-血管界面内的体液和细胞活动中起重要但尚未被认识的作用。在这个项目中，我们的目标是：（a）表征与肿瘤组织实体相关的eRNA并分析肿瘤特异性eRNA;（B）分析RNA酶在肿瘤和内皮细胞中的表达和功能;（c）表征肿瘤细胞的eRNA依赖性细胞活性（增殖、迁移）和内皮细胞（渗透性、血管生成）以及鉴定eRNA依赖性受体/信号通路;（e）描述不同肿瘤模型中eRNA相关的肿瘤相关高凝状态的机制，并追求RNA酶可能作为新的抗肿瘤模式的概念。从这些提出的在体内和体外实验的结果将获得新的见解eRNA依赖的分子和细胞的相互关系的肿瘤血管接口的可能性，适用于肿瘤治疗的有前途的策略。

The tumor-vessel interface constitutes a fragile interaction system that is associated with continuous tissue remodelling including cell invasion, proliferation and apoptosis, regulated by humoral and cellular mediators. Tumor burden in patients has been correlated with a hypercoagulable state and thromboembolic complications, yet, any insights into causal relations or molecular mechanisms are missing. We have recently identified extracellular RNA (eRNA) as a novel procoagulant cofactor for serine proteases and eRNA promotes the initiation and progression of blood coagulation in vivo. On the other hand RNase administration had a potent antithrombotic effect in animal models of thrombosis. Moreover, both natural and artificial eRNA lead to activation of endothelial cells. Based on these findings we hypothesize that eRNA plays an important but yet unrecognized role in humoral and cellular activities within the tumor-vessel interface. In this project we aim to: (a) characterize eRNA in association with tumor tissue entities and analyse tumor-specific eRNA; (b) analyse the expression and function of RNases in tumor and endothelial cells; (c) characterize eRNA-dependent cellular activities of tumor cells (proliferation, migration) and endothelial cells (permeability, angiogenesis) as well as identify eRNA-dependent receptor/signaling pathways; (e) describe the mechanism of eRNA-related tumor-associated hypercoagulability in different tumor models, and pursue the concept that RNases may serve as novel anti-tumor modality. Results from these proposed in vivo and in vitro experiments will gain novel insights into eRNA-dependent molecular and cellular interrelations of the tumor-vessel interface with the possibility to apply promising strategies for tumor therapy.