Roles of the Polyphosphate/ Factor XII- pathway in malignancy-associated inflammatory and prothrombotic diseases: New biomarkers and therapeutic drug targets.

癌症诱导血栓炎性状态，反之亦然，血栓形成和炎症有助于癌症生长。今天，炎症、凝血和癌症之间的因果关系被广泛接受;然而，许多介导这种关系的分子和细胞机制仍然是谜。凝血因子XII（FXII，Hageman因子）及其激活剂聚磷酸盐（polyP）在血栓形成、促进细胞增殖和诱导促炎反应中发挥核心作用。该提案的目标是分析polyP/FXII通路在癌症中的机制、诊断应用和治疗意义。我们的目的是分析（1）聚P/FXII通路对肿瘤生长和肿瘤相关的促炎和促凝血机制的作用，（2）建立聚P作为评估炎症和凝血的预后生物标志物，（3）开发基于聚P/FXII的治疗方法，用于干扰癌症患者的炎症和促凝血反应以及肿瘤生长。转化项目包括分子生物学，细胞生物学，先进诊断学，对癌症中polyP/FXII轴功能的全面深入了解为开发预测性肿瘤和血栓形成生物标志物提供了新颖独特的机会，并通过建立安全的抗凝治疗与额外的抗血栓形成治疗来改善患者护理。炎症和抗有丝分裂活性。

Cancer induces a thrombo-inflammatory state and vice versa thrombosis and inflammation contribute to cancer growth. Today, the causal relationship between inflammation, coagulation and cancer is widely accepted; however, many of the molecular and cellular mechanisms mediating this relationship have remained enigmatic. Coagulation factor XII (FXII, Hageman factor) and its activator polyphosphate (polyP) have a central role for thrombosis, promote cell-proliferation and induce proinflammatory reactions. The goal of this proposal is to analyze mechanisms, diagnostic application and therapeutic implications of the polyP/FXII pathway in cancer. We aim to analyse (1) the role of the polyP/FXII-pathway for tumor growth and tumor associated proinflammatory and procoagulant mechanisms, (2) establish polyP as a prognostic biomarker for assessment of inflammation and coagulation, and (3) develop polyP/FXII-based therapies for interference with inflammatory and procoagulant reactions and tumor growth in cancer patients. The translational project comprises molecular biology, cell biology, advanced diagnostics, genetically altered animal models and patient materials to explore impact of polyP and FXII for malignant diseases.A comprehensive insight into the functions of the polyP/FXII axis in cancer offers a novel and unique opportunity for development of predictive tumor and thrombosis biomarkers and improved patient care by establishing a safe anticoagulation therapy with additional anti-inflammatory and anti-mitogenic activities.