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

癌症导致血栓-炎症状态，反之亦然，血栓和炎症有助于癌症的生长。今天，炎症、凝血和癌症之间的因果关系已经被广泛接受；然而，许多调节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(Polyp)在血栓形成、促进细胞增殖和诱导促炎反应中起着重要作用。这项建议的目标是分析息肉/FXII途径在癌症中的机制、诊断应用和治疗意义。我们的目标是分析(1)息肉/FXII通路在肿瘤生长和肿瘤相关的促炎和促凝血机制中的作用，(2)建立息肉作为评估炎症和凝血的预后生物标志物，以及(3)开发基于息肉/FXII的治疗方法，以干扰癌症患者的炎症和促凝血反应和肿瘤生长。该翻译项目包括分子生物学、细胞生物学、高级诊断、转基因动物模型和患者材料，以探索息肉和FXII对恶性肿瘤的影响。全面了解息肉/FXII轴在癌症中的功能为开发预测肿瘤和血栓形成的生物标志物提供了新的独特机会，并通过建立具有额外抗炎和抗有丝分裂活性的安全抗凝治疗来改善患者护理。

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.