Gieseler Frank, Lühr Inke, Kunze Thomas, Mundhenke Christoph, Maass Nicolai, Erhart Tobias, Denker Momme, Beckmann Dennis, Tiemann Markus, Schulte Christoph, Dohrmann Peter, Cavaillé Françoise, Godeau François, Gespach Christian
University Hospital of Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany.
Thromb Haemost. 2007 Jun;97(6):1023-30.
We have shown that the thrombin G-protein coupled receptors (GPCR) designated as protease-activated receptors (PAR-1) are expressed in primary cancer cells isolated from peritoneal and pleural malignant effusions. Here, our main goal was to evaluate several coagulation and thrombin activation effectors and markers in a series of 136 malignant effusions from cancer patients with gastrointestinal, lung and mammary carcinomas. All these patients present a highly activated coagulation system in blood and their malignant effusions, as indicated by high levels of prothrombin F1.2 fragments and D-dimers. Notably, we detected in the effusions all the coagulation factors of the tissue factor pathway inducing thrombin activation, namely factors VII, V, X and II, as well as high VEGF levels and IGF-II in mature and precursor forms. Fibrin clot formation also correlated with higher levels of free ionized calcium (iCa), suggesting that iCa and its binding protein albumin are regulatory factors for fibrinogenesis in effusions. Consequently, thrombin, VEGF and IGFII appear to converge in the promotion of survival and invasivity of the metastatic cancer cells from blood to the malignant effusions. Thus, we add new insights on the interconnections between blood coagulation disorders in cancer patients and thrombin activation in malignant effusions, including their functional interaction with PAR in metastatic cancer cells. Based on these data we propose to counteract the metastatic cascades by targeted invalidation of key effectors of the coagulation system. Therefore, potential therapeutic approaches include the application of thrombin protease inhibitors, VEGF-blocking antibodies, and drugs targeting the VEGF and thrombin signaling pathways, such as tyrosine kinase or GPCR inhibitors.
我们已经表明，被指定为蛋白酶激活受体（PAR-1）的凝血酶G蛋白偶联受体（GPCR）在从腹腔和胸腔恶性积液中分离出的原发性癌细胞中表达。在此，我们的主要目标是评估一系列来自胃肠道、肺癌和乳腺癌患者的136例恶性积液中的几种凝血和凝血酶激活效应物及标志物。所有这些患者血液及其恶性积液中的凝血系统均高度激活，凝血酶原F1.2片段和D-二聚体水平升高即表明了这一点。值得注意的是，我们在积液中检测到了诱导凝血酶激活的组织因子途径的所有凝血因子，即因子VII、V、X和II，以及成熟和前体形式的高VEGF水平和IGF-II。纤维蛋白凝块形成也与较高水平的游离离子钙（iCa）相关，这表明iCa及其结合蛋白白蛋白是积液中纤维蛋白生成的调节因子。因此，凝血酶、VEGF和IGFII似乎在促进转移性癌细胞从血液向恶性积液的存活和侵袭方面具有共同作用。因此，我们对癌症患者的凝血障碍与恶性积液中的凝血酶激活之间的相互联系有了新的认识，包括它们与转移性癌细胞中PAR的功能相互作用。基于这些数据，我们建议通过靶向灭活凝血系统的关键效应物来对抗转移级联反应。因此，潜在的治疗方法包括应用凝血酶蛋白酶抑制剂、VEGF阻断抗体以及靶向VEGF和凝血酶信号通路的药物，如酪氨酸激酶或GPCR抑制剂。
