Vascular Biology Group, ANZAC Research Institute, University of Sydney, Concord, Australia.
Cancer Pharmacology Unit, ANZAC Research Institute, University of Sydney, Concord, Australia.
J Thromb Haemost. 2017 Mar;15(3):477-486. doi: 10.1111/jth.13612. Epub 2017 Feb 14.
Essentials Cancer cachexia and cancer-associated thrombosis have not previously been mechanistically linked. We assessed thrombin generation and coagulation parameters in cachectic C26 tumor-bearing mice. C26 mice are hypercoagulable, partially corrected by blocking tumor derived interleukin-6. Coagulability and anti-inflammatory interventions may be clinically important in cancer cachexia.
Background Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer, which have not previously been mechanistically linked. The colon 26 (C26) carcinoma is a well-established mouse model of complications of advanced cancer cachexia, partially dependent on high levels of interleukin-6 (IL-6) produced by the tumor. Objectives To assess if cancer cachexia altered the coagulation state and if this was attributable to tumor IL-6 production. Methods In male BALB/c*DBA2 (F1 hybrid) mice with a C26 tumor we used modified calibrated automated thrombogram and fibrin generation (based on overall hemostatic potential) assays to assess the functional coagulation state, and also examined fibrinogen, erythrocyte sedimentation rate (ESR), platelet count, tissue factor pathway inhibitor (TFPI) and hepatic expression of coagulation factors by microarray. C26 mice were compared with non-cachectic NC26, pair-fed and sham control mice. IL-6 expression in C26 cells was knocked down by lentiviral shRNA constructs. Results C26 mice with significant weight loss and highly elevated IL-6 had elevated thrombin generation, fibrinogen, ESR, platelets and TFPI compared with all control groups. Fibrin generation was elevated compared with pair-fed and sham controls but not compared with NC26 tumor mice. Hepatic expression of coagulation factors and fibrinolytic inhibitors was increased. Silencing IL-6 in the tumor significantly, but incompletely, attenuated the increased thrombin generation, fibrinogen and TFPI. Conclusions Cachectic C26 tumor-bearing mice are in a hypercoagulable state, which is partly attributable to IL-6 release by the tumor. The findings support the importance of the coagulation state in cancer cachexia and the clinical utility of anti-inflammatory interventions.
以前尚未从机制上把癌症恶病质和癌症相关的血栓形成联系起来。我们评估了恶病质 C26 荷瘤小鼠的凝血酶生成和凝血参数。C26 小鼠是高凝的，通过阻断肿瘤来源的白细胞介素 6 部分纠正。凝血和抗炎干预在癌症恶病质中可能具有重要的临床意义。
背景：癌症恶病质和癌症相关的血栓形成是晚期癌症的潜在致命后果，以前尚未从机制上联系起来。结肠 26（C26）癌是晚期癌症恶病质并发症的一种成熟的小鼠模型，部分依赖于肿瘤产生的高水平白细胞介素 6（IL-6）。
评估癌症恶病质是否改变了凝血状态，以及这是否归因于肿瘤 IL-6 的产生。
在雄性 BALB/c*DBA2（F1 杂种）小鼠中，我们使用改良的校准自动血栓图和纤维蛋白生成（基于总体止血潜能）测定法来评估功能性凝血状态，并通过微阵列检查纤维蛋白原、红细胞沉降率（ESR）、血小板计数、组织因子途径抑制剂（TFPI）和肝脏凝血因子的表达。将 C26 小鼠与非恶病质 NC26、配对喂养和假对照小鼠进行比较。通过慢病毒 shRNA 构建物敲低 C26 细胞中的 IL-6 表达。
与所有对照组相比，体重明显减轻且 IL-6 水平极高的 C26 小鼠的凝血酶生成、纤维蛋白原、ESR、血小板和 TFPI 升高。与配对喂养和假对照相比，纤维蛋白生成升高，但与 NC26 肿瘤小鼠相比没有升高。肝脏凝血因子和纤维蛋白溶解抑制剂的表达增加。肿瘤中 IL-6 的沉默显著但不完全减弱了凝血酶生成、纤维蛋白原和 TFPI 的增加。
恶病质 C26 荷瘤小鼠处于高凝状态，部分归因于肿瘤释放的 IL-6。这些发现支持凝血状态在癌症恶病质中的重要性和抗炎干预的临床实用性。
