Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer
Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer
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DOI：
10.1182/blood-2012-01-402156
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发表时间：
2012-06-07
期刊：
影响因子：
20.3
通讯作者：
Mackman, Nigel
中科院分区：
文献类型：
--
作者：
Wang, Jian-Guo;Geddings, Julia E.;Mackman, Nigel
癌症患者通常具有活化的凝血系统，并且静脉血栓形成的风险增加。在本研究中，我们分析了组织因子（TF）的表达在4个不同的人胰腺癌细胞系的目的，在体内产生衍生肿瘤。我们发现，2个线表达TF和TF阳性微粒（MP）释放到培养基中。培养液中的大部分TF蛋白与MP相关。只有TF阳性细胞系才能激活裸小鼠的凝血功能，而这种激活作用可被抗人TF抗体消除。在2个TF阳性细胞系中，只有一个细胞系在裸鼠原位生长时血浆中产生可检测水平的人MP TF活性。令人惊讶的是，来自荷瘤小鼠的血浆中< 5%的人TF蛋白与MP相关。TF阳性肿瘤和循环TF阳性MP水平升高的小鼠在隐静脉模型中血栓形成增加。相比之下，我们在下腔静脉狭窄模型中观察到荷瘤小鼠和对照小鼠之间的血栓重量没有差异。本研究使用异种移植小鼠模型的结果表明，肿瘤TF激活凝血，而TF对循环MP可能引发静脉血栓形成。（血。2012;119（23）：5543-5552）
Cancer patients often have an activated clotting system and are at increased risk for venous thrombosis. In the present study, we analyzed tissue factor (TF) expression in 4 different human pancreatic tumor cell lines for the purpose of producing derivative tumors in vivo. We found that 2 of the lines expressed TF and released TF-positive microparticles (MPs) into the culture medium. The majority of TF protein in the culture medium was associated with MPs. Only TF-positive cell lines activated coagulation in nude mice, and this activation was abolished by an anti-human TF Ab. Of the 2 TF-positive lines, only one produced detectable levels of human MP TF activity in the plasma when grown orthotopically in nude mice. Surprisingly, < 5% of human TF protein in plasma from tumor-bearing mice was associated with MPs. Mice with TF-positive tumors and elevated levels of circulating TF-positive MPs had increased thrombosis in a saphenous vein model. In contrast, we observed no difference in thrombus weight between tumor-bearing and control mice in an inferior vena cava stenosis model. The results of the present study using a xenograft mouse model suggest that tumor TF activates coagulation, whereas TF on circulating MPs may trigger venous thrombosis. (Blood. 2012;119(23):5543-5552)