The MET oncogene drives a genetic programme linking cancer to haemostasis
The MET oncogene drives a genetic programme linking cancer to haemostasis
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DOI：
10.1038/nature03357
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发表时间：
2005-03-17
期刊：
影响因子：
64.8
通讯作者：
Comoglio, PM
中科院分区：
文献类型：
--
作者：
Boccaccio, C;Sabatino, G;Comoglio, PM
凝血激活与癌症之间的密切关系是一个古老的谜。 1865 年，游走性血栓静脉炎（“一种容易自发凝血的血液状况”）被描述为隐匿性恶性肿瘤的预警（特鲁索征（1））。这一开创性的观察强调了与癌症发病相关的止血障碍的存在。此后，这种现象在临床和流行病学研究中得到了广泛报道(2-4)，但迄今为止尚未找到机制解释。在这里，我们报告了基于体细胞遗传操作的散发性肿瘤发生的小鼠模型。将激活的人类 MET 癌基因靶向成人肝脏会导致缓慢进展的肝癌发生。在此之前并伴随着一种综合征，首先表现为血液高凝（静脉血栓），然后发展为致命的内出血。该综合征的发病机制是由对癌基因的转录反应驱动的，包括 1 型纤溶酶原激活剂抑制剂 (PAI-1) 和环氧合酶 2 (COX-2) 基因的显着上调。体内分析表明，这两种蛋白质都支持血栓出血表型，从而为癌基因激活和止血之间长期寻求的联系提供了直接的遗传证据。
The close relationship between activation of blood coagulation and cancer is an old enigma. In 1865, migrans trombophlebitis ('a condition of the blood that predisposes it to spontaneous coagulation') was described as a forewarning of occult malignancy ( Trousseau's sign(1)). This pioneering observation emphasized the existence of haemostasis disorders associated with cancer onset; this phenomenon has since been extensively reported in clinical and epidemiological studies(2-4), but has so far resisted a mechanistic explanation. Here we report a mouse model of sporadic tumorigenesis based on genetic manipulation of somatic cells. Targeting the activated, human MET oncogene to adult liver caused slowly progressing hepatocarcinogenesis. This was preceded and accompanied by a syndrome manifesting first with blood hypercoagulation ( venous thromboses), and then evolving towards fatal internal haemorrhages. The pathogenesis of this syndrome is driven by the transcriptional response to the oncogene, including prominent upregulation of plasminogen activator inhibitor type 1 (PAI-1) and cyclooxygenase-2 (COX-2) genes. In vivo analysis showed that both proteins support the thrombohaemorrhagic phenotype, thus providing direct genetic evidence for the long-sought-after link between oncogene activation and haemostasis.