Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis
Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis
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DOI：
10.1182/blood-2004-02-0434
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发表时间：
2004-07-15
期刊：
影响因子：
20.3
通讯作者：
Coughlin, SR
中科院分区：
文献类型：
--
作者：
Camerer, E;Qazi, AA;Coughlin, SR
对肿瘤细胞的促凝血活性可以增强它们通过循环扩散到远处器官的能力。为了确定主要宿主对血行转移的凝血反应的相对重要性，我们检查了静脉注射黑色素瘤细胞后Nf-E2（-/-）小鼠的肺转移，Nf-E2（-/-）小鼠实际上没有循环血小板; Par 4（-/-）小鼠，其血小板对凝血酶有反应; Par 1和Par 2（-/-）小鼠，其对凝血蛋白酶的内皮反应显著减弱;以及Fib（-/-）小鼠，其缺乏纤维蛋白原。在严重联合免疫缺陷（SCID）背景下，Nf-E2（-/-）、Par 4（-/-）和Fib（-/-）小鼠的中位肺肿瘤计数分别为野生型的6%、14%和24%;总肿瘤负荷仅为野生型的4%、9%和3%。分别。在同基因C57 BL 6背景中观察到类似的结果。相比之下，蛋白酶激活受体1（PAR 1）或PAR 2的缺陷并没有提供保护。这些结果提供了强有力的遗传学证据，表明血小板在血行转移中起关键作用，并通过凝血酶依赖性和非依赖性机制促进这一过程。重要的是，PAR 4杂合性在该模型中赋予了一些针对转移的保护。因此，即使血小板功能的部分减弱也足以提供益处。(C)2004年，美国血液学会。
Procoagulant activity on tumor cells can enhance their ability to spread via the circulation to colonize distant organs. Toward defining the relative importance of the main host responses to coagulation for hematogenous metastasis, we examined lung metastases after intravenous injection of melanoma cells in Nf-E2(-/-) mice, which have virtually no circulating platelets; Par4(-/-) mice, which have platelets that fall to respond to thrombin; Par1 and Par2(-/-) mice, which have markedly attenuated endothelial responses to coagulation proteases; and Fib(-/-) mice, which lack fibrinogen. In a severe combined immunodeficiency (SCID) background, median lung tumor count in Nf-E2(-/-), Par4(-/-), and Fib(-/-) mice was 6%, 14%, and 24% of wild type, respectively; total tumor burden was only 4%, 9%, and 3% of wild type, respectively. Similar results were seen in a syngeneic C57BL6 background. By contrast, deficiencies of protease-activated receptor 1 (PAR1) or PAR2 did not provide protection. These results provide strong genetic evidence that platelets play a key role in hematogenous metastasis and contribute to this process by both thrombin-dependent and -independent mechanisms. Importantly, PAR4 heterozygosity conferred some protection against metastasis in this model. Thus even partial attenuation of platelet function may be sufficient to provide benefit. (C) 2004 by The American Society of Hematology.