Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells.
Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells.
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DOI：
10.1182/blood.v96.10.3302.h8003302_3302_3309
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发表时间：
2000-11
期刊：
影响因子：
20.3
通讯作者：
J. Palumbo;K. Kombrinck;A. Drew;Timothy S. Grimes;John H. Kiser;J. Degen;T. Bugge
中科院分区：
文献类型：
--
作者：
J. Palumbo;K. Kombrinck;A. Drew;Timothy S. Grimes;John H. Kiser;J. Degen;T. Bugge
对肿瘤细胞相关的促凝剂和纤溶因子的详细研究表明，局部凝血酶的产生和纤维蛋白的沉积和溶解可能在肿瘤的生长和扩散中起重要作用。为了直接确定纤维蛋白（原）或纤溶酶（原）是否是循环肿瘤细胞转移潜力的决定因素，本研究检测了这些关键止血因子中的每一种的遗传缺陷对2种已建立的小鼠肿瘤（刘易斯肺癌和B16-BL 6黑色素瘤）的血行性肺转移的影响。在这两种肿瘤模型中，纤维蛋白原缺乏强烈减少，但不能阻止肺转移的发展。纤维蛋白原缺陷小鼠转移的定量减少不是由于肿瘤间质形成或肿瘤生长的任何明显差异。相反，肿瘤细胞命运研究表明，纤维蛋白（原）在肺内肿瘤细胞的持续粘附和存活中起重要作用。特异性凝血酶抑制剂水蛭素进一步降低了纤维蛋白原缺陷小鼠循环肿瘤细胞的转移潜力，尽管该抑制剂在体外对肿瘤细胞增殖没有明显影响。纤溶酶原的缺乏和纤溶酶介导的纤溶对血行转移无显著影响。作者得出结论，纤维蛋白（原）是循环肿瘤细胞转移潜力的关键决定因素。此外，凝血酶似乎通过至少一种纤维蛋白（原）非依赖性机制促进肿瘤播散。这些发现表明，集中于多种不同止血因子的治疗策略可能有利于遏制肿瘤转移。
Detailed studies of tumor cell-associated procoagulants and fibrinolytic factors have implied that local thrombin generation and fibrin deposition and dissolution may be important in tumor growth and dissemination. To directly determine whether fibrin(ogen) or plasmin(ogen) are determinants of the metastatic potential of circulating tumor cells, this study examined the impact of genetic deficits in each of these key hemostatic factors on the hematogenous pulmonary metastasis of 2 established murine tumors, Lewis lung carcinoma and the B16-BL6 melanoma. In both tumor models, fibrinogen deficiency strongly diminished, but did not prevent, the development of lung metastasis. The quantitative reduction in metastasis in fibrinogen-deficient mice was not due to any appreciable difference in tumor stroma formation or tumor growth. Rather, tumor cell fate studies indicated an important role for fibrin(ogen) in sustained adhesion and survival of tumor cells within the lung. The specific thrombin inhibitor, hirudin, further diminished the metastatic potential of circulating tumor cells in fibrinogen-deficient mice, although the inhibitor had no apparent effect on tumor cell proliferation in vitro. The absence of plasminogen and plasmin-mediated fibrinolysis had no significant impact on hematogenous metastasis. The authors concluded that fibrin(ogen) is a critical determinant of the metastatic potential of circulating tumor cells. Furthermore, thrombin appears to facilitate tumor dissemination through at least one fibrin(ogen)-independent mechanism. These findings suggest that therapeutic strategies focusing on multiple distinct hemostatic factors might be beneficial in the containment of tumor metastasis.