Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis
Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis
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DOI：
10.1182/blood-2004-03-1047
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发表时间：
2004-11-01
期刊：
影响因子：
20.3
通讯作者：
Karpatkin, S
中科院分区：
文献类型：
--
作者：
Hu, L;Lee, M;Karpatkin, S
通过使用水蛭素（一种高效的凝血酶特异性抑制剂），通过小鼠肿瘤生长和转移实验研究肿瘤/宿主产生的凝血酶（内源性凝血酶）。在皮下注射 2 个人类和 2 个小鼠肿瘤后，用水蛭素预处理可抑制裸鼠或同系小鼠中的肿瘤植入。与磷酸盐缓冲盐水（PBS）处理相比，水蛭素在肿瘤生长的出现方面诱导了相当长的滞后期，但对体内已形成的肿瘤结节生长或体外肿瘤生长没有影响。与PBS处理没有效果相比，水蛭素处理引起肿瘤结节的中央坏死。治疗持续时间越长，保护作用就越大。用绿色荧光蛋白（GFP）标记的肿瘤细胞检查肿瘤在血液中的种植情况。水蛭素抑制播散到血液和全身器官中，其程度从完全保护到血液中的15至32倍和肺中的17至395倍不等。水蛭素通过减少肺部肿瘤结节的数量来抑制皮下植入肿瘤的自发转移。皮下注射高侵袭性 4T1 细胞的小鼠存活率显示，第 40 天，PBS 处理的动物中有 5 只死亡，而水蛭素处理则没有死亡，水蛭素处理的存活期延长了 16 天至 31 天以上。因此，内源性凝血酶有助于肿瘤植入、播种和自发转移。有效的抗凝血酶药物应该对癌症患者有临床益处。 (C) 2004 年，美国血液学会。
Tumor/host-generated thrombin (endogenous thrombin) was investigated with tumor growth and metastasis experiments in mice by the use of hirudin, a highly potent specific inhibitor of thrombin. Pretreatment with hirudin inhibited tumor implantation in nude or syngeneic mice, following subcutaneous injection of 2 human and 2 murine tumors. Hirudin induced a considerable lag period in the appearance of tumor growth, compared with phosphate-buffered saline (PBS) treatment, but had no effect on established tumor nodule growth in vivo or on tumor growth in vitro. Hirudin treatment induced central necrosis of the tumor nodule compared with no effect with PBS treatment. Greater protection was noted with longer duration of treatment. Tumor seeding into blood was examined with green fluorescent protein (GFP)-labeled tumor cells. Hirudin inhibited seeding into the blood as well as systemic organs which varied from complete protection to 15- to 32-fold in the blood and 17- to 395-fold in the lung. Hirudin inhibited spontaneous metastases from subcutaneously implanted tumor by reducing the number of tumor nodules in the lungs. Mouse survival in animals injected subcutaneously with highly aggressive 4T1 cells revealed 5 of 5 deaths of PBS-treated animals on day 40 compared with no deaths with hirudin treatment, with prolongation of survival with hirudin treatment of 16 days to more than 31 days. Thus, endogenous thrombin contributes to tumor implantation, seeding, and spontaneous metastasis. A potent antithrombin agent should be of clinical benefit to patients with cancer. (C) 2004 by The American Society of Hematology.