THROMBIN INCREASES THE METASTATIC POTENTIAL OF TUMOR-CELLS
THROMBIN INCREASES THE METASTATIC POTENTIAL OF TUMOR-CELLS
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DOI：
10.1002/ijc.2910540514
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发表时间：
1993-07-09
影响因子：
6.4
通讯作者：
HONN, KV
中科院分区：
文献类型：
--
作者：
WOJTUKIEWICZ, MZ;TANG, DG;HONN, KV
肿瘤细胞在微血管系统中的最初停滞及其与内皮和内皮下基质(SEM)的附着是发生转移的必要前提。介导这些相互作用的因素被认为是肿瘤-细胞转移表型的重要决定因素。在这项工作中，我们研究了凝血酶及其类似物及其前体对肿瘤细胞黏附特性和转移潜能的影响。我们发现，作为关键凝血酶的天然形式，α-凝血酶能够增强肿瘤细胞与内皮细胞和以纤维连接蛋白为代表的扫描电子显微镜成分的粘附性。在亚凝状态下，生理浓度的α-凝血酶可使肿瘤细胞粘附性增加2至5倍。剂量-效应曲线呈钟形，在0.1U/ml时效果最好，作用15min时效果最好，作用4h后，肿瘤细胞与肿瘤细胞的粘附力增强。与凝血酶的长时间孵育导致凝血酶增强的粘附力下降，在24小时时达到未刺激的对照水平。凝血酶前体和活性部位抑制的凝血酶类似物只有最小的黏附增强活性；保留功能活性部位的硝基和外切α-凝血酶模仿了α-凝血酶的作用，尽管程度较小。肿瘤细胞与凝血酶孵育后，细胞表面α(IIbk)β3整合素的表达上调，这是一种介导肿瘤细胞与内皮细胞、肿瘤细胞与扫描电子显微镜之间相互作用的受体。针对α(IIb)β3整合素的抗体有效地抑制凝血酶增强的肿瘤细胞黏附。凝血酶对肿瘤细胞的作用涉及PKC信号转导途径，因为与PKC抑制剂预先孵育可抑制凝血酶增强的黏附，并且在凝血酶攻击后观察到PKC从胞浆到细胞膜的短暂移位。在体内，经凝血酶处理的肿瘤细胞在肺部的定植能力增加了2倍。与粘连结果相反，凝血酶前体(凝血酶原)和凝血酶类似物模拟了α-凝血酶促进转移的作用。(C)1993年Wiley-Liss，Inc.
Initial arrest of tumor cells in the microvasculature and their attachment to the endothelium and subendothelial matrix (SEM) are essential prerequisites for metastasis to occur. Factors mediating these interactions are viewed as important determinants of the tumor-cell metastatic phenotype. In this work we have studied the effects of thrombin, its analogs and its precursors on the adhesive properties and metastatic potential of tumor cells. We show that alpha-thrombin, the native form of the key coagulation enzyme, is capable of enhancing tumor-cell adhesion to both the endothelium and SEM components represented by fibronectin. Subclotting, physiological concentrations of alpha-thrombin produced a 2- to 5-fold increase in tumor-cell adhesion. A bell-shaped dose-response curve was observed, with maximal effect at 0.1 U/ml. Maximum effect occurred when cells were exposed to the agonist for 15 min and exposure for up to 4 hr resulted in enhanced tumor-cell adhesion. Prolonged incubation with thrombin resulted in a decline in the thrombin-enhanced adhesion which reached unstimulated control levels by 24 hr. Thrombin precursors and active-site-inhibited thrombin analogs only had minimal adhesion-enhancing activity; nitro- and exosite-alpha-thrombin, which retain a functional active site, mimicked, although to a lesser degree, the action of alpha-thrombin. Tumor-cell incubation with thrombin resulted in an upregulated cell-surface expression of the alpha(IIbk)beta3 integrin, a receptor mediating interactions between tumor cells and endothelial cells, and between tumor cells and SEM. Antibodies against alpha(IIb)beta3 integrin effectively inhibited thrombin-enhanced tumor-cell adhesion. Thrombin effects on tumor cells involved the PKC signal transduction pathway as thrombin-enhanced adhesion was inhibited by pre-incubation with PKC inhibitors and a transient PKC translocation from cytosol to membrane was observed following thrombin challenge. In vivo, thrombin-treated tumor cells demonstrated a 2-fold increase in their lung-colonizing ability. In contrast to the adhesion results, the metastasis-enhancing effects of alpha-thrombin were mimicked by a thrombin precursor (prothrombin) and thrombin analogs. (C) 1993 Wiley-Liss, Inc.