THROMBIN INCREASES THE METASTATIC POTENTIAL OF TUMOR-CELLS

被引:105
作者
WOJTUKIEWICZ, MZ
TANG, DG
CIARELLI, JJ
NELSON, KK
WALZ, DA
DIGLIO, CA
MAMMEN, EF
HONN, KV
机构
[1] WAYNE STATE UNIV,DEPT RADIAT ONCOL,431 CHEM BLDG,DETROIT,MI 48202
[2] WAYNE STATE UNIV,DEPT PHYSIOL,DETROIT,MI 48202
[3] WAYNE STATE UNIV,DEPT PATHOL,DETROIT,MI 48202
[4] WAYNE STATE UNIV,DEPT OBSTET & GYNECOL,DETROIT,MI 48202
[5] WAYNE STATE UNIV,DEPT CHEM,DETROIT,MI 48202
关键词
D O I
10.1002/ijc.2910540514
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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页码:793 / 806
页数:14
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