Thrombomodulin modulates growth of tumor cells independent of its anticoagulant activity
Thrombomodulin modulates growth of tumor cells independent of its anticoagulant activity
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DOI：
10.1172/jci925
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发表时间：
1998-04-01
影响因子：
15.9
通讯作者：
Nawroth, PP
中科院分区：
文献类型：
--
作者：
Zhang, YM;Weiler-Guettler, H;Nawroth, PP
血栓调节蛋白(TM)被认为是抗血栓形成机制中重要的血管壁辅助因子，在多种肿瘤细胞中也有表达。从4例恶性黑色素瘤患者体内亚克隆的肿瘤细胞株中，TM的表达与体内外细胞增殖呈负相关。野生型TM过表达可抑制体外细胞增殖和体内肿瘤生长。蛋白C激活能力改变的TM突变体也会产生类似的效果。相反，用突变的TM结构来转染黑色素瘤细胞，其中细胞质或凝集素结构域的一部分被缺失，取消了与野生型TM过表达相关的抗增殖作用。使用凝血酶受体的多肽激动剂/拮抗剂、水飞蓟素或凝血酶-TM相互作用的抑制剂都没有改变TM过表达对细胞生长的抑制作用。这些数据表明，TM对细胞增殖的影响不依赖于凝血酶和凝血酶受体，可能与新的配体与凝集素结构域上的决定簇结合有关，这可能触发依赖于细胞质结构域的信号转导途径。
Thrombomodulin (TM), recognized as an essential vessel wall cofactor of the antithrombotic mechanism, is also expressed by a wide range of tumor cells. Tumor cell lines subcloned from four patients with malignant melanoma displayed a negative correlation between TM expression and cell proliferation in vitro and in vivo. Overexpression of wild-type TM decreased cell proliferation in vitro and tumor growth in vivo. TM mutants with altered protein C activation capacity lead to a similar effect. In contrast, transfection of melanoma cells with mutant TM constructs, in which a portion of the cytoplasmic or lectin domain was deleted, abrogated the antiproliferative effect associated with overexpression of wild-type TM. Experiments performed with either peptide agonists/antagonists of the thrombin receptor, with hirudin, or with inhibitors of thrombin-TM interaction did not alter the growth inhibitory effect of TM overexpression, These data suggest that TM exerts an effect on cell proliferation independent of thrombin and the thrombin receptor, possibly related to the binding of novel ligands to determinants in the lectin domain which might trigger signal transduction pathways dependent on the cytoplasmic domain.