THROMBIN STIMULATES TUMOR-PLATELET ADHESION INVITRO AND METASTASIS INVIVO
THROMBIN STIMULATES TUMOR-PLATELET ADHESION INVITRO AND METASTASIS INVIVO
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DOI：
10.1172/jci114976
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发表时间：
1991-01-01
影响因子：
15.9
通讯作者：
KARPATKIN, S
中科院分区：
文献类型：
--
作者：
NIERODZIK, ML;PLOTKIN, A;KARPATKIN, S
最近的研究表明，血小板和血小板粘附蛋白，纤连蛋白和血管性血友病因子（vWF）在体外血小板-肿瘤细胞相互作用和体内转移中的作用。 本报告记录了凝血酶处理血小板对体外和体内这种相互作用的影响。 在体外，100- 1，000 mU/ml的凝血酶最大程度地刺激来自三个不同物种的六种不同肿瘤细胞系的粘附，增加2至5倍。 低至1-10 mU/ml有效。 凝血酶的作用是特异性的（可通过水蛭素、丹磺酰-精氨酸N-（3-乙基-1，5戊二基）酰胺进行竞争，并且与无活性的凝血酶类似物N-P-甲苯磺酰-L-苯基氯甲基酮-凝血酶和D-苯丙氨酰-L-丙基-L-精氨酸氯甲基酮-凝血酶（PPACK-凝血酶）不反应，并且需要高亲和力凝血酶受体（与PPACK-凝血酶竞争，但不与N-P-甲苯磺酰-L-赖氨酸-氯甲基-酮-凝血酶竞争）。血小板表面需要功能活性凝血酶。肿瘤细胞与凝血酶活化的血小板的结合可通过已知干扰血小板GPIIb-GPIIIa整联蛋白的试剂进行：单克隆抗体10 E5、四肽RGDS和γ链纤维蛋白原十肽LGGAKQAGDV，以及抗血小板粘附配体、纤连蛋白和vWF的多克隆抗体。 在体内，每只动物250-500 mU的凝血酶使CT 26结肠癌细胞的小鼠肺转移增加4倍，使B16无黑色素黑色素瘤细胞的小鼠肺转移增加68-413倍。 因此，凝血酶通过占据高亲和力血小板凝血酶受体，并通过RGD依赖性机制调节GPIIb-GPIIIa粘附，将体外肿瘤-血小板粘附放大2至5倍。 在体内，凝血酶使两种不同肿瘤细胞系的肿瘤转移增强4-413倍。
Recent studies have revealed a role for platelets and the platelet-adhesive proteins, fibronectin and von Willebrand factor (vWF) in platelet-tumor cell interaction in vitro and metastasis in vivo. The present report documents the effect of thrombin treatment of platelets on this interaction in vitro and in vivo. In vitro, thrombin at 100-1,000 mU/ml maximally stimulated the adhesion of six different tumor cell lines from three different species two- to fivefold. As little as 1-10 mU/ml was effective. The effect of thrombin was specific (inhibitable by hirudin, dansyl-arginine N-(3-ethyl-1,5 pentanediyl) amide and unreactive with the inactive thrombin analogue N-P-tosyl-L-phenylchloromethylketone-thrombin and D-phenylalanyl-L-propyl-L-arginine chloromethylketone-thrombin (PPACK-thrombin), and required high-affinity thrombin receptors (competition with PPACK-thrombin but not with N-P-tosyl-L-lysine-chloromethyl-ketone-thrombin). Functionally active thrombin was required on the platelet surface. Binding of tumor cells to thrombin-activated platelets was inhibitable by agents known to interfere with the platelet GPIIb-GPIIIa integrin: monoclonal antibody 10E5, tetrapeptide RGDS and gamma-chain fibrinogen decapeptide LGGAKQAGDV, as well as polyclonal antibodies against the platelet adhesive ligands, fibronectin and vWF. In vivo, Thrombin at 250-500 mU per animal increased murine pulmonary metastases fourfold with CT26 colon carcinoma cells and 68-413-fold with B16 amelanotic melanoma cells. Thus thrombin amplifies tumor-platelet adhesion in vitro two- to fivefold via occupancy of high-affinity platelet thrombin receptors, and modulation of GPIIb-GPIIIa adhesion via an RGD-dependent mechanism. In vivo, thrombin enhances tumor metastases 4-413-fold with two different tumor cells lines.