Targeting a novel domain in podoplanin for inhibiting platelet-mediated tumor metastasis.
Targeting a novel domain in podoplanin for inhibiting platelet-mediated tumor metastasis.
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DOI：
10.18632/oncotarget.6598
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发表时间：
2016-01-26
期刊：
影响因子：
--
通讯作者：
Fujita N
中科院分区：
文献类型：
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作者：
Sekiguchi T;Takemoto A;Takagi S;Takatori K;Sato S;Takami M;Fujita N
Podoplanin/Aggrus是一种在多种癌症中表达的唾液酸糖蛋白。我们以前确定podoplanin是肿瘤诱导的血小板聚集的关键因素。Podoplanin介导的血小板聚集通过分泌生长因子和在微血管系统中形成肿瘤栓塞来促进肿瘤生长和转移。因此，精确分析podoplanin介导的血小板聚集的机制对于开发抗肿瘤疗法至关重要。在这里，我们报告了一个新的血小板聚集诱导结构域，PLAG 4（81-EDLPT-85）的发现。PLAG 4与先前报道的PLAG 3具有高度同源性，并有助于其血小板受体CLEC-2的结合。突变体分析表明，PLAG 4表现出相对于PLAG 3的主要血小板聚集功能，PLAG 4中保守的Glu 81/Asp 82/Thr 85残基对于CLEC-2结合是必不可少的。通过建立抗PLAG 4中和单克隆抗体，我们证实了其在CLEC-2结合、血小板聚集和肿瘤栓塞形成中的作用。我们的研究结果表明，需要同时抑制PLAG 3/4完全抑制podoplanin介导的肿瘤生长和转移。
Podoplanin/Aggrus is a sialoglycoprotein expressed in various cancers. We previously identified podoplanin as a key factor in tumor-induced platelet aggregation. Podoplanin-mediated platelet aggregation enhances tumor growth and metastasis by secreting growth factors and by forming tumor emboli in the microvasculature. Thus, precise analysis of the mechanisms of podoplanin-mediated platelet aggregation is critical for developing anti-tumor therapies. Here we report the discovery of a novel platelet aggregation-inducing domain, PLAG4 (81-EDLPT-85). PLAG4 has high homology to the previously reported PLAG3 and contributes to the binding of its platelet receptor CLEC-2. Mutant analyses indicated that PLAG4 exhibits a predominant platelet-aggregating function relative to PLAG3 and that conserved Glu81/Asp82/Thr85 residues in PLAG4 are indispensable for CLEC-2 binding. By establishing anti-PLAG4-neutralizing monoclonal antibodies, we confirmed its role in CLEC-2 binding, platelet aggregation, and tumor emboli formation. Our results suggest the requirement of simultaneous inhibition of PLAG3/4 for complete suppression of podoplanin-mediated tumor growth and metastasis.