Platelet-activating factor podoplanin: from discovery to drug development.
Platelet-activating factor podoplanin: from discovery to drug development.
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DOI：
10.1007/s10555-017-9672-2
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Fujita N
中科院分区：
文献类型：
--
作者：
Takemoto A;Miyata K;Fujita N
肿瘤细胞诱导的血小板聚集通过促进肿瘤栓塞、防止免疫攻击和剪切应力来促进血行转移，并且血小板释放生长因子支持肿瘤生长和侵袭。 Podoplanin，也称为 Aggrus，是一种 I 型跨膜粘蛋白样糖蛋白，在多种肿瘤细胞中表达。 Podoplanin 通过与其血小板受体 C 型凝集素样受体 2 (CLEC-2) 结合，在血小板聚集和转移形成中发挥作用。 podoplanin研究最初始于从小鼠结肠26癌细胞系中克隆高转移性NL-17亚克隆，并建立可中和NL-17诱导的血小板聚集和血行转移的8F11单克隆抗体（mAb）。后来，podoplanin被鉴定为8F11 mAb的抗原，其异位表达给细胞带来了血小板聚集能力和血行转移表型。从 8F11 mAb 识别表位中，发现 podoplanin 含有串联重复、高度保守的基序，称为血小板聚集刺激 (PLAG) 结构域。使用表达突变体的细胞和已建立的中和性抗平足蛋白单克隆抗体进行的一系列分析发现，PLAG3 和 PLAG4 结构域均与 CLEC-2 结合相关。靶向PLAG3或PLAG4的中和单克隆抗体可以通过抑制podoplanin-CLEC-2结合来抑制podoplanin诱导的血小板聚集和血行转移。因此，这些结构域肯定通过其血小板聚集活性在足足蛋白介导的转移中发挥作用。本文综述了血小板在转移形成中的功能、血小板聚集诱导因子podoplanin在病理和生理情况下的作用以及未来开发podoplanin靶向药物的可能性。
Tumor cell-induced platelet aggregation facilitates hematogenous metastasis by promoting tumor embolization, preventing immunological assaults and shear stress, and the platelet-releasing growth factors support tumor growth and invasion. Podoplanin, also known as Aggrus, is a type I transmembrane mucin-like glycoprotein and is expressed on wide range of tumor cells. Podoplanin has a role in platelet aggregation and metastasis formation through the binding to its platelet receptor, C-type lectin-like receptor 2 (CLEC-2). The podoplanin research was originally started from the cloning of highly metastatic NL-17 subclone from mouse colon 26 cancer cell line and from the establishment of 8F11 monoclonal antibody (mAb) that could neutralize NL-17-induced platelet aggregation and hematogenous metastasis. Later on, podoplanin was identified as the antigen of 8F11 mAb, and its ectopic expression brought to cells the platelet-aggregating abilities and hematogenous metastasis phenotypes. From the 8F11 mAb recognition epitopes, podoplanin is found to contain tandemly repeated, highly conserved motifs, designated platelet aggregation-stimulating (PLAG) domains. Series of analyses using the cells expressing the mutants and the established neutralizing anti-podoplanin mAbs uncovered that both PLAG3 and PLAG4 domains are associated with the CLEC-2 binding. The neutralizing mAbs targeting PLAG3 or PLAG4 could suppress podoplanin-induced platelet aggregation and hematogenous metastasis through inhibiting the podoplanin–CLEC-2 binding. Therefore, these domains are certainly functional in podoplanin-mediated metastasis through its platelet-aggregating activity. This review summarizes the platelet functions in metastasis formation, the role of platelet aggregation-inducing factor podoplanin in pathological and physiological situations, and the possibility to develop podoplanin-targeting drugs in the future.
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DOI：
10.1042/bj20071216
发表时间：
2008-04-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Christou CM;Pearce AC;Watson AA;Mistry AR;Pollitt AY;Fenton-May AE;Johnson LA;Jackson DG;Watson SP;O'Callaghan CA
通讯作者：
O'Callaghan CA
影响因子：
--
作者：
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通讯作者：
Tseng CP
影响因子：
3.5
作者：
Kaneko, Mika Kato;Kato, Yukinari;Osawa, Motoki
通讯作者：
Osawa, Motoki
DOI：
10.1007/s00432-015-2068-1
发表时间：
2016-03-01
影响因子：
3.6
作者：
Hisakane, Kakeru;Saruwatari, Koichi;Ishii, Genichiro
通讯作者：
Ishii, Genichiro
DOI：
10.1073/pnas.0710412105
发表时间：
2008-03-04
影响因子：
11.1
作者：
Amano, Koh;Chiba, Yasunori;Narimatsu, Hisashi
通讯作者：
Narimatsu, Hisashi