Platelets promote tumor growth and metastasis via direct interaction between Aggrus/podoplanin and CLEC-2.
Platelets promote tumor growth and metastasis via direct interaction between Aggrus/podoplanin and CLEC-2.
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DOI：
10.1371/journal.pone.0073609
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Fujita N
中科院分区：
文献类型：
--
作者：
Takagi S;Sato S;Oh-hara T;Takami M;Koike S;Mishima Y;Hatake K;Fujita N
血小板聚集诱导因子Aggrus，也被称为podoplan in，在几种类型的肿瘤中经常上调，并通过与血小板受体CLEC-2相互作用和激活来增强血道转移。因此，Aggrus-CLEC-2结合可能是肿瘤治疗的分子机制。我们制备了一种新的抗人Aggrus单抗MS-1，它可以抑制Aggrus-CLEC-2的结合、Aggrus诱导的血小板聚集和Aggrus介导的肿瘤转移。有趣的是，MS-1单抗在体内抑制了Aggrus阳性肿瘤的生长。此外，人源化的嵌合MS-1抗体ChMS-1对移植到NOD-SCID小鼠体内的Aggrus阳性肺鳞状细胞癌也显示出很强的抗肿瘤活性，并折中了抗体依赖的细胞毒和补体依赖的细胞毒活性。由于Aggrus基因在体外抑制了血小板诱导的肺鳞癌的增殖，在体内抑制了肿瘤的生长，因此Aggrus可能不仅参与了肿瘤的转移，而且可能通过促进体内的血小板-肿瘤相互作用、血小板活化和血小板衍生因子的分泌而参与肿瘤的生长。我们的结果表明，抑制血小板-肿瘤特异性相互作用的分子靶向药物可以作为既抑制肿瘤转移又抑制肿瘤增殖的抗肿瘤药物，如肺鳞状细胞癌。
The platelet aggregation-inducing factor Aggrus, also known as podoplanin, is frequently upregulated in several types of tumors and enhances hematogenous metastasis by interacting with and activating the platelet receptor CLEC-2. Thus, Aggrus–CLEC-2 binding could be a therapeutic molecular mechanism for cancer therapy. We generated a new anti-human Aggrus monoclonal antibody, MS-1, that suppressed Aggrus–CLEC-2 binding, Aggrus-induced platelet aggregation, and Aggrus-mediated tumor metastasis. Interestingly, the MS-1 monoclonal antibody attenuated the growth of Aggrus-positive tumors in vivo. Moreover, the humanized chimeric MS-1 antibody, ChMS-1, also exhibited strong antitumor activity against Aggrus-positive lung squamous cell carcinoma xenografted into NOD-SCID mice compromising antibody-dependent cellular cytotoxic and complement-dependent cytotoxic activities. Because Aggrus knockdown suppressed platelet-induced proliferation in vitro and tumor growth of the lung squamous cell carcinoma in vivo, Aggrus may be involved in not only tumor metastasis but also tumor growth by promoting platelet-tumor interaction, platelet activation, and secretion of platelet-derived factors in vivo. Our results indicate that molecular target drugs inhibiting specific platelet–tumor interactions can be developed as antitumor drugs that suppress both metastasis and proliferation of tumors such as lung squamous cell carcinoma.
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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
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O'Callaghan CA
影响因子：
7.3
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影响因子：
3.5
作者：
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通讯作者：
Osawa, Motoki
DOI：
10.1016/j.bbrc.2006.08.171
发表时间：
2006-11-03
影响因子：
3.1
作者：
Kato, Yukinari;Kaneko, Mika Kato;Osawa, Motoki
通讯作者：
Osawa, Motoki
DOI：
10.1073/pnas.61.1.46
发表时间：
1968-01-01
影响因子：
11.1
作者：
GASIC, GJ;GASIC, TB;STEWART, CC
通讯作者：
STEWART, CC