The platelet aggregation-inducing factor aggrus/podoplanin promotes pulmonary metastasis
The platelet aggregation-inducing factor aggrus/podoplanin promotes pulmonary metastasis
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DOI：
10.2353/ajpath.2007.060790
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发表时间：
2007-04-01
影响因子：
6
通讯作者：
Fujita, Naoya
中科院分区：
文献类型：
--
作者：
Kunita, Akiko;Kashima, Takeshi G.;Fujita, Naoya
据报道，肿瘤细胞诱导的血小板聚集促进了血行转移。聚集蛋白/podoplanin是一种血小板聚集诱导因子，在许多人类癌症中上调，并与肿瘤进展有关。我们在此研究了聚集蛋白在体内肿瘤生长、转移和存活中的作用。中国仓鼠卵巢细胞中Aggrus的表达促进了实验性和自发性小鼠模型的肺转移。在两组小鼠中均未发现转移灶大小或原发性肿瘤生长的差异。在注射后30分钟，被血小板覆盖的表达聚集蛋白的细胞在肺微血管中停滞。此外，由Aggrus表达引起的肺转移降低了小鼠的存活率。通过产生几个Aggrus点突变体，我们发现，在血小板聚集刺激结构域的Aggrus（Thr 34和Thr 52）的点突变消除血小板聚集和转移。此外，阿司匹林给药小鼠减少了转移灶的数量。这些结果表明，聚集蛋白通过促进血小板聚集而不影响随后的生长，有助于转移的建立。因此，Aggrus可以作为药物开发的理想治疗靶点来阻断转移。
Tumor cell-induced platelet aggregation has been reported to facilitate hematogenous metastasis. Aggrus/podoplanin is a platelet aggregation-inducing factor that is up-regulated in a number of human cancers and has been implicated in tumor progression. We studied herein the role of Aggrus in tumor growth, metastasis, and survival in vivo. Aggrus expression in Chinese hamster ovary cells promoted pulmonary metastasis in both an experimental and a spontaneous mouse model. No differences in the size of metastatic foci or in primary tumor growth were found in either set of mice. Aggrus-expressing cells, which were covered with platelets, arrested in the lung microvasculature 30 minutes after injection. in addition, lung metastasis resulting from Aggrus expression decreased the survival of the mice. By generating several Aggrus point mutants, we revealed that point mutation at the platelet aggregation-stimulating domain of Aggrus (Thr34 and Thr52) obliterated both platelet aggregation and metastasis. Furthermore, administration of aspirin to mice reduced the number of metastatic foci. These results indicate that Aggrus contributes to the establishment of metastasis by promoting platelet aggregation without affecting subsequent growth. Thus, Aggrus could serve as an ideal therapeutic target for drug development to block metastasis.