关于癌细胞是如何将起血液凝固作用的血小板聚集到自己周围来进行扩散这一问题，科学家提出新的详细证据。日本科学家首次在血小板表面发现了一种蛋白，这种蛋白在癌症引起的血小板聚集中扮演重要角色。这一发现有助于开发新的药物，防止癌细胞在体内转移或扩散。
“为了扩散，癌细胞需释放化学物质使附近的血小板聚集并包绕癌细胞，以便逃避免疫系统并使自己附着在血管壁上。”研究人员铃木说。“我们已经发现其中一种叫podoplanin的化学物质是如何结合到血小板上并使它们聚集的。尽管这种物质在1990年就被认识，但直到现在对它如何引起血小板聚集这一问题才有所认识。”
科学家过去研究发现，蛇毒rhodocytin通过与位于血小板表面的C型血细胞凝集素受体-2（CLEC-2）结合促进血小板凝集。为了详细研究在血小板聚集以前和聚集过程中有什么事情发生，科学家观察到被癌细胞podoplanin引起的血小板凝集有许多相似之处。无论rhodocytin 或 podoplanin引起的血小板聚集开始都缓慢，一旦聚集以后，血小板内被激活的蛋白在两种情况下是相似的。研究人员推测，CLEC-2不仅能与rhodocytin 结合，也能与podoplanin结合。为了验证这一假说，科学家首先培养出CLEC-2 ，并将它们加入到有podoplanin表达的培养细胞中。结果证明推断是正确的：CLEC-2 与podoplanin结合同CLEC-2 与rhodocytin结合是同一种锁钥关系。
“我们很惊喜。”铃木说。“这么多年来我们终于发现与podoplanin结合并促进血小板凝集的蛋白了。”通过podoplanin表达细胞与遗传发生变异的血小板混合没有发现血小板表面的CLEC-2与podoplanin结合这一现象进一步证明了他们的研究结果。血小板凝集受到抑制，证明了CLEC-2 是podoplanin引起的血小板聚集所必需的蛋白。这一结果证明，通过阻止CLEC-2与podoplanin结合来防止癌细胞引发的、促使癌症转移的血小板凝集是可能的。“我们的研究清楚显示，肿瘤细胞表面的podoplanin通过与血小板表面的CLEC-2相互作用引发血小板凝集。”铃木说。“防止CLEC-2与podoplanin相互结合是预防肿瘤转移的很好疗法。
Podoplanin与CLEC-2相互作用就不能阻止肿瘤的转移。当Podoplanin与CLEC-2结合后，不仅会发生血小板凝集，而且还会释放化学物质形成新的血管，为肿瘤生长提供氧和营养。封闭Podoplanin与CLEC-2的结合，不仅防止了癌症转移，也会限制癌症生长。研究人员还发现，存在于运送血浆和白细胞的淋巴管中的podoplanin也会引发血小板凝集。这说明，更好地了解Podoplanin与CLEC-2是如何结合的，能为淋巴管是如何形成和工作的提供信息。
科学家正在试图研制能与Podoplanin结合的CLEC-2样抗体，来预防Podoplanin与血小板结合。他们还在研究Podoplanin与CLEC-2结合在血液凝集和淋巴管形成上的作用。
该文章发表在9月7日出版的《生物化学》杂志上。（援引中国公众科技网）
原始出处:
J. Biol. Chem., Vol. 282, Issue 36, 25993-26001, September 7, 2007
Involvement of the Snake Toxin Receptor CLEC-2, in Podoplanin-mediated Platelet Activation, by Cancer Cells*
Katsue Suzuki-Inoue1, Yukinari Kato, Osamu Inoue, Mika Kato Kaneko, Kazuhiko Mishima¶, Yutaka Yatomi||, Yasuo Yamazaki**, Hisashi Narimatsu, and Yukio Ozaki
From the Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, the Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), OSL C2, 1-1-1, Umezono, Tsukuba 305-8568, the ¶Saitama Medical University International Medical Center, 1397-1 Yamane Hidaka-shi, Saitama, the ||Department of Laboratory Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, and the **Department of Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
Podoplanin (aggrus), a transmembrane sialoglycoprotein, is involved in tumor cell-induced platelet aggregation, tumor metastasis, and lymphatic vessel formation. However, the mechanism by which podoplanin induces these cellular processes including its receptor has not been elucidated to date. Podoplanin induced platelet aggregation with a long lag phase, which is dependent upon Src and phospholipase C2 activation. However, it does not bind to glycoprotein VI. This mode of platelet activation was reminiscent of the snake toxin rhodocytin, the receptor of which has been identified by us as a novel platelet activation receptor, C-type lectin-like receptor 2 (CLEC-2) (Suzuki-Inoue, K., Fuller, G. L., Garcia, A., Eble, J. A., Pohlmann, S., Inoue, O., Gartner, T. K., Hughan, S. C., Pearce, A. C., Laing, G. D., Theakston, R. D., Schweighoffer, E., Zitzmann, N., Morita, T., Tybulewicz, V. L., Ozaki, Y., and Watson, S. P. (2006) Blood 107, 542–549). Therefore, we sought to evaluate whether CLEC-2 serves as a physiological counterpart for podoplanin. Association between CLEC-2 and podoplanin was confirmed by flow cytometry. Furthermore, their association was dependent on sialic acid on O-glycans of podoplanin. Recombinant CLEC-2 inhibited platelet aggregation induced by podoplanin-expressing tumor cells or lymphatic endothelial cells, suggesting that CLEC-2 is responsible for platelet aggregation induced by endogenously expressed podoplanin on the cell surfaces. These findings suggest that CLEC-2 is a physiological target protein of podoplanin and imply that it is involved in podoplanin-induced platelet aggregation, tumor metastasis, and other cellular responses related to podoplanin.
Received for publication, March 19, 2007 , and in revised form, June 11, 2007.
* This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant 18591052) (to K. S.-I.), from the Mitsubishi Pharma Research Foundation (to K. S.-I.), from the Japan Society for the Promotion of Science for Young Scientists, Japan (to Y. K.), from the Kanae Foundation for Life and Socio-medical Science (to Y. K.), and from the Osaka Cancer Research Foundation (to Y. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
This article was selected as a Paper of the Week.
1 To whom correspondence should be addressed. Tel.: 81-55-273-9884; Fax: 81-55-273-6713; E-mail: katsuei@yamanashi.ac.jp .
