關(guān)于癌細(xì)胞是如何將起血液凝固作用的血小板聚集到自己周圍來進(jìn)行擴(kuò)散這一問題,，科學(xué)家提出新的詳細(xì)證據(jù),。日本科學(xué)家首次在血小板表面發(fā)現(xiàn)了一種蛋白，這種蛋白在癌癥引起的血小板聚集中扮演重要角色,。這一發(fā)現(xiàn)有助于開發(fā)新的藥物,，防止癌細(xì)胞在體內(nèi)轉(zhuǎn)移或擴(kuò)散。
“為了擴(kuò)散,，癌細(xì)胞需釋放化學(xué)物質(zhì)使附近的血小板聚集并包繞癌細(xì)胞,，以便逃避免疫系統(tǒng)并使自己附著在血管壁上。”研究人員鈴木說,。“我們已經(jīng)發(fā)現(xiàn)其中一種叫podoplanin的化學(xué)物質(zhì)是如何結(jié)合到血小板上并使它們聚集的,。盡管這種物質(zhì)在1990年就被認(rèn)識，但直到現(xiàn)在對它如何引起血小板聚集這一問題才有所認(rèn)識,。”
科學(xué)家過去研究發(fā)現(xiàn),，蛇毒rhodocytin通過與位于血小板表面的C型血細(xì)胞凝集素受體-2（CLEC-2）結(jié)合促進(jìn)血小板凝集。為了詳細(xì)研究在血小板聚集以前和聚集過程中有什么事情發(fā)生,，科學(xué)家觀察到被癌細(xì)胞podoplanin引起的血小板凝集有許多相似之處。無論rhodocytin 或 podoplanin引起的血小板聚集開始都緩慢,，一旦聚集以后,，血小板內(nèi)被激活的蛋白在兩種情況下是相似的。研究人員推測,，CLEC-2不僅能與rhodocytin 結(jié)合,，也能與podoplanin結(jié)合。為了驗(yàn)證這一假說,，科學(xué)家首先培養(yǎng)出CLEC-2 ,，并將它們加入到有podoplanin表達(dá)的培養(yǎng)細(xì)胞中。結(jié)果證明推斷是正確的：CLEC-2 與podoplanin結(jié)合同CLEC-2 與rhodocytin結(jié)合是同一種鎖鑰關(guān)系。
“我們很驚喜,。”鈴木說,。“這么多年來我們終于發(fā)現(xiàn)與podoplanin結(jié)合并促進(jìn)血小板凝集的蛋白了。”通過podoplanin表達(dá)細(xì)胞與遺傳發(fā)生變異的血小板混合沒有發(fā)現(xiàn)血小板表面的CLEC-2與podoplanin結(jié)合這一現(xiàn)象進(jìn)一步證明了他們的研究結(jié)果,。血小板凝集受到抑制,，證明了CLEC-2 是podoplanin引起的血小板聚集所必需的蛋白。這一結(jié)果證明,，通過阻止CLEC-2與podoplanin結(jié)合來防止癌細(xì)胞引發(fā)的,、促使癌癥轉(zhuǎn)移的血小板凝集是可能的。“我們的研究清楚顯示,，腫瘤細(xì)胞表面的podoplanin通過與血小板表面的CLEC-2相互作用引發(fā)血小板凝集,。”鈴木說。“防止CLEC-2與podoplanin相互結(jié)合是預(yù)防腫瘤轉(zhuǎn)移的很好療法,。
Podoplanin與CLEC-2相互作用就不能阻止腫瘤的轉(zhuǎn)移,。當(dāng)Podoplanin與CLEC-2結(jié)合后，不僅會發(fā)生血小板凝集,，而且還會釋放化學(xué)物質(zhì)形成新的血管,，為腫瘤生長提供氧和營養(yǎng)。封閉Podoplanin與CLEC-2的結(jié)合,，不僅防止了癌癥轉(zhuǎn)移,，也會限制癌癥生長。研究人員還發(fā)現(xiàn),，存在于運(yùn)送血漿和白細(xì)胞的淋巴管中的podoplanin也會引發(fā)血小板凝集,。這說明，更好地了解Podoplanin與CLEC-2是如何結(jié)合的,，能為淋巴管是如何形成和工作的提供信息,。
科學(xué)家正在試圖研制能與Podoplanin結(jié)合的CLEC-2樣抗體，來預(yù)防Podoplanin與血小板結(jié)合,。他們還在研究Podoplanin與CLEC-2結(jié)合在血液凝集和淋巴管形成上的作用,。
該文章發(fā)表在9月7日出版的《生物化學(xué)》雜志上。（援引中國公眾科技網(wǎng)）
原始出處:
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: [email protected] .
