肿瘤细胞如何聚集血小板保护自己转移

How Cancer Spreads By Aggregating Platelets
肿瘤细胞如何聚集血小板保护自己转移

Science Daily — Scientists have provided new details about how cancer cells spread by surrounding themselves with platelets -- the blood cells needed for blood clotting. Katsue Suzuki-Inoue, Associate Professor of Medicine at the University of Yamanashi, Japan, and colleagues have identified for the first time a protein on the surface of platelets that plays a key role in cancer-induced platelet aggregation.
Science日报-科学家们为癌细胞如何用血小板-血液凝结所需的血细胞-包裹自己进行扩散提供了新的细节。日本Yamanashi大学医学副教授Katsue Suzuki-Inoue和她的同事们已首次确定血小板表面蛋白在肿瘤诱导血小板聚集中发挥的关键作用。

These results could help design new drugs that prevent cancer cells from metastasizing, or spreading throughout the body.
这一结果将有助于设计新药来阻止癌细胞转移、蔓延到全身。

\"In order to spread, cancer cells release chemicals that make neighboring platelets aggregate and surround the cancer cells, helping them evade the immune system and allowing them to bind to the blood vessels' inner linings,\" Suzuki-Inoue says. \"We have discovered how one of these chemicals, called podoplanin, binds to the platelet cells and stimulate their aggregation. Although podoplanin has been known since 1990, how it induces platelet cell aggregation has been a mystery -- until now.\"
\"肿瘤细胞释放化学物质使邻近的血小板聚集，并包裹肿瘤细胞以帮助他们逃避免疫系统检测，结合到血管内层来进行传播\" Suzuki-Inoue 说。 \"我们已经发现其中的一种化学物质，podoplanin ，是如何结合到血小板上并诱导它们聚集的。虽然自1990年以来podoplanin已为人所认识，但是直到现在，它是如何诱导血小板聚集的仍是未解之谜。”

Suzuki-Inoue and colleagues had previously discovered that the snake venom rhodocytin stimulates platelet aggregation by binding to a protein called C-type lectin-like receptor 2 (CLEC-2) located on the surface of the platelets in a way similar to a key (rhodocytin) binding to a lock (CLEC-2).
Suzuki-Inoue及其同事以前发现，蛇毒rhodocytin是通过与位于血小板表面的蛋白C凝集素样受体2（CLEC-2）结合来刺激血小板聚集的，这在某种程度上与钥匙和锁的结合相似。

By studying the details of what happens inside these platelets before and during aggregation, the scientists noticed many similarities with the way platelets aggregate when they are induced by podoplanin from cancer cells. Whether stimulated by rhodocytin or podoplanin, the platelets are slow to aggregate at first and, after they start aggregating, the proteins that are activated inside the platelets are similar in both cases.
通过研究血小板在聚集前和聚集过程中的细节，研究人员注意到，源自肿瘤细胞的podoplanin在诱导血小板聚集时的方式有许多相似之处。不论是被rhodocytin还是podoplanin刺激，血小板开始聚集后，第一阶段总是聚集缓慢，血小板内部被激活的蛋白在这两种情况下是相似的。

Suzuki-Inoue and her team reasoned that maybe CLEC-2 binds not only to rhodocytin but also to podoplanin. The scientists tested this hypothesis by first growing CLEC-2 in culture and then by adding them to cultured cells expressing podoplanin. The hypothesis was confirmed: CLEC-2 and podoplanin bound to each other in the same lock-and-key mechanism displayed by CLEC-2 and rhodocytin.
Suzuki-Inoue和她的研究小组推断，也许CLEC-2不仅与rhodocytin结合，也与podoplanin结合 。研究人员通过在培液中先培养CLEC-2，然后再将其加入表达podoplanin的细胞的方法来验证这一假说。该假说得到证实：CLEC-2与podoplanin相互结合显示了与CLEC-2与rhodocytin 相同的锁与钥机制。

\"We were pleasantly surprised,\" Suzuki-Inuoue says. \"After all these years, we finally found the long-missing protein to which podoplanin binds to promote platelet aggregation.\"
\"我们很惊喜，\" Suzuki-Inuoue说。 \"经过这些年，我们终于找到这个长期失踪的、与podoplanin结合以促进血小板聚集的蛋白了\" 。

The scientists confirmed their findings by mixing podoplanin-expressing cells with platelet cells genetically altered so that the CLEC-2 on their surface could not bind to podoplanin. Platelet aggregation was completely inhibited, confirming that CLEC-2 was the protein necessary for podoplanin-induced platelet aggregation.
研究人员通过将表达podoplanin的细胞与基因改变的血小板相混合，证实了他们的发现：血小板聚集被完全抑制。血小板基因改变后其表面的CLEC-2不能结合podoplanin 。确定CLEC-2是podoplanin诱导血小板聚集过程中的必需蛋白。

This result also suggested that it may be possible to prevent cancer cells from stimulating platelet aggregation -- and thus allow the cancer cells to metastasize -- by blocking the interaction between CLEC-2 and podoplanin.
这一结果还表明，通过阻断CLEC-2 和podoplanin之间的相互作用来阻断肿瘤细胞刺激血小板聚集-这会让肿瘤细胞转移-是有可能的。

\"Our study clearly shows that podoplanin on the surface of tumor cells induces platelet aggregation by interacting with CLEC-2 on the surface of platelet cells,\" Suzuki-Inuoue says. \"reventing CLEC-2 and podoplanin from binding to each other may be a good therapeutic way of preventing tumor metastasis.\"
\"我们的研究清楚的说明，对肿瘤细胞表面的podoplanin通过与血小板表面的CLEC-2相互作用来诱导血小板聚集\"，Suzuki-Inuoue 说。 \"预防CLEC-2和podoplanin彼此结合对预防肿瘤转移将会是一个很好的治疗途径\" 。

The role of podoplanin-CLEC-2 interaction may not be limited to tumor metastasis, the scientists note. When podoplanin and CLEC-2 bind to each other, not only do platelets aggregate, but they also release chemicals that may form new blood vessels which, in turn, provide the tumor with the nutrients and oxygen it needs to grow. As a result, locking the podoplanin-CLEC-2 interaction may not only prevent cancer metastasis but also limit the growth of cancer cells, Suzuki-Inuoue says.
研究人员注意到，podoplanin-CLEC-2的相互作用可能不仅仅限于肿瘤转移。podoplanin和CLEC-2相互结合不仅影响血小板凝聚，也释放化学物质，这可能促进形成新生血管，并为肿瘤提供成长所需的养分和氧气。因此，阻断podoplanin和CLEC-2的相互作用不仅可以防止癌症转移，也会限制肿瘤细胞生长， Suzuki-Inuoue 说。

The researchers also found that podoplanin present within lymphatic vessels -- which carry plasma and white blood cells -- also induces platelet aggregation, showing that a better understanding of how podoplanin and CLEC-2 bind together may provide information on how lymphatic vessels form and work.
研究者还发现，表达于淋巴管的podoplanin-淋巴管携带血浆和白细胞-也会诱导血小板聚集，更好的了解podoplanin和CLEC-2如何结合将为淋巴管如何形成和工作提供信息。

Suzuki-Inuoue and colleagues are now trying to develop antibodies that look like CLEC-2 and that can bind to podoplanin, preventing it from attaching to platelet cells. The scientists are also investigating the role of the podoplanin-CLEC-2 interaction in the formation of blood clots and the development of lymphatic vessels.
现在，Suzuki-Inuoue 及其同事正在试图开发形似CLEC-2并能与podoplanin结合的抗体，去抑制podoplanin结合血小板。科学家们也正在研究podoplanin-CLEC-2相互作用在血凝和淋巴管发展中的作用。

The new study, to be published in the September 7 issue of the Journal of Biological Chemistry, was selected as a \"aper of the Week\" by the journal's editors, meaning that it belongs to the top one percent of papers reviewed in significance and overall importance.