Empêcher les métastases : on s'approche.

How Cancer Spreads By Aggregating Platelets

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.

Les scientifiques ont fourni de nouveaux détails sur comment les cellules canécreuses se répandent à travers l'organisme. Les scientifiques ont identifié pour la première fois une protéine sur la surface des plaquettes qui jouent un rôle dans l'aggrégation des plaquettes.

These results could help design new drugs that prevent cancer cells from metastasizing, or spreading throughout the body.

Ces résultats pourraient aider à faire de nouveaux médicament pour prévenir le cancer de métastaser ou de se répandre à d'autres parties du corps.

"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."

"Pour se répandre, les cellules cancéreuses laisse échapper des éléments chimiques qui font que les plaquettes en viennent à se souder ensemble et entourent les cellules cancéreuses les aidant ainsi à échapper au système immunitaire et à leur permettant de se lier à l,intérieur des  vaisseaux sanguins Suzuki-Inoue dit :" nous avons découvert comment un de ces éléments chimiques appelé podolanin se lie aux plaquettes et stimule leur aggrégation. Même si ce podoladin était connu depuis 1990, la façcon dont il provoquait les cellules à se coller demeurait un mystère"

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).

Les chercheurs avaient auparavant découvert que le venin de serpent rhodocytine stimulait les plaquettes à se souder en se liant à une protéine appelé récepteur 2 de type lectine (CLEC-2) localisé sur la surface des plaquettes.

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.

Les scientifiques ont noté des similarité entre les deux protéines.

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.

Les scientifiques ont émis l'hypothèse que le CLEC-2 se liait non seulement à rhodocytine mais aussi à podoplanine.

"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."

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.

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.

Ce résultat suggère que cela pourrait être possible de prévenir l'aggrégation des palquettes - et donc éviter la métastase - en bloquant l'interaction entre CLEC-2 et podoplanine.

"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. "Preventing CLEC-2 and podoplanin from binding to each other may be a good therapeutic way of preventing tumor metastasis."

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.

Le rôle de podoplanine-CECL-2 ne serait pas seulement limité à faciliter les métastases mais pourrait être lié à la croissance des tumeurs également en fournissant des éléments chimqiues pour faier de nouveaux vaisseaux sanguins. donc bloquer l'interaction podoplanine et CLEC-2 limiterait aussi la croissance des cellules cancéreuses en plus de prévenir les métastases.

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.

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.

Les scientifiques tentent maintenant de développer des anticorps qui ressemblent à CLEC-2 et qui pourraient se lier à podoplanine empêchant ainsi celui-ci de se lier avec les plaquettes.

The new study, to be published in the September 7 issue of the Journal of Biological Chemistry, was selected as a "Paper 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.

Cette étude a été sélectionné "articel de la semaine" par le journal de "biological chemistry"

Article: "Involvement of the snake toxin receptor CLEC-2 in podoplanin-mediated platelet activation by cancer cells," by Katsue Suzuki-Inoue, Yukinari Kato, Osamu Inoue, Mika Kato Kaneko, Kazuhiko Mishima, Yutaka Yatomi, Yasuo Yamazaki, Hisashi Narimatsu, and Yukio Ozaki