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

“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.”

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.

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).

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.

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.

“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.”

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