illustration by VSA Partners

Sticky-Fingered Culprit

Researchers are discovering how the blood’s wound-healing platelets have a hand in metastasis as well.

Sometimes, it pays to revisit an old idea.

In the 1960s, scientists began to see evidence that platelets do more than gather around wounds to staunch bleeding and promote wound healing. These tiny fragments in the bloodstream appeared to also promote metastasis, the spread of cancer cells through the body, which is responsible for 90 percent of cancer deaths. But how?

Richard Hynes, an HHMI investigator at the Massachusetts Institute of Technology, is especially interested in cell adhesion—how cells stick to each other and to body tissues—and the ways it contributes to human disease. In experiments conducted nearly 10 years ago, Hynes and collaborators demonstrated that cell adhesion proteins known as selectins, located on the surface of platelets, are involved in metastasis.

At the time, the Hynes group was occupied with studying the role of cell adhesion in vascular development and screening for adhesion-related genes that enhance or suppress tumor metastasis. “No one had time to concentrate on the platelet question,” he says.

When postdoc Myriam Labelle joined the Hynes lab four years ago, she picked up the platelet thread—with illuminating results. In a series of experiments published November 15, 2011, in Cancer Cell, the team revealed unexpected features of the roles platelets play in enhancing metastasis.

The metastasis-enhancing effects of platelets have most often been attributed either to their ability to promote cell adhesion or to their capacity to surround and protect cancer cells as they migrate through the bloodstream and stick to a secondary site. But platelets are also loaded with growth factors that could affect the behavior of cancer cells, “and that hadn’t really been explored,” says Hynes.

“The first thing I tried was to see whether pretreating tumor cells with platelets would promote metastasis,” Labelle says. The answer was a resounding yes: mice injected with colon and breast cancer cells that had been incubated along with platelets—and then rinsed, to rule out platelets’ known adhesion properties—showed a marked increase in metastasis to the lungs.

At the same time, Labelle noticed that cancer cells that had been directly exposed to platelets grew longer and thinner. That change in shape is consistent with a process known as epithelial-mesenchymal transition (EMT), which increases the capacity of cells to migrate and invade. EMT is involved in metastasis, and it is known to be enhanced by TGF-beta, one of the growth factors present in platelets. Gene expression array analysis of the platelet-treated cancer cells showed increased activation of EMT-related genes and of genes responding to TGF-beta.

To further test the link between platelets, TGF-beta, and metastasis, Labelle injected cancer cells into mice that lacked TGF-beta in their platelets. The mice experienced a lower incidence of metastasis than animals whose platelets had TGF-beta.

Labelle also observed that when she treated cancer cells with platelet-derived TGF-beta, rather than exposing them to actual platelets, the resulting tumors were not nearly as aggressive. “It turns out that platelets promote metastasis much better than does TGF-beta alone,” Hynes says. The next question, then, was why.

Digging further, Labelle discovered that contact between platelets and cancer cells activates another signaling pathway, called NF-kappa B, which is implicated in metastasis. NF-kappa B had never been tied to the role of platelets in metastasis.

Moreover, inhibiting the NF-kappa B pathway in cancer cells that had been pretreated with platelets prevented an increase in metastasis just as effectively as suppressing TGF-beta. “Both signaling pathways are required,” says Hynes. “Block either one of them, and the platelet effect goes away.”

Unlike TGF-beta, which still promotes metastasis (albeit to a lesser degree) when there is no physical contact between platelets and cancer cells, the NF-kappa B pathway requires direct contact for activation. And that brings us back to the experiments conducted nearly a decade ago, which demonstrated a link between metastasis, platelets, and sticky-fingered selectins.

“The platelets have to contact the cancer cells, and in the circulation that probably means they have to stick to them—and that’s where the selectins come in,” Hynes says. “You need adhesion between the platelets and the tumor cells to get the full effect.”

Many questions remain. How do the platelets activate the NF-kappa B pathway? And does the pathway simply boost the effect of TGF-beta, or does it promote metastasis in some other, entirely distinct way? “Probably both,” predicts Hynes. Labelle is working on experiments to find out.

In the meantime, the team’s latest results already point to potential therapies for preventing metastasis. “Both of these pathways,” says Hynes, “are targets that would be readily exploitable.”

Scientist Profile

Investigator
Massachusetts Institute of Technology
Cancer Biology, Developmental Biology

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