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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.”