Major finding: Intravascular interactions between platelets and tumor cells promote metastasis.
Concept: Platelet-derived TGF-β and platelet–tumor cell contact synergistically induce EMT.
Impact: Tumor cells respond to prometastatic host signals outside of the primary tumor.
Host cells in the tumor microenvironment secrete factors that promote an epithelial-to-mesenchymal transition (EMT) and metastasis. However, once tumor cells disseminate into the bloodstream, whether they encounter additional prometastatic host signals remains unclear. Platelets, well-known for their role in hemostasis, have been shown to enhance tumor cell cohesion and shield tumor cells from immune recognition. Labelle and colleagues demonstrate a prometastatic role for platelets: direct interactions between platelets and tumor cells induce EMT and promote metastasis. In the presence of tumor cells, platelets released transforming growth factor-β (TGF-β), a signaling protein implicated in metastatic progression, leading to mesenchymal-like changes in vitro and to enhanced metastatic activity in vivo. To establish the necessity of platelet-derived TGF-β, the authors created a mouse model in which expression of TGF-β1 was knocked out specifically in megakaryocytes, which are platelet precursors. In addition to having fewer metastases, these mice also had delayed tumor cell extravasation, suggesting that platelets may play a role in tumor cell exit from the bloodstream. However, although necessary, secreted TGF-β was not sufficient to promote metastasis, and further experiments revealed that direct platelet–tumor cell contact activated the NF-κB signaling pathway in tumor cells, which was also necessary for metastasis. Together, the findings suggest that direct platelet contact synergizes with signaling pathway activation, secondary to platelet releasate, to promote metastasis. The discovery that disseminated tumor cells continue to interact with their changing microenvironment has the potential to inform the development of new antimetastatic therapies.
Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 2011;20:576–90.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at www.AACR.org/CDnews.