Abstract IA25: Signaling roles of platelets during metastatic seeding
Authors: Labelle Myriam 
Published: May 2019

During metastasis, host cells are recruited to disseminated tumor cells to form dynamic, specialized microenvironments (niches) that promote metastatic progression. Platelets interact with tumor cells during their transit through the circulation and are key components of the early metastatic niches, which are formed when tumor cells initially arrest in distant organs. Interestingly, high platelet counts are frequently associated with poor outcome and disease progression in patients with solid tumors. Coincident with these clinical observations, platelets have been shown to promote metastasis via multiple mechanisms, including their ability to form physical shields around tumor cells, which prevent attacks from natural killer (NK) cells and facilitate tumor cell adhesion to the endothelium. However, in addition to these adhesive properties, platelets contain several signaling factors, which are released upon platelet activation, raising the possibility that platelet-derived signals modulate the metastatic potential of tumor cells and the function of host cells present in metastatic niches.

We tested this hypothesis and found that direct contact between platelets and tumor cells triggers EMT (epithelial-mesenchymal transition) via activation of the TGFβ1 and NF-κB signaling pathways in tumor cells. We further showed that these two signaling pathways synergize to enhance the invasive potential of tumor cells and increase their ability to extravasate and seed metastases in vivo. Thus, cancer cells rely on platelet-derived signals provided in the early metastatic niche for efficient metastasis.

In addition, we found that platelets influence metastasis by signaling not only to tumor cells but also to host cells present in the same metastatic niches. Importantly, platelet-derived rather than tumor cell-derived signals are required for the rapid recruitment of granulocytes to early metastatic niches. Granulocyte recruitment relies on CXCL5 and CXCL7 chemokines, which are released by platelets upon contact with tumor cells. Furthermore, blockade of the CXCL5/7 receptor CXCR2, or transient depletion of either platelets or granulocytes prevents the formation of early metastatic niches and significantly reduces metastatic seeding and progression. Thus, in addition to promoting metastasis via direct platelet-to-tumor cell signaling, platelets are required for the recruitment of prometastatic granulocytes to early metastatic niches.

Overall, our work establishes platelets as key signaling platforms during metastatic seeding. On this basis, we propose that specific inhibition of platelet-to-tumor cell or platelet-to-granulocyte signaling may represent valuable antimetastatic interventions in combination with cancer cell-centered treatments.

References:

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 Nov 15;20(5):576-90.

Labelle M, Begum S, Hynes RO. Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):E3053-61.

Labelle M, Hynes RO. The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discov. 2012 Dec;2(12):1091-9.

Citation Format: Myriam Labelle. Signaling roles of platelets during metastatic seeding. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA25.