Introduction: It is now recognized that tumor cells activate platelets, causing them to degranulate and release soluble factors that promote angiogenesis and metastasis. However, it is unknown if these released factors ('platelet releasate') can also affect tumor cell signaling to further drive metastasis.

Methods: We used in vitro arrays, ELISA, and invasion assays to study the interactions between platelets and tumor cells in culture. In addition we used an in vivo murine model of mice treated with aspirin and ex vivo patient data from breast cancer patients on aspirin therapy.

Results: Breast tumor cells secrete up to 50-fold increased levels of interleukin 8 (IL-8, CXCL8) in response to platelet releasate in vitro, and this tumor-secreted IL-8 is necessary in driving platelet-mediated invasion. Upon characterizing the contents of the platelet releasate, we determined that chemokine (C-C motif) ligand 5 (CCL5) was the component of the platelet releasate that drove IL8 induction in tumor cell lines expressing the CCL5 receptor, CCR5. The mechanism of this platelet-mediated IL-8 induction was found to be activation of the AKT pathway in breast tumor cells; inhibition of this pathway eliminated IL-8 production.

We therefore hypothesized that inhibiting platelet activation with aspirin could reverse the effects of platelets on pro-metastatic tumor cell signaling. Platelets treated ex vivo with 100 uM aspirin had up to 51% lower activation in response to tumor cells, released 40% less CCL5, did not activate the AKT pathway, resulted in lower levels of IL-8 production, and did not significantly increase breast tumor cell invasion. In a murine in vivo breast cancer model, immunohistochemistry of MCF-7ras tumor cells revealed that oral administration of aspirin resulted in less secretion of IL-8. In addition, samples were collected from breast cancer patients on aspirin therapy or not; patients on aspirin had 42% less circulating IL-8 and their platelets were less able to drive tumor cell invasion in vitro when compared to patients not on aspirin.

Conclusions: Our data suggest that platelets drive breast tumor metastasis by releasing CCL5, activating AKT signaling, and stimulating tumor cells to upregulate and secrete IL-8. Furthermore, we propose aspirin acts as an anti-cancer agent by disrupting the communication between platelets and breast tumor cells.

Disclosures

Italiano: Platelet BioGenesis: Equity Ownership; VCAN Bio: Membership on an entity's Board of Directors or advisory committees.

Author notes

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Asterisk with author names denotes non-ASH members.

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