Platelet and Megakaryocytic Regulation of Tumor Progression
Authors: Battinelli Elisabeth M. 
Published: April 2021

Traditionally viewed as the bandaids of the blood, the contribution of platelets to the progression of malignancy is emerging as a compelling focus for therapeutic intervention. Complex interactions between tumor cells, and circulating platelets play an important role in tumor growth and dissemination, and a growing body of data supports a role for platelet activation and release of chemokines in metastases and neovascularization. Supporting this concept is the evidence that elevated platelet counts (thrombocytosis) at time of diagnosis with malignancy is a harbinger of an aggressive cancer with a poor prognosis. One very interesting and provocative connection between cancer and platelets is the increasing evidence that tumor cells hijack platelets to promote a more pro-malignant phenotype to drive disease progression. Our laboratories have been instrumental in establishing the pro-malignant role of platelets in metastasis and neovascularization. We have demonstrated that tumor cells can instruct platelets to release key cytokines that promote angiogenesis and metastasis of tumor cells. Perhaps the most compelling clinical evidence of the link between platelets and malignancy is the finding that anti-platelet agents can have a profound impact on malignancy. We have demonstrated previously, anti-platelet agents such as aspirin and anticoagulants suppress release of key neovascularization factors from platelets and suppress the neovascularization potential. Aspirin also suppresses the invasive properties of platelets in mouse metastasis models as well as in vitro metastasis assays. Similarly, we have also demonstrated that tamoxifen, a selective estrogen receptor modulator often used to treat breast cancer, can also diminish the ability of platelets to support malignancy by diminishing the platelet's role in promoting neovascularization as well as metastasis. Although much is understood regarding how tumors communicate with platelets less is understood about how platelets manipulate tumor cells. Our laboratory has elucidated the role of key chemokines released from platelets in response to tumor cells and how these factors promote tumor growth and metastasis. We have recently discovered that tumor cells can instruct platelets to release CCL5, a known driver of tumor cell invasion and metastasis, and have expanded the role of CCL5 not only as a regulator of metastasis but also as a central controller of platelet production. Despite this progress many questions still remain regarding the interaction between tumor cells and platelets. We are particularly interested in how tumor cells instruct megakaryocytes to increase platelet production. In addition malignancy may also reprogram megakaryocytes thereby manipulating the platelet phenotype to support tumor growth and metastasis. Because most cancer therapies focus on the tumor itself, the idea of targeting platelets in the tumor microenvironment to arrest tumor growth and metastatic spread represents a novel therapeutic strategy.

Disclosures
No relevant conflicts of interest to declare.