Platelets and the Tumor Cell Microenvironment

The link between tumors and the hemostatic system, first of all platelets, has been acknowledged by numerous studies. Platelets activation at the tumor microenvironment and subsequent intravascular clotting are often associated with cancer complications. Recent clinical studies demonstrated that platelet inhibitors substantially decrease risk of tumor metastasis and mortality in cancer patients, thereby emphasizing clinical importance of platelets. However, the precise function of platelets in cancer progression remains enigmatic. Growing tumors secrete a plethora of growth factors and cytokines (tumor secretome) aiming to change its micro- and macro-environment. These factors promote angiogenesis, induce inflammation, and even stimulate changes in bones prior to metastasis. Tumor secretome signals are likely transmitted through the circulation; however, these signals need to be protected from degradation or utilization prior to reaching their target. Due to their ability to intake and secrete back a wide spectrum of proteins, platelets could function as a mobile storage compartment for the tumor secretome. Using platelet infusion and depletion during tumor growth, we assessed the role of platelets in tumor growth and tumor-induced bone remodeling. We demonstrated that platelet infusion stimulates communications between bone marrow and the tumor, while platelet depletion had the opposite effects. Importantly, tumor-induced changes in bone structure were completely abolished in the absence of platelets. Using platelets from knockout mice with various platelet defects, we demonstrated that platelet secretion (but not aggregation) was crucial for their function in tumor progression. In particular, the function of platelet α-granules is essential for the pro-tumorigenic role of platelets. Analysis of the tumor secretome revealed that 77 percent of tumor-secreted factors are highly enriched within platelets over plasma. Several of these factors are essential mediators of bone remodeling. Thus, our data show that platelet α-granule sequestration and secretion represent a cellular mechanism mediating communication between the bone microenvironment and the primary tumor.