Abstract

Tumors can be considered parasites that exploit the host’s resources in order to promote their own growth. Tumors secrete growth factors and cytokines (tumor secretome) which recruit platelets, blood vessels, and bone marrow-derived cells (BMDCs) to promote angiogenesis and tumor progression. We have recently demonstrated that distant tumor growth can stimulate bone formation and BMDC mobilization prior to metastasis. However, the mechanism of communication between the primary tumor and the bone microenvironment remains unknown. Signals from the tumor to the bone microenvironment are likely transmitted through the circulation; nevertheless, these signals need to be protected from degradation or utilization prior to reaching their target. We hypothesized that platelets could function as regulated storage compartments for the tumor secretome. Using a murine platelet depletion model during tumor growth, we assessed the role of platelets in BMDC homing and bone remodeling. We demonstrate that platelet depletion prevents BMDC mobilization and recruitment into tumors. Further, platelet depletion inhibited tumor-induced bone formation. To determine which tumor-derived proteins in platelets were responsible for changes in BMDC mobilization and bone remodeling, we analyzed the tumor secretome components and found that 77% of proteins are enriched within platelets over plasma, and that these proteins regulate BMDC mobilization and bone remodeling. In addition, we discovered that tumor-derived proteins, specifically transforming growth factor (TGF)-β1 and matrix metalloproteinases, sequestered within platelets could stimulate osteoblast differentiation and mineralization in vitro. We also found that thrombospondin (TSP)-1 levels are increased in the platelets of tumor-bearing mice. Finally, we assessed the role of the TSP-1/TGF-β1 signaling axis in tumor-induced bone formation and BMDC mobilization. Tumors in TSP-1 null mice were larger, however tumor-induced bone remodeling decreased. Interestingly, in tumor-bearing mice, high levels of TGF-β1 were being retained in the platelets due to a lack of TSP-1 to activate and release TGF-β1. To examine the role of platelet TGF-β1 in the process of tumor-induced bone remodeling, tumors were implanted in platelet-specific TGF-β1 conditional knockout mice and the changes in tumor size and the bone microenvironment were assessed. In summary, our data show that platelet sequestration and secretion of tumor-derived proteins represent a cellular mechanism mediating communication between the bone microenvironment and the primary tumor.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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