Platelet TSP-1 controls prostate cancer-induced osteoclast differentiation and bone marrow-derived cell mobilization through TGFbeta-1

Am J Clin Exp Urol. 2021 Feb 15;9(1):18-31. eCollection 2021.ABSTRACTThe development of distant metastasis is the leading cause of prostate cancer (CaP)-related death, with the skeleton being the primary site of metastasis. While the progression of primary tumors and the growth of bone metastatic tumors are well described, the mechanisms controlling pre-metastatic niche formation and homing of CaP to bone remain unclear. Through prior studies, we demonstrated that platelet secretion was required for ongoing tumor growth and pre-metastatic tumor-induced bone formation. Platelets stimulated bone marrow-derived cell (BMDC) mobilization to tumors supporting angiogenesis. We hypothesized that proteins released by the platelet α granules were responsible for inducing changes in the pre-metastatic bone niche. We found that the classically anti-angiogenic protein thrombospondin (TSP)-1 was significantly increased in the platelets of mice with RM1 murine CaP tumors. To determine the role of increased TSP-1, we implanted tumors in TSP-1 null animals and assessed changes in tumor growth and pre-metastatic niche. TSP-1 loss resulted in increased tumor size and enhanced angiogenesis by immunohistochemistry. Conversely, TSP-1 deletion reduced BMDC mobilization and enhanced osteoclast formation resulting in decreased tumor-induced bone formation as measured by microcomputed tomography. We hypothesized that changes in the pre-metastatic niche were due to the retention of TGF-β1 in the plat...
Source: Clinical Prostate Cancer - Category: Cancer & Oncology Authors: Source Type: research