Adipocyte-Induced Inflammation In Prostate Tumor Progression In Bone: Role Of Cxcr2 And Osteopontin

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men. Evidence suggests that age and obesity, conditions associated with adipocyte accumulation in the bone marrow, are linked to increased risk of developing PCa and progressing to metastatic disease. Studies presented in this dissertation were based on the hypothesis that metastatic progression in bone is a result of a cooperative effort between bone marrow adipocytes, macrophages, osteoclasts, and PCa cells. We specifically focused on two adipocyte-supplied chemokines, CXCL1 and CXCL2, and bone marrow macrophage-secreted osteopontin as key drivers of pro-inflammatory environment in the bone marrow and important regulators of tumor growth and survival in bone. Our results revealed that adipocyte-supplied CXCL1 and CXCL2 are significant contributors to tumor-driven osteolysis in metastatic disease. We showed, that interaction of CXCL1 and CXCL2 with their receptor CXCR2 on osteoclast precursor cells drives osteoclastogenesis in vitro and bone degradation in vivo. Our studies also demonstrated that in addition to its effects on osteoclasts, CXCR2 signaling axis is important for macrophage phenotype and function. Specifically, blocking the CXCR2 interaction with its ligands reduces macrophage invasiveness. We also showed, that interaction of PCa cells with bone marrow macrophages in vitro and in vivo promotes phenotypic switch towards more pro-tumorigenic phenotype. Importantly, we were able to show that upon exposure to tumor cells macrophages secrete significant levels of osteopontin, powerful pro-inflammatory protein that contributes to tumor growth and survival in the bone metastatic niche. Collectively, our studies unravelled new mechanisms behind metastatic PCa progression in bone. This work will serve as basis for future studies towards discovering novel therapeutic targets for treatment of this incurable disease