Much evidence suggested that chronic inflammation is one of the causative factors in prostate tumor development involving infiltration of inflammatory cells, such as macrophages, dendritic cells and lymphocytes. The tumor lesions are often enriched with proinflammatory cytokines, which are correlated with influx of tumor-associated macrophages (TAMs), suggesting that TAMs play an important role in tumor microenvironment, cytokine secretion, as well as promoting tumor cell growth, invasion, and metastasis. Understanding the roles of TAMs and their secreted cytokines in prostate tumor development and progression will help in development of therapeutic designs against prostate tumor. We have identified a novel role of the androgen receptor (AR) in regulating cytokine expression and chemotaxis of macrophages in a mouse wound healing model. This interesting study prompts us to link the potential regulation of AR in TAMs to prostate tumor development and progression. Therefore, we hypothesize the macrophage AR may play a key role in prostate tumor microenvironment, and promote prostate tumor development and progression through the induction of cytokine production. Objective/hypothesis: The macrophage AR may control the expression of inflammatory cytokines that may contribute to the prostate tumor development and progression.
By establishing an in vitro co-culture model between macrophages and prostate tumor cells, and generating mouse models of PTEN or TRAMP tumor/macrophage AR WT and KO mice, or PTEN or TRAMP/ cytokine WT and KO mice, we can investigate the function of macrophage AR and inflammatory cytokines in prostate tumor development and progression. From the in vitro co-culture system, we will determine the AR role in macrophages and identify which cytokine is vital for influencing prostate cancer cells. In the in vivo mouse model, we will examine whether macrophage AR and inflammatory cytokines will influence the latency of prostate tumor development and the potential of tumor invasiveness and distal metastasis.

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