Prostate cancer (PCa) selectively metastasizes to bone as opposed to other sites. Over 80% of men with advance PCa develop bone metastases that cause bone pain and is the harbinger of the patient's death. Accordingly, it is crucial to define mechanisms through which PCa bone metastases develop and progress to allow for developing effective therapies. The observation that PCa selectively metastasizes to bone suggests that the bone microenvironment offers a selective advantage for attracting and/or growth of PCa cells. To that end we have begun to evaluate the role of osteocytes (OCys), which are the most common cells in bone, in their ability to promote PCa bone metastases. We have found that OCys promote both PCa growth and invasive ability. Furthermore, we have identified several candidate proteins through which OCy may mediate-these activities. Specifically, it appears that CCL5 (RANTES) and RANKL promote OCy-mediated invasion; whereas, a decrease of OCy-produced noggin, a bone morphogenetic protein (BMP) inhibitor, promotes PCa growth. These data lead us to hypothesize that OCys promote PCa bone metastasis progression through promoting PCa growth in bone or through promoting invasion into bone or both. To test this hypothesis, we will perform the following specific aims:
Aim 1. Determine if OCy-induced CLL5- and RANKL-mediated invasion is a component of the mechanism that favors progression of PCa bone metastases.
Aim 2. Determine if OCy-induced BMP-mediated tumor growth is a component of the mechanism that favors progression of PCa bone metastases.
Aim 3. Determine the presence and localization of mediators through which OCys promote PCa bone metastasis in patients' PCa bone metastases biopsies. When completed, we will have determined mechanisms through which OCys contribute to PCa bone metastases and the use of an OCy-specific protein as a biomarker.
The majority of men with advance prostate cancer develop bone metastases which are uncurable. Thus, it is critical to develop an understanding of the process of bone metastasis so that we can develop cures. This project explores how the osteocyte, a unique cell in the bone, promotes bone metastasis so that we can identify targets to diminish the development and progression of bone metastasis.
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