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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA190554-01
Application #
8799405
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Woodhouse, Elizabeth
Project Start
2015-02-12
Project End
2020-01-31
Budget Start
2015-02-12
Budget End
2016-01-31
Support Year
1
Fiscal Year
2015
Total Cost
$355,039
Indirect Cost
$126,289
Name
University of Michigan Ann Arbor
Department
Urology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Dai, Jinlu; Lu, Yi; Roca, Hernan et al. (2017) Immune mediators in the tumor microenvironment of prostate cancer. Chin J Cancer 36:29
Park, Sun H; Keller, Evan T; Shiozawa, Yusuke (2017) Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis. Calcif Tissue Int :
Dai, Jinlu; Hensel, Janine; Wang, Ning et al. (2016) Mouse models for studying prostate cancer bone metastasis. Bonekey Rep 5:777
Sottnik, Joseph L; Dai, Jinlu; Zhang, Honglai et al. (2015) Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases. Cancer Res 75:2151-8