The common occurrence and serious outcome of prostate cancer (PCa) skeletal metastases has risen to the forefront of public concern and subsequently the NCI. In the first three years of this program award, we have addressed this important issue, resulting in over 50-grant-related publications. In the current competitive renewal, we continue to attack this problem by combining leading expertise in PCa research and bone metabolism. The ultimate goal is to define the cellular and molecular mechanisms that surround PCa skeletal metastases so as to set the groundwork for translation into clinical applications. The central theme of this Program is that there is crosstalk between PCa cells and the bone microenvironment that foster the development and progression of PCa metastasis. This crosstalk promotes the ability of PCa cells to migrate, attach, and manipulate the cells in bone thus enhancing the tumor's capacity to alter the bone microenvironment to render it conducive to tumor growth. To expand on this theme the Program encompasses closely interrelated hypotheses of four scientific projects supported by three cores. Project 1 explores the novel concept that the similar to an endocrine organ, the primary PCa modulates the distant bone marrow, in part through production of CCLZ, to make it conducive for receiving metastatic PCa cells;Project 2 examines the exciting idea that PCa cells co-opt the hematopoietic stem cell (HSC) niche in the bone marrow;Project 3 explores the unexpected role of the Wnt inhibitor Dickopff as a molecular switch that promotes the osteoblastic phenotype of PCa;and, Project 4 investigates the novel hypothesis that PCa, through PTHrP, modulates osteoblasts and HSCs leading to angiogenesis in the bone microenvironment that promotes PCa progression. These projects will be supported by three integral cores: Core A (Administration) that will coordinate reporting, evaluation, and committee activities, facilitate interactions among the projects and provide biostatistical support;Core B (Animal) provides mouse models and imaging and assistance with their use and Core C (Bone) provides expertise with bone histology processing and interpretation. This combination of investigators, projects and cores result in a highly synergistic Program that will continue to provide cutting-edge research on PCa bone metastases.

Public Health Relevance

Prostate cancer (PCa) is the most common cancer of American men and the second leading cause of cancer-related death. When men die from PCa, it is almost always accompanied by the painful and debilitating spread of cancer to the skeleton. Our Program is directed to understand how the cancer spreads to and thrives in the skeleton so that we can develop method to prevent or treat the spread of PCa to the bone.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA093900-09
Application #
8284227
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (J1))
Program Officer
Mohla, Suresh
Project Start
2001-12-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$1,506,835
Indirect Cost
$531,537
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
Jung, Younghun; Wang, Jingcheng; Lee, Eunsohl et al. (2015) Annexin 2-CXCL12 interactions regulate metastatic cell targeting and growth in the bone marrow. Mol Cancer Res 13:197-207
Yumoto, Kenji; Berry, Janice E; Taichman, Russell S et al. (2014) A novel method for monitoring tumor proliferation in vivo using fluorescent dye DiD. Cytometry A 85:548-55
Yumoto, Kenji; Eber, Matthew R; Berry, Janice E et al. (2014) Molecular pathways: niches in metastatic dormancy. Clin Cancer Res 20:3384-9
Dai, Jinlu; Zhang, Honglai; Karatsinides, Andreas et al. (2014) Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions. Clin Cancer Res 20:617-30
Yang, Kimberline R; Mooney, Steven M; Zarif, Jelani C et al. (2014) Niche inheritance: a cooperative pathway to enhance cancer cell fitness through ecosystem engineering. J Cell Biochem 115:1478-85
Wan, Liling; Hu, Guohong; Wei, Yong et al. (2014) Genetic ablation of metadherin inhibits autochthonous prostate cancer progression and metastasis. Cancer Res 74:5336-47
Zhang, H; Yu, C; Dai, J et al. (2014) Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of *-catenin activation of the DKK1 promoter in prostate cancer. Oncogene 33:2464-77
Soki, Fabiana N; Koh, Amy J; Jones, Jacqueline D et al. (2014) Polarization of prostate cancer-associated macrophages is induced by milk fat globule-EGF factor 8 (MFG-E8)-mediated efferocytosis. J Biol Chem 289:24560-72
Deng, Xiyun; He, Guangchun; Liu, Junwen et al. (2014) Recent advances in bone-targeted therapies of metastatic prostate cancer. Cancer Treat Rev 40:730-8
Roca, Hernan; Pande, Manjusha; Huo, Jeffrey S et al. (2014) A bioinformatics approach reveals novel interactions of the OVOL transcription factors in the regulation of epithelial - mesenchymal cell reprogramming and cancer progression. BMC Syst Biol 8:29

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