We have identified monocyte chemoattractant protein - 1 (MCP-1, CCL2) as a novel potent regulator of prostate cancer proliferation and migration. CCL2 is a member of the CC chemokine family and was originally described for its sentinel role in regulating monocyte / macrophage migration to sites of inflammation and wound repair. We have reported that human bone marrow endothelial (HBME) cells secrete significantly high levels of CCL2 compared to human aortic endothelial cells and human dermal microvascular endothelial cells. Similarly, previous reports have demonstrated that both osteoblasts (OB) and prostate cancer epithelial cells secrete CCL2. CCL2 has been shown to be important in the bone microenvironment via its roles in stimulating prostate cancer cell proliferation, chemoattraction of tumor associated macrophages, and in osteoclast formation and activity. The ability of CCL2 to influence prostate cancer (PCa) tumorigenesis and metastasis appears to occur via at least two distinct mechanisms;1) a direct promotional effect on tumor cell growth and function, and 2) a modulatory effects on the tumor microenvironment that include promoting macrophage mobilization and infiltration into the tumor bed as well as OC maturation. We have demonstrated that PCa cells in vitro and in human cancer tissues exhibit an upregulation of the CCL2 receptor, CCR2. Simultaneously, a major role of CCL2 on tumor growth and metastasis has been linked to its regulatory role in mediating monocyte / macrophage infiltration into the tumor microenvironment and stimulating a phenotypic change within these immune cells to promote tumor growth (tumor associated macrophages, TAMs). The role of infiltrating macrophages in PCa tumorigenesis and bone metastasis has not been well investigated. Several reports have demonstrated that CCL2 promotes the fusion events of macrophage-like cells resulting in multinucleation and osteoclast formation. In the absence of RANKL, CCL2 and macrophage colony-stimulating factor (M-CSF) induced multinucleated cells that were TRAP+ and CTR+ (markers of differentiated osteoclasts) but these cells were incapable of bone resorption. Osteoclast formation and activation are two independent steps leading to the development of a bone metastasis and are mutually essential for prostate cancer establishment in the bone microenvironment. Overall Proposal Hypothesis: PCa facilitates osteoclast development via a CCL2-dependent mechanism, promoting pea bone metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA093900-10
Application #
8464644
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
2013-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$213,604
Indirect Cost
$71,032
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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