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.

Public Health Relevance

Once prostate cancer metastasizes it is incurable and advanced PCa continues to kill over 28,000 men per year in the United States. An example of newer targeted therapies refers to those that interfere with the cancer cells'inappropriate use of a specific growth factor. We believe that CCL2, which stimulates PCa cells, recruits tumor promoting macrophages and modulates OC development, is essential for successful prostate cancer metastasis within bone and could be a target for cancer therapy.

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Hill, Elliott E; Kim, Jin Koo; Jung, Younghun et al. (2018) Integrin alpha V beta 3 targeted dendrimer-rapamycin conjugate reduces fibroblast-mediated prostate tumor progression and metastasis. J Cell Biochem 119:8074-8083
Axelrod, Haley D; Valkenburg, Kenneth C; Amend, Sarah R et al. (2018) AXL Is a Putative Tumor Suppressor and Dormancy Regulator in Prostate Cancer. Mol Cancer Res :
de Groot, Amber E; Pienta, Kenneth J (2018) Epigenetic control of macrophage polarization: implications for targeting tumor-associated macrophages. Oncotarget 9:20908-20927
Roca, Hernan; Jones, Jacqueline D; Purica, Marta C et al. (2018) Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone. J Clin Invest 128:248-266
Wu, Amy; Liao, David; Kirilin, Vlamimir et al. (2018) Cancer dormancy and criticality from a game theory perspective. Cancer Converg 2:1
Park, Sun H; Keller, Evan T; Shiozawa, Yusuke (2018) Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis. Calcif Tissue Int 102:152-162
Singhal, Udit; Wang, Yugang; Henderson, James et al. (2018) Multigene Profiling of CTCs in mCRPC Identifies a Clinically Relevant Prognostic Signature. Mol Cancer Res 16:643-654
Lee, Eunsohl; Wang, Jingcheng; Jung, Younghun et al. (2018) Reduction of two histone marks, H3k9me3 and H3k27me3 by epidrug induces neuroendocrine differentiation in prostate cancer. J Cell Biochem 119:3697-3705
van der Toom, Emma E; Axelrod, Haley D; de la Rosette, Jean J et al. (2018) Prostate-specific markers to identify rare prostate cancer cells in liquid biopsies. Nat Rev Urol :
Roca, Hernan; McCauley, Laurie K (2018) Efferocytosis and prostate cancer skeletal metastasis: implications for intervention. Oncoscience 5:174-176

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