We have identified monocyte chemoattractact protein - 1 (MCP-1, CCL2) as a novel potent regulator of Drostate cancer proliferation and migration. The ability of CCL2 to influence prostate cancer (PCa) tumorigenesis and metastasis may occur via direct promotional effect on tumor cell growth and function as well as a modulatory effect on the tumor microenvironment by promoting macrophage mobilization and infiltration into the tumor bed. We have demonstrated that PCa cells in vitro and in human cancer tissues exhibit an upregulation of the CCL2 receptor, CCR2. In addition, 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). CCL2 has previously been shown to be an important determinant of monocyte / macrophage infiltration in breast, cervix and pancreatic carcinomas and the levels of CCL2 expression have been correlated with the involvement of lymphocyte and macrophage localization n secondary sites of tumor formation. We were the first to establish a direct stimulatory role of CCL2 on PCa cells in vitro. Utilizing anti-human (CNTO888) and anti-mouse (C1142) specific neutralizing antibodies to CCL2, we have demonstrated an inhibition of prostate tumor growth and migration in vivo through direct effects on the PCa cells as well as blocking the infiltration of TAMs into the tumors. The availability of the human antibody CNTO888 to CCL2 will allow us to test our observations and hypothesis in humans: Overall Proposal Hypothesis: Systemic inhibition of monocvte chemoattractant protein -1 (MCP-1; CCL2) will be an effective treatment for prostate cancer. To test this hypothesis we will perform the following specific aims: 1) We will dissect the role of increased CCL2 expression on monocyte mobilization in response to prostate cancer, 2) we will dissect the role of CCL2 on macrophage infiltration and subsequent tumor growth and metastasis of prostate cancer, and 3) we will test the human antibody CNTO888 to CCL2 in patients with prostate cancer. Completion of these experiments will define the role of infiltrating macrophages in prostate cancer biology and characterize the validity of targeting CCL2 for the treatment ol advanced prostate cancer.
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