We have identified monocyte chemoattractact protein - 1 (MCP-1, CCL2) as a novel potent regulator ofDrostate 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 aswell as a modulatory effect on the tumor microenvironment by promoting macrophage mobilization andinfiltration into the tumor bed. We have demonstrated that PCa cells in vitro and in human cancer tissuesexhibit an upregulation of the CCL2 receptor, CCR2. In addition, a major role of CCL2 on tumor growth andmetastasis has been linked to its. regulatory role in mediating monocyte / macrophage infiltration into thetumor microenvironment and stimulating a phenotypic change within these immune cells to promote tumorgrowth (tumor associated macrophages, TAMs). CCL2 has previously been shown to be an importantdeterminant of monocyte / macrophage infiltration in breast, cervix and pancreatic carcinomas and the levelsof CCL2 expression have been correlated with the involvement of lymphocyte and macrophage localizationn secondary sites of tumor formation. We were the first to establish a direct stimulatory role of CCL2 on PCacells in vitro. Utilizing anti-human (CNTO888) and anti-mouse (C1142) specific neutralizing antibodies toCCL2, we have demonstrated an inhibition of prostate tumor growth and migration in vivo through directeffects on the PCa cells as well as blocking the infiltration of TAMs into the tumors. The availability of thehuman 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 thefollowing specific aims: 1) We will dissect the role of increased CCL2 expression on monocyte mobilization inresponse to prostate cancer, 2) we will dissect the role of CCL2 on macrophage infiltration and subsequenttumor growth and metastasis of prostate cancer, and 3) we will test the human antibody CNTO888 to CCL2in patients with prostate cancer. Completion of these experiments will define the role of infiltratingmacrophages in prostate cancer biology and characterize the validity of targeting CCL2 for the treatment oladvanced prostate cancer.
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