Systemic Inhibition of Monocyte Chemoattractant Protein-1 (MCP-1; CCL2)

我们已经确定单核细胞趋化蛋白-1（MCP-1，CCL 2）是一种新的有效的调节剂， 腺样体癌的增殖和迁移。CCL 2影响前列腺癌（PCa）的能力 肿瘤发生和转移可能通过直接促进肿瘤细胞生长和功能而发生， 以及通过促进巨噬细胞动员对肿瘤微环境的调节作用， 浸润到肿瘤床。我们已经证明体外和人类癌组织中的PCa细胞 表现出CCL 2受体CCR 2的上调。此外，CCL 2对肿瘤生长和肿瘤细胞增殖的主要作用是抑制肿瘤细胞增殖。 转移与其有关。调节作用，介导单核细胞/巨噬细胞浸润到 肿瘤微环境和刺激这些免疫细胞内的表型变化以促进肿瘤微环境的改变。 生长（肿瘤相关巨噬细胞，TAM）。CCL 2以前被证明是一种重要的 乳腺癌、宫颈癌和胰腺癌中单核细胞/巨噬细胞浸润的决定因素及其水平 CCL 2表达的增加与淋巴细胞和巨噬细胞定位的参与有关 n肿瘤形成的继发部位。我们是第一个建立CCL 2对PCa的直接刺激作用的人。 体外细胞利用抗人（CNTO 888）和抗小鼠（C1142）特异性中和抗体 CCL 2，我们已经证明了抑制前列腺肿瘤的生长和迁移，在体内通过直接 对PCa细胞的作用以及阻断TAM向肿瘤中的浸润。的可用性 针对CCL 2的人抗体CNTO 888将允许我们在人类中测试我们的观察结果和假设： 总体假设：单核细胞趋化蛋白-1（MCP-1; CCL 2）将是前列腺癌的有效治疗方法。为了验证这一假设，我们将执行 以下具体目标：1）我们将分析CCL 2表达增加对单核细胞动员的作用， 2）我们将剖析CCL 2对巨噬细胞浸润的作用， 前列腺癌的肿瘤生长和转移，以及3）我们将测试针对CCL 2的人抗体CNTO 888 前列腺癌的患者。这些实验的完成将确定渗透的作用 巨噬细胞在前列腺癌生物学中的作用，并表征靶向CCL 2治疗前列腺癌的有效性。 晚期前列腺癌

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.