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

我们发现单核细胞趋化蛋白-1(MCP-1，CCL2)是一种新的有效的细胞外信号调节因子。 前列腺癌的增殖和迁移。CCL2对前列腺癌(PCa)的影响 肿瘤的发生和转移可能是通过直接促进肿瘤细胞的生长和功能而发生的 以及通过促进巨噬细胞动员和促进肿瘤微环境的调节作用 渗入肿瘤床。我们已经在体外和人类癌症组织中证明了PCA细胞 表现出CCL2受体CCR2的上调。此外，CCL2在肿瘤生长和生长中的重要作用 转移与其相关。调控单核/巨噬细胞侵袭血管内皮细胞的作用 肿瘤微环境和刺激这些免疫细胞内的表型变化促进肿瘤 生长(肿瘤相关巨噬细胞，TAMs)。CCL2以前已经被证明是一个重要的 乳腺癌、宫颈癌和胰腺癌中单核/巨噬细胞浸润的决定因素及其水平 CCL2的表达与淋巴细胞和巨噬细胞的定位有关 N个肿瘤形成的次要部位。我们首先建立了CCL2对PCa的直接刺激作用 体外培养的细胞。利用抗人(CNTO888)和抗鼠(C1142)特异性中和抗体 CCL2，我们已经证明了通过直接的 对前列腺癌细胞的影响以及阻断TAMs对肿瘤的渗透。可供使用的 抗CCL2的人类抗体CNTO888将使我们能够在人体上测试我们的观察结果和假设： 总体建议假说：全身抑制单核细胞趋化蛋白-1(MCP-1； CCL2)将成为前列腺癌的有效治疗方法。为了检验这一假设，我们将执行 具体目标如下：1)我们将剖析CCL2表达增加在单核细胞动员中的作用 前列腺癌的反应，2)我们将剖析CCL2在巨噬细胞浸润和随后的 前列腺癌的生长和转移；3)检测抗CCL2的人源抗体CNTO888 在前列腺癌患者中。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及靶向CCL2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.