Monocyte chemotactic protein-1 mediates prostate cancer-induced bone resorption
Monocyte chemotactic protein-1 mediates prostate cancer-induced bone resorption
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DOI：
10.1158/0008-5472.can-06-1210
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发表时间：
2007-04-15
期刊：
影响因子：
11.2
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
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作者：
Lu, Yi;Cai, Zhong;Zhang, Jian
前列腺癌优先转移到骨，导致高死亡率。抑制前列腺癌转移的策略包括靶向肿瘤诱导的成骨细胞病变和潜在的破骨细胞活动。我们和其他人之前已经表明，核因子κ B配体阻断受体激活剂（RANKL）部分阻断骨肿瘤的建立和发展。然而，在这些研究中使用的细胞系中，RANKL的水平非常低，这表明除了RANKL之外的可溶性因子可能介导癌症诱导的破骨细胞活性。为了确定这些因素，我们使用人细胞因子抗体阵列来检测从原代前列腺上皮细胞（PrEC）、前列腺癌LNCaP及其衍生物C4-2B和PO细胞中收集的条件培养基中细胞因子的表达。与PrEC细胞相比，所有前列腺癌细胞都产生大量的单核细胞趋化蛋白-1 （MCP-1）。此外，PC3中白细胞介素(IL)-6、IL-8、GRO α、ENA-78和CXCL-16的水平高于LNCaP。结果经酶联免疫吸附试验证实。最后用PC3条件培养基培养人骨髓单个核细胞（HBMC）。虽然重组人MCP-1和IL-8都直接刺激了HRMC向破骨细胞样细胞的分化，但在没有RANKL的情况下，IL-8而不是MCP-1在培养21天后诱导了牙本质片的骨吸收。然而，条件培养基诱导的骨吸收被MCP-1中和抗体抑制，并进一步与IL-8抗体协同抑制，表明MCP-1除IL-8外，还介导肿瘤诱导的破骨细胞发生和骨吸收。MCP-1可能促进破骨细胞前细胞融合，形成多核抗酒石酸酸性磷酸酶阳性的破骨细胞样细胞。本研究可能为前列腺癌骨转移的治疗提供新的治疗靶点。
Prostate cancer preferentially metastasizes to bone, resulting in high mortality. Strategies to inhibit prostate cancer metastasis include targeting both tumor-induced osteoblastic lesions and underlying osteoclastic activities. We and others have previously shown that blocking receptor activator of nuclear factor-kappa B ligand (RANKL) partially blocks tumor establishment and progression in bone in murine models. However, levels of RANKL in the cell lines used in these studies were very low, suggesting that soluble factors other than RANKL may mediate the cancer-induced osteoclast activity. To identify these factors, a human cytokine antibody array was used to measure cytokine expression in conditioned medium collected from primary prostate epithelial cells (PrEC), prostate cancer LNCaP and its derivative C4-2B, and PO cells. All prostate cancer cells produced high amounts of monocyte chemotactic protein-1 (MCP-1) compared with PrEC cells. Furthermore, levels of interleukin (IL)-6, IL-8, GRO alpha, ENA-78, and CXCL-16 were higher in PC3 than LNCaP. These results were confirmed by ELISA. Finally, human bone marrow mononuclear cells (HBMC) were cultured with PC3 conditioned medium. Although both recombinant human MCP-1 and IL-8 directly stimulated HRMC differentiation into osteoclast-like cells, IL-8, but not MCP-1, induced bone resorption on dentin slices with 21 days of culture in the absence of RANKL. However, the conditioned medium-induced bone resorption was inhibited by MCP-1 neutralizing antibody and was further synergistically inhibited with IL-8 antibody, indicating that MCP-1, in addition to IL-8, mediates tumor-induced osteoclastogenesis and bone resorption. MCP-1 may promote preosteoclast cell fusion, forming multinucleated tartrate-resistant acid phosphatase-positive osteoclast-like cells. This study may provide novel therapeutic targets for treatment of prostate cancer skeletal metastasis.