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首页> 外文期刊>PLoS One >An Antimicrobial Peptide Regulates Tumor-Associated Macrophage Trafficking via the Chemokine Receptor CCR2, a Model for Tumorigenesis
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An Antimicrobial Peptide Regulates Tumor-Associated Macrophage Trafficking via the Chemokine Receptor CCR2, a Model for Tumorigenesis

机译：抗菌肽通过趋化因子受体CCR2（肿瘤发生模型）调节肿瘤相关巨噬细胞的运输。

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Background Tumor-associated macrophages (TAMs) constitute a significant part of infiltrating inflammatory cells that are frequently correlated with progression and poor prognosis of a variety of cancers. Tumor cell-produced human β-defensin-3 (hBD-3) has been associated with TAM trafficking in oral cancer; however, its involvement in tumor-related inflammatory processes remains largely unknown. Methodology The relationship between hBD-3, monocyte chemoattractant protein-1 (MCP-1), TAMs, and CCR2 was examined using immunofluorescence microscopy in normal and oral carcinoma in situ biopsy specimens. The ability of hBD-3 to chemoattract host macrophages in vivo using a nude mouse model and analysis of hBD-3 on monocytic cell migration in vitro, applying a cross-desensitization strategy of CCR2 and its pharmacological inhibitor (RS102895), respectively, was also carried out. Conclusions/Findings MCP-1, the most frequently expressed tumor cell-associated chemokine, was not produced by tumor cells nor correlated with the recruitment of macrophages in oral carcinoma in situ lesions. However, hBD-3 was associated with macrophage recruitment in these lesions and hBD-3-expressing tumorigenic cells induced massive tumor infiltration of host macrophages in nude mice. HBD-3 stimulated the expression of tumor-promoting cytokines, including interleukin-1α (IL-1α), IL-6, IL-8, CCL18, and tumor necrosis factor-α (TNF-α) in macrophages derived from human peripheral blood monocytes. Monocytic cell migration in response to hBD-3 was inhibited by cross-desensitization with MCP-1 and the specific CCR2 inhibitor, RS102895, suggesting that CCR2 mediates monocyte/macrophage migration in response to hBD-3. Collectively, these results indicate that hBD-3 utilizes CCR2 to regulate monocyte/macrophage trafficking and may act as a tumor cell-produced chemoattractant to recruit TAMs. This novel mechanism is the first evidence of an hBD molecule orchestrating an in vivo outcome and demonstrates the importance of the innate immune system in the development of tumors.
机译：背景与肿瘤相关的巨噬细胞（TAM）构成浸润性炎症细胞的重要组成部分，其通常与多种癌症的进展和不良预后相关。肿瘤细胞产生的人β-防御素3（hBD-3）与口腔癌中TAM的运输有关。然而，它在肿瘤相关的炎症过程中的参与仍然未知。方法学使用免疫荧光显微镜检查了正常和口腔癌原位活检标本中的hBD-3，单核细胞趋化蛋白-1（MCP-1），TAM和CCR2之间的关系。还使用裸鼠模型和分别对CCR2及其药理抑制剂（RS102895）进行交叉脱敏策略的hBD-3裸鼠模型体内hBD-3体内趋化宿主巨噬细胞的能力。执行。结论/发现MCP-1，最常表达的肿瘤细胞相关趋化因子，不是由肿瘤细胞产生的，也不与口腔癌原位病变中巨噬细胞的募集有关。然而，hBD-3与这些病变中的巨噬细胞募集相关，并且表达hBD-3的致瘤细胞在裸鼠中诱导宿主巨噬细胞的大量肿瘤浸润。 HBD-3刺激人外周血巨噬细胞中促肿瘤细胞因子的表达，包括白介素-1α（IL-1α），IL-6，IL-8，CCL18和肿瘤坏死因子-α（TNF-α）。单核细胞。通过与MCP-1和特定CCR2抑制剂RS102895交叉脱敏作用，抑制了响应hBD-3的单核细胞迁移，这表明CCR2介导了响应hBD-3的单核细胞/巨噬细胞迁移。总体而言，这些结果表明，hBD-3利用CCR2来调节单核细胞/巨噬细胞的运输，并可能充当肿瘤细胞产生的趋化因子来招募TAM。这种新颖的机制是hBD分子协调体内结果的第一个证据，并证明了先天免疫系统在肿瘤发展中的重要性。

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