Macrophages induce invasiveness of epithelial cancer cells via NF-κB and JNK
Macrophages induce invasiveness of epithelial cancer cells via NF-κB and JNK
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DOI：
10.4049/jimmunol.175.2.1197
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发表时间：
2005-07-15
影响因子：
4.4
通讯作者：
Balkwill, FR
中科院分区：
文献类型：
--
作者：
Hagemann, T;Wilson, J;Balkwill, FR
肿瘤相关巨噬细胞可能影响肿瘤的进展、血管生成和侵袭。为了研究巨噬细胞与肿瘤细胞相互作用的机制，我们开发了一种体外共培养模型。以前我们报道过共培养以TNF-α和基质金属蛋白酶依赖的方式增强肿瘤细胞的侵袭力。在这篇报告中，我们研究了巨噬细胞共培养影响下恶性细胞的细胞内信号通路和炎症基因的诱导。我们报道了巨噬细胞与卵巢癌或乳腺癌细胞系的共培养导致肿瘤细胞中JNK和NF-κ B通路的TNF-α依赖性激活，但在良性永生化上皮细胞中没有。JNK和NF-κ B活性增加的肿瘤细胞表现出增强的侵袭性。通过TNF-α中和抗体、NF-κ B抑制剂、针对Re 1A的RNAi或I κ B的过表达抑制NF-κ B通路可抑制肿瘤细胞的侵袭性。阻断JNK也显著降低了侵袭性，但阻断p38 MAPK或p42 MAPK没有影响。筛选共培养的肿瘤细胞中22种与炎症和侵袭相关的基因的表达，这些基因还包含AP-1和NF-κ B结合位点。EMMPRIN和MIF在共培养的肿瘤细胞中以JNK和NF-κ B依赖的方式上调。通过RNAi敲低肿瘤细胞中的MIF或EMMPRIN显著降低了共培养上清液中肿瘤细胞的侵袭力和基质金属蛋白酶活性。我们的结论是TNF-α通过NF-κ B和JNK诱导巨噬细胞与肿瘤细胞共培养物中的MIF和EMMPRIN，这导致肿瘤细胞的侵袭能力增加。
Tumor-associated macrophages may influence tumor progression, angiogenesis and invasion. To investigate mechanisms by which macrophages interact with tumor cells, we developed an in vitro coculture model. Previously we reported that coculture enhanced invasiveness of the tumor cells in a TNF-alpha- and matrix metalloprotease-dependent manner. In this report, we studied intracellular signaling pathways and induction of inflammatory genes in malignant cells under the influence of macrophage coculture. We report that coculture of macrophages with ovarian or breast cancer cell lines led to TNF-alpha-dependent activation of JNK and NF-kappa B pathways in tumor cells, but not in benign immortalized epithelial cells. Tumor cells with increased JNK and NF-kappa B activity exhibited enhanced invasiveness. Inhibition of the NF-kappa B pathway by TNF-alpha neutralizing Abs, an NF-kappa B inhibitor, RNAi to Re1A, or overexpression of I kappa B inhibited tumor cell invasiveness. Blockade of JNK also significantly reduced invasiveness, but blockade of p38 MAPK or p42 MAPK had no effect. Cocultured tumor cells were screened for the expression of 22 genes associated with inflammation and invasion that also contained an AP-1 and NF-kappa B binding site. EMMPRIN and MIF were up-regulated in cocultured tumor cells in a JNK- and NF-kappa B-dependent manner. Knocking down either MIF or EMMPRIN by RNAi in the tumor cells significantly reduced tumor cell invasiveness and matrix metalloprotease activity in the coculture supernatant. We conclude that TNF-alpha, via NF-kappa B, and JNK induces MIF and EMMPRIN in macrophage to tumor cell cocultures and this leads to increased invasive capacity of the tumor cells.