Tumour cell-derived debris and IgG synergistically promote metastasis of pancreatic cancer by inducing inflammation via tumour-associated macrophages
Tumour cell-derived debris and IgG synergistically promote metastasis of pancreatic cancer by inducing inflammation via tumour-associated macrophages
复制标题
肿瘤细胞来源的碎片和 IgG 通过肿瘤相关巨噬细胞诱导炎症协同促进胰腺癌的转移
DOI：
10.1038/s41416-019-0595-2
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发表时间：
2019-10-29
影响因子：
8.8
通讯作者：
Bai, Xueli
中科院分区：
文献类型：
--
作者：
Chen, Qi;Wang, Jianxin;Bai, Xueli
背景：胰腺导管腺癌（PDAC）的进展和转移高度依赖于肿瘤微环境。大多数肿瘤相关巨噬细胞（TAMs）是M2型巨噬细胞，其在许多疾病中通常表现出抗炎功能。此前，我们发现选择性活化的巨噬细胞在受到肝癌细胞来源的碎片刺激时表现出促炎特性；然而，其分子机制尚不清楚。
方法：采用体外和体内实验来研究分子机制。利用胰腺癌细胞系、小鼠模型和人体组织，我们全面了解了肿瘤细胞来源的碎片通过肿瘤相关巨噬细胞诱导炎症从而促进胰腺癌转移的情况。
结果：我们表明M2巨噬细胞衍生的炎症在PDAC中也存在。PDAC细胞的碎片通过TLR4/TRIF/NF - κB信号通路诱导M2巨噬细胞大量释放白细胞介素 - 1β，并且来自PDAC细胞的IgG进一步增强了这种效应。白细胞介素 - 1β增加促进了PDAC细胞的上皮 - 间质转化以及随之而来的转移。一种选择性环氧化酶 - 2（COX - 2）抑制剂塞来昔布增强了吉西他滨的抗肿瘤功效。
结论：这些数据揭示了PDAC中的一种促炎机制，这表明白细胞介素 - 1β和COX - 2可能是治疗PDAC的抗炎策略的治疗靶点。
BackgroundThe progression and metastasis of pancreatic ductal adenocarcinoma (PDAC) is highly dependent on the tumour microenvironment. Most tumour-associated macrophages (TAMs) are M2 phenotype macrophages, which normally show anti-inflammatory functions in numerous disorders. Previously, we found that alternatively activated macrophages showed pro-inflammatory characteristics upon stimulation with hepatoma cell-derived debris; however, the molecular mechanism was unclear.MethodsIn vitro and in vivo experiments were employed to investigate the molecular mechanism. Using pancreatic cancer cell lines, mouse models and human tissues, we obtained a general picture of tumour cell-derived debris promoting metastasis of pancreatic cancer by inducing inflammation via TAMs.ResultsWe showed that M2 macrophage-derived inflammation also exists in PDAC. Debris from PDAC cells induced potent IL-1β release by M2 macrophages via TLR4/TRIF/NF-κB signalling, and this effect was further boosted by IgG that was also derived from PDAC cells. Increased IL-1β promoted epithelial–mesenchymal transition and consequent metastasis of PDAC cells. A selective COX-2 inhibitor, celecoxib, enhanced the anti-tumoural efficacy of gemcitabine.ConclusionsThese data revealed a pro-inflammatory mechanism in PDAC, which indicated that IL-1β and COX-2 could be therapeutic targets of an anti-inflammatory strategy to treat PDAC.