Abstract
BACKGROUND: The 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. METHODS: In 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. RESULTS: We 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. CONCLUSIONS: These 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.