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Tumour cell-derived debris and IgG synergistically promote metastasis of pancreatic cancer by inducing inflammation via tumour-associated macrophages.

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.

SUBMITTER: Chen Q

PROVIDER: S-EPMC6889176 | biostudies-literature |

REPOSITORIES: biostudies-literature

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