Cancer-Associated Fibroblast-Secreted Exosomes Regulate Macrophage Polarization in Pancreatic Cancer via the NOD1 Pathway.

Metastasis is a major cause of poor prognosis of pancreatic cancer. Exosomes (Exos) regulate cancer progression by modulating macrophage polarization. This study aimed to investigate the effects of cancer-associated fibroblast (CAF)-released Exos on macrophage polarization in pancreatic cancer and the molecular mechanisms. THP-1 cells or xenografted tumor mice were treated with Exos from CAFs, and macrophage polarization was analyzed using quantitative real-time PCR (qPCR) and flow cytometry. THP-1 cells were cocultured with BXPC-3 cells, and metastasis was analyzed using Transwell assay and scratch test. Exosomal PTGS2 was detected using qPCR, and the NOD1 pathway was evaluated using western blot analysis. The results showed that Exos promoted M2-type polarization and inhibited M1-type polarization, and then facilitated pancreatic cancer cell migration, invasion, and epithelial-mesenchymal transition. PTGS2 expression was increased in Exo-treated macrophages, and its knockdown in CAFs facilitated M2 to M1 macrophage polarization. Moreover, Exos promoted the NOD1 pathway via PTGS2, and inhibition of NOD1 reversed the polarization caused by Exos. Additionally, NOD1 was required in M1/M2 polarization in vivo mediated by Exos. In conclusion, CAF-secreted Exos facilitated M2 macrophage polarization by carrying PTGS2 to activate the NOD1 pathway, thereby promoting pancreatic cancer metastasis, providing evidence that CAF-Exos accelerating pancreatic cancer progression.