Helicobacter pylori-induced exosomal MET educates tumour-associated macrophages to promote gastric cancer progression

Helicobacter pylori (H.pylori) infection triggers chronic inflammation that has been associated with gastric cancer (GC). Exosomes are small extracellular vesicles that have become the key mediators of intercellular communication. In this study, we investigated exosome-mediated communication between H.pylori-infected GC cells and macrophages, focusing on the transfer of activated mesenchymal-epithelial transition factor (MET). We observed a significant decrease in MET protein expression in GC cells after infection with H.pylori, whereas MET mRNA levels remained unchanged. Intriguingly, MET expression, specifically the phosphorylated active form, was increased in exosomes released from H.pylori-infected GC cells. Confocal microscopy and Western blotting analyses showed that these exosomes containing MET were delivered to and internalized by macrophages. Indeed, in human GC tissues positive for H.pylori, we also observed that activated MET was highly expressed in tumour-infiltrating macrophages. After internalization, exosomal MET then appeared to educate the macrophages towards a pro-tumorigenesis phenotype. This included exosomal MET-mediated stimulation of proinflammatory cytokine secretion IL-1, which subsequently promoted tumour growth and progression invitro and invivo. Taken together, these data were the first to demonstrate H.pylori infection-induced upregulation of activated MET in exosomes and the pro-tumorigenic effect on tumour-associated macrophages.