CEACAM6-positive extracellular vesicles released during Helicobacter pylori infection promote gastric tumor...

Extracellular vesicles (EVs) are lipid bilayer-encased nano-size carriers that orchestrate molecular exchanges in the tumor microenvironment (TME) and carry significant information about the tumor development, progression and aggressiveness. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) mediates Helicobacter pylori adhesion to gastric epithelial cells and is markedly upregulated in gastric cancer (GC). This study identified that EVs secreted by H. pylori-infected gastric cancer cells (GCCs) were loaded with CEACAM6. In order to examine the tumorigenic potential of EVs released by H. pylori-infected cells with and without CEACAM6 overexpression, EVs were thoroughly characterised and several functional assays were conducted. CEACAM6 overexpressed cell-derived EVs mimicked the elevated status of CEACAM6 as in their source cells which were found to be further enhanced in EVs collected from infected cells. As revealed by the population-doubling, clonogenicity, wound-healing and matrigel invasion assays, CEACAM6-enriched EVs promoted oncogenic properties of recipient cells while EVs from H. pylori-infected CEACAM6-expressing cells further amplified these tumorigenic abilities. A novel approach of EV-sonication and fractionation identified that CEACAM6 were mainly located in the EV membrane. Interestingly, aligned with the finding of elevated CEACAM6 protein in the H. pylori infection-led metastatic GC tissue samples, sera from those GC patients exhibited significantly high CEACAM6 compared to those from the healthy volunteers. Collectively, these findings highlight CEACAM6-containing EVs as mediators of tumorigenesis. This study also showcases the technical, translational and clinical advantages of considering CEACAM6 as a diagnostic biomarker for the detection of GC in a minimally-invasive manner.