Exosomes Released by Gastric Cancer Cells Induce Transition of Pericytes Into Cancer-Associated Fibroblasts

BACKGROUND: Cancer-associated fibroblasts (CAFs) are functionally and structurally essential for tumor progression. There are 3 main origins of CAFs: mesenchymal stem cells (MSCs), epithelial-to-mesenchymal (EMT) transition cells, and tissue-resident cells. Pericytes retain characteristics of progenitor cells and can differentiate into other cells under normal physiological conditions and into myofibroblasts under pathological conditions. Exosomes play an important role in intercellular communication by transferring membrane components and nucleic acids between different cells. In this study, we evaluated whether cancer cell-derived exosomes are involved in regulating the transition of pericytes to CAFs.
MATERIAL AND METHODS: Exosomes from GES-1 and SGC7901 cells were isolated by serial centrifugation and purified from the supernatant by the 30% sucrose/D2O cushion method. A transmission electron microscope was used to observe exosome morphologies, and nanoparticle tracking analysis was used to analyze size distribution of exosomes. Western blot analysis, immunofluorescent staining, and qPCR were employed to detect CAFs marker expression and signaling pathways involved in CAFs transition.
RESULTS: Gastric cancer cell-derived exosomes enhanced pericytes proliferation and migration and induced the expression of CAFs marker in pericytes. We then demonstrated that the PI3K/AKT and MEK/ERK pathways were activated by tumor-derived exosomes, and BMP pathway inhibition reverses cancer exosomes-induced CAFs transition.
CONCLUSIONS: Our results suggest that gastric cancer cells induce the transition of pericytes to CAFs by exosomes-mediated BMP transfer and PI3K/AKT and MEK/ERK pathway activation, and suggest that pericytes may be an important source of CAFs.

Keywords: exosomes, Pericytes, tumor microenvironment