Annexin A1 Released in Extracellular Vesicles by Pancreatic Cancer Cells Activates Components of the Tumor Microenvironment, through Interaction with the Formyl-Peptide Receptors
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Volume
9
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Publisher URL
DOI
10.3390/cells9122719
Journal
CELLS
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Pancreatic cancer (PC) is one of the most aggressive cancers in the world. Several extracellular
factors are involved in its development and metastasis to distant organs. In PC, the protein Annexin
A1 (ANXA1) appears to be overexpressed and may be identified as an oncogenic factor, also because it
is a component in tumor-deriving extracellular vesicles (EVs). Indeed, these microvesicles are known
to nourish the tumor microenvironment. Once we evaluated the autocrine role of ANXA1-containing
EVs on PC MIA PaCa-2 cells and their pro-angiogenic action, we investigated the ANXA1 paracrine
effect on stromal cells like fibroblasts and endothelial ones. Concerning the analysis of fibroblasts,
cell migration/invasion, cytoskeleton remodeling, and the different expression of specific protein markers,
all features of the cell switching into myofibroblasts, were assessed after administration of wild type more
than ANXA1 Knock-Out EVs. Interestingly, we demonstrated a mechanism by which the ANXA1-EVs
complex can stimulate the activation of formyl peptide receptors (FPRs), triggering mesenchymal
switches and cell motility on both fibroblasts and endothelial cells. Therefore, we highlighted the
importance of ANXA1/EVs-FPR axes in PC progression as a vehicle of intercommunication tumor
cells-stroma, suggesting a specific potential prognostic/diagnostic role of ANXA1, whether in soluble
form or even if EVs are captured in PC.