Abstract

Extracellular Vesicles in Cancer Progression

Lucia R. Languino, Professor of Cancer Biology, Thomas Jefferson University

Cancer cells crosstalk with the tumor microenvironment (TME) by releasing small extracellular vesicles (sEVs).  sEVs are enriched in integrins, cell surface receptors for extracellular matrix proteins.  We have shown that alphaV integrins are markers for prostate cancer cell sEVs, which were isolated by density gradients, and characterized by electron microscopy, NTA and immunoblotting analysis, as per MISEV2018 guidelines.  These sEVs were also characterized for integrin and tetraspanin colocalization by ExoView analysis. We show now that some alphaV integrins promote the formation of unique, low density sEVs and bind a soluble ligand, as quantified using ExoView.  sEV integrins, upon release, are then transferred to microvascular endothelial cells and macrophages in the TME.  In functional assays using prostate cancer cells, we provide evidence that sEV integrins, upon transfer, modulate recipient cell proliferation and migration.  We also describe, as evaluated by our proteomic and immunoblotting analyses, alterations of signaling pathways in recipient microvascular endothelial cells and macrophages upon transfer of cancer cell derived sEVs.  Finally, alphaV integrins’ expression in donor cancer cells reduces sEV levels of molecules that have a tumor suppressive role, or promotes enrichment of effectors that support cancer cell differentiation into aggressive metastatic phenotypes. Overall, our studies show that sEVs from cancer cells may contribute to a horizontal propagation of integrin-activated pathways from cancer cells to the neighboring cells to promote a pro-tumorigenic TME.