Exosomal survivin facilitates vesicle internalization

Abstract

Survivin, a member of the inhibitor of apoptosis (IAP) protein family plays a significant role in cell fate and function. It is significantly overexpressed in tumor cells and has been identified in most cancer cell types. A novel extracellular population has recently been identified and its function is still unknown. Emerging evidence continues to shed light on the important role the tumor microenvironment (TME) has on tumor survival and progression. This new population of survivin has been seen to enhance the tumor phenotype when internalized by recipient cells. In this paper, we sought to better understand the mechanism by which survivin is taken up by cancer cells and the possible role it plays in this phenomenon. We isolated the exosomal carriers of extracellular survivin and using a lipophilic stain, PKH67, we tracked their uptake with immunofluorescence and flow cytometry. We found that by blocking exosomal survivin, exosome internalization is reduced, signifying a novel function for this protein. We also discovered that the common membrane receptors, transferrin receptor, endothelin B receptor, insulin receptor alpha, and membrane glucocorticoid receptor all facilitate exosomal internalization. This understanding further clarifies the protein-protein interactions in the TME that may influence tumor progression and identifies additional potential chemotherapeutic targets.

Differential effects of extracellular vesicles from aging and young mesenchymal stem cells in acute lung injury

“…Gonda et al reported that survivin in cancer EVs facilitated vesicle internalization. EV internalization was reduced when survivin was inhibited [43]. Eitan et al found that plasma EVs from aging individuals were more easily internalized by B cells [44].…”

The Presence of Survivin on B Cells from Myasthenia Gravis Patients and the Potential of an Antibody to a Modified Survivin Peptide to Alleviate Weakness in an Animal Model

“…In the tumor microenvironment, survivin expression in exosomes appears to support cell proliferation and treatment resistance (17,19,20). Abs to survivin can reduce the ability of exosomes to internalize on the target cell (20). In our model, the localization of survivin to the external cell surface would allow for recognition by an Ab and could inhibit the role of survivin in supporting persistence of autoreactive cells.…”

“…In this study, we demonstrated expression of survivin on the outer surface of CD20 + cells, suggesting that survivin may have a role in cell-cell signaling. In the tumor microenvironment, survivin expression in exosomes appears to support cell proliferation and treatment resistance (17,19,20). Abs to survivin can reduce the ability of exosomes to internalize on the target cell (20).…”

Cellular-Defined Microenvironmental Internalization of Exosomes

“…Two proteins commonly active in caveolae-dependent endocytosis, which have also been identified on the surface of exosomes, are the insulin receptor and albumin [34,38,39]. The cellular insulin receptor itself has also recently been found to influence exosome uptake [18].…”

“…The methods by which exosomes influence the cells with which they interact are still under review. Some exosomes have been shown to fuse to the recipient cell [15,16], while others are internalized by specific receptor-ligand interactions [17,18] or by stimulating an indirect uptake by macropinocytosis [19]. Exosome binding to cells has been seen both as a mechanism of transferring luminal contents [15,16] and as an initial step in the endocytosis process [17,20].…”