Internalization of Exosomes through Receptor-Mediated Endocytosis

Abstract

The tumor microenvironment is replete with factors secreted and internalized by surrounding cells. Exosomes are nanosized, protein-embedded, membrane-bound vesicles that are released in greater quantities from cancer than normal cells and taken up by a variety of cell types. These vesicles contain proteins and genetic material from the cell of origin and in the case of tumor-derived exosomes, oncoproteins and oncogenes. With increasing understanding of the role exosomes play in basic biology, a more clear view of the potential exosomes are seen to have in cancer therapeutics emerges. However, certain essential aspects of exosome function, such as the uptake mechanisms, are still unknown. Various methods of cell-exosome interaction have been proposed, but this review focuses on the protein-protein interactions that facilitate receptor-mediated endocytosis, a broadly used mechanism by a variety of cells.

Exosomes from mesenchymal stromal cells reduce murine colonic inflammation via a macrophage-dependent mechanism

“…In line with these studies, our results demonstrated the antiinflammatory effects of metallothionein-2 on both macrophages and mouse colitis models. It is noteworthy that the presence of this protein in exosomes may offer a therapeutic advantage over its free form because free proteins are unlikely to interact with cells or have uptake into cells (57,58). Furthermore, the role of metallothionein-2 might not be unique for colitis.…”

Cellular-Defined Microenvironmental Internalization of Exosomes

“…This varies from other forms of endocytosis in its formation of separate and distinct intracellular vesicles (macropinosomes) and the internalization of material that is considered non-specific exosomal has been recorded in microglia [56], human epidermoid carcinomaderived A431 cells stimulated by endothelial growth factor receptor (EGFR) and by the pancreatic cancer MiaPaCa-2 cell line [19]. Macropinocytosis is not selective in which molecules are internalized from the extracellular environment, and so uptake may be dictated simply by proximity to the cells and not targeted by the exosome specifically [121]. However, it has been shown that some exosomes naturally induce macropinocytosis internalization [90] and others, through manipulation of exosomal content, can selectively activate this mechanism in order to increase uptake [122].…”

“…Phagocytosis is a much more common method of taking up exosomes, especially with phagocytic cells of the immune system. Feng et al, showed that two leukemia cell lines, K562 and MT4, solely utilized phagocytosis for exosome internalization [20,121].…”

“…Clathrin and caveolin are both cytosolic proteins that form specific pits with which to internalize various substances [25]. The exact reasons why and when a cell uses clathrin, caveolin, or neither, is still incompletely understood but particle size and cell type seem to play a role [43,115,121]. Caveolin-dependent endocytosis is important in albumin uptake, cholesterol transport, and intracellular signaling.…”

Engineering Extracellular Vesicles as Nanotherapeutics for Regenerative Medicine

“…Different types of molecules are involved in these targeting interactions, such as integrins, lipids, lectins, proteoglycans and extracellular matrix components [7,23,24]. Once the exosome is bound to the cell surface, it can affect cell function by either (1) remaining on the cell surface and triggering intracellular signaling pathways or (2) be internalized by the cell through endocytosis, of which both clathrin-and caveolae-dependent and -independent mechanisms have been implicated [24,37,38]. In both cases, exosome contents can be released via fusion and carry out their specific effector functions.…”