Extracellular vesicles including exosomes are mediators of signal transduction: are they protective or pathogenic?

Abstract

Extracellular vesicles (EVs) are signaling organelles that are released by many cell types and is highly conserved in both prokaryotes and eukaryotes. Based on the mechanism of biogenesis, these membranous vesicles can be classified as exosomes, shedding microvesicles, and apoptotic blebs. It is becoming clearer that these EVs mediate signal transduction in both autocrine and paracrine fashion by the transfer of proteins and RNA. While the role of EVs including exosomes in pathogenesis is well established, very little is known about their function in normal physiological conditions. Recent evidences allude that EVs can mediate both protective and pathogenic effects depending on the precise state. In this review, we discuss the involvement of EVs as mediators of signal transduction in neurodegenerative diseases and cancer. In addition, the role of EVs in mediating Wnt and PI3K signaling pathways is also discussed. Additional findings on the involvement of EVs in homeostasis and disease progression will promote a better biological understanding, advance future therapeutic, and diagnostic applications.

Keywords: Animal proteomics; Exosomes; Extracellular vesicles; Microvesicles; Neurodegenerative diseases; Tumor microenvironment.

Figure 1. EV mediated signalling in tumor microenvironment

Cancer cell secreted EVs are known to influence cancer progression. EVs can elicit various signalling pathways inducing proliferation, anchorage-independent growth and metastasis. EVs can trigger endothelial cells to promote angiogenesis, apoptosis of immune cells and increase the secretion of growth factor from stromal cells.

Figure 2. EV-mediated signaling in recipient cells

Protein sorting during MVB formation results in packaging of key molecules in exosomes. Exosomes bound-signaling ligands once released from host cells interacts with the receptors on the recipient cells to induce downstream signaling cascades pivotal in the initiation and progression of cancer. This horizontal transfer of proteomic content of exosomes can mediate signaling pathways including Wnt, PI3K and TGFβ in recipient cells.

Figure 3. Neuronal EV-mediated release of proteins implicated in neurodegenerative diseases

EVs released from infected neurons carry disease associated proteins; PrP^Sc, α-synuclein, Aβ, tau, SOD1 and possibly including α-synuclein and Aβ aggregates. Exosomal release and transfer to surrounding neuronal cells may facilitate in neurodegenerative disease progression.