Extracellular vesicles as emerging targets in cancer: Recent development from bench to bedside

Abstract

Extracellular vesicles (EVs) have emerged as important players of cancer initiation and progression through cell-cell communication. They have been recognized as critical mediators of extracellular communications, which promote transformation, growth invasion, and drug-resistance of cancer cells. Interestingly, the secretion and uptake of EVs are regulated in a more controlled manner than previously anticipated. EVs are classified into three groups, (i) exosomes, (ii) microvesicles (MVs), and (iii) apoptotic bodies (ABs), based on their sizes and origins, and novel technologies to isolate and distinguish these EVs are evolving. The biologically functional molecules harbored in these EVs, including nucleic acids, lipids, and proteins, have been shown to induce key signaling pathways in both tumor and tumor microenvironment (TME) cells for exacerbating tumor development. While tumor cell-derived EVs are capable of reprogramming stromal cells to generate a proper tumor cell niche, stromal-derived EVs profoundly affect the growth, resistance, and stem cell properties of tumor cells. This review summarizes and discusses these reciprocal communications through EVs in different types of cancers. Further understanding of the pathophysiological roles of different EVs in tumor progression is expected to lead to the discovery of novel biomarkers in liquid biopsy and development of tumor specific therapeutics. This review will also discuss the translational aspects of EVs and therapeutic opportunities of utilizing EVs in different cancer types.

Trial registration: ClinicalTrials.gov NCT01668849 NCT01294072.

Keywords: Apoptotic body; Cancer; Exosome; Extracellular vesicles; Microvesicle; Translational studies.

Copyright © 2017 Elsevier B.V. All rights reserved.

Figures

Figure 1. Pathways of cargo sorting in exosomes

A, ESCRT-related sorting. Proteins belonging to ESCRT family regulate cargo sorting from cells to exosomes. Binding of syndencan to ALIX-ESCRT complex results in incorporation of syndecan, VEGF and HGF. SIMPLE affects CD63 and ALIX expression in exosome. VPS proteins controls loading of selective cargoes such as THPO and ANGPTLs. B, Lipid-related sorting. The nSMase catalyzes ceramide formation from sphingolipids. Ceramide is associated with Ago2 and miRNA sorting. C, Membrane protein-regulated sorting. Tetraspanins and integral membrane proteins regulate exosomal cargo sorting. Membrane anchors also control the selectivity of exosomal cargo. D, Other sorting mechanisms. Other proteins (such as hnRNPs) and modification (uridylation of miRNA and N-linked glycosylation of protein) also regulate cargo sorting.

Figure 2. Intercellular communication through EVs

EVs-mediated intercellular communication occurs between cancer cells. Aggressive cancer cells secrete exosomes and MVs containing oncogenic factors to transform indolent cancer cells into aggressive phenotypes. EVs also mediate the intercellular communication between cancer cells and TME cells. EVs derived from cancer cells modulate TME cells thus generating a favorable microenvironment for the growth and metastasis of cancer cells. TME cells could also secrete EVs to affect cancer cells, inducing aggressive phenotypes in indolent cancer cells.

Figure 3. Therapeutic Applications of EVs

Exosomes purified from tumor cells and dendritic cells are used as tumor vaccine. By loading tumor specific antigens to exosomes, they can activate and mobilize immune cells to kill tumor cells. Exosomes derived from tumor cells, dendritic cells, MSCs and HEK293 cells can be used as drug carrier for cancer theray. Specifc ligands or receptors are expressed in exosomes, if not, can be introduced into exosomes to achieve targeted delivery. Loading drugs into exosomes results in better biodistribution, stablility and less side effects. Inhibition of EV biogenesis by drugs is also reported to suppress the tumor growth.