Cancer Letters

Cancer Letters

Volume 356, Issue 2, Part B, 28 January 2015, Pages 339-346
Cancer Letters

Mini-review
The role of exosomes and “exosomal shuttle microRNA” in tumorigenesis and drug resistance

https://doi.org/10.1016/j.canlet.2014.10.027Get rights and content

Highlights

  • Exosomes can guide communication between cells.

  • Exosomes serve a dual role in anti/pro-tumor.

  • Exosome can mediate drug efflux and tumor resistance.

  • Exosome-derived miRNAs can be exploited as tumor diagnostic and prognostic markers.

  • Exosome-derived miRNAs play key roles in drug resistance.

Abstract

How are intracellular proteins and nucleic acids transported to the appropriate sites, and how do they function at the proper time? This problem has plagued scientists for a long time. The roles of vesicles, and nanovesicles called exosomes, as carriers were revealed in 2013. Many types of cells can release exosomes, particularly tumor cells. Tumor-derived (TD) exosomes are rich in proteins and nucleic acids derived from parental cells. With the activity of signal transmission, these exosomes can guide communication between cells and induce cancer-related disorders in many signaling pathways. TD-exosomes can be a source of tumor antigen to induce an anti-tumor immune response but can also suppress the immune system. TD-exosomes are especially rich in microRNAs (miRNAs), which are in various pathological and physiological states. Therefore, exosomal miRNA can serve as a new diagnostic marker for cancers. Moreover, miRNAs in exosomes can shuttle between cells to communicate and exchange genetic material. Thus, TD-exosomes can be used as targeted therapies. Cell-type specificity, stability and accessibility from body fluids make exosomes valuable candidates for tumor diagnosis and targeted treatment.

Introduction

Exosomes are adsorption vesicles with a lipid bilayer. Exosomes are 50-100 nm in diameter and 1.13-1.19 g/mL in density, with a classic “cup” or “dish” morphology. Exosomes were first discovered in sheep reticulocytes and then were found to be secreted by a wide range of mammalian cell types [1]. Exosomes can be released by the fusion of multivesicular bodies (MVBs) to the plasma membrane, or can be formed by the breakage of endosome-like bodies from the membrane [2]. The past 30 years of research on exosomes has yielded three major breakthroughs. Exosomes were initially considered as garbage bags for abandoned membrane parcels and molecular fragments. However, in the mid-1990s, with the finding of the role of exosomes in the presentation of B lymphocyte antigens, exosomes were recognized as being closely related to the function of the immune system [3]. Thereafter, exosome research focused on immune response, especially the physiological roles of the interaction between the immune system and tumor cells. The second major leap occurred in the 2010s, when researchers found that miRNA and mRNA can be loaded as “goods” in exosomes. In recent years, another function of exosomes was revealed: they can serve as “communication shuttles” between cells and transduct signals between cells. Exosomes play important roles in many physiological and pathological processes such as immune surveillance, inflammation, tumorigenesis, and drug resistance. Exosomes are especially important in communication between cells, which could re-encode genes of target cells and plays a part in tumor development, invasion and metastasis [4]. Here, we review some of the current knowledge about how exosomes play critical roles in tumorigenesis and drug resistance.

Exosomes consist of a lipid bilayer membrane surrounding a small cytosol; the conserved lipid matches the characteristics of the original cell. The structured lipids not only mold the exosomes, but are also involved in cell communication by regulating cell signaling pathways away from the origin. The lipid structures of exosomes can carry various important proteins, and can band together and guide cell signaling pathways between the normal and disease states of an organism.

To date, 4563 proteins, 1639 mRNAs, and 764 miRNAs have been identified in exosomes derived from different tissues (Fig. 1). Exosome-carried RNA can shuttle between cells and thus is called “exosomal shuttle RNA.” Exosomal shuttle RNA can be transferred to remote sites to regulate the function of distant cells and may affect the processes of receptor cells, especially by promoting interaction between various cells in the tumor microenvironment [5]. Exosomes, as a way of exporting biomass, are generated to circulate in the blood and interact with platelets and endothelial cells in vivo [6]. Because they retain the membrane protein label of parallel cells, exosomes can affect the biological behavior of distant cells and play an important role in disease development [7], [8].

At present, commonly used isolation methods include ultracentrifugation, sucrose gradient ultracentrifugation combined with ultrafiltration centrifugation (SGUUC), and magnetic activated cell sorting (MACS); many commercial kits are available. Researchers may use different methods for different experimental requirements. Ultracentrifugation or SGUUC can be used when the sample is ample and exosomes are abundant; MACS and commercial kits can be used when there is little sample and a low level of exosomes. Next, researchers can use transmission electron microscopy (TEM) for shape and size analysis. Specific proteins and lipid raft structures in lipid-rich membranes detected by western blot and flow cytometry (FCM) are widely used for exosome identification. Finally, qPCR, nucleic acid sequencing, western blot or ELISA can be used for exosome RNA and protein identification in the follow-up study.

Many studies confirm that exosomes can interact with recipient cells [9], but it is unclear how the exosomes interact with and regulate the function of target cells. Based on indirect evidence and studies in vitro, several mechanisms of interactions have been proposed: (1) binding to the surface of a recipient cell through exosomal adhesion molecules; (2) direct fusion of vesicles with recipient plasma membrane after adhesion; or (3) internalization of vesicles into endocytic compartments through receptor-mediated endocytosis or phagocytosis. The interaction between exosomes and target cells can lead to direct stimulation of target cells via surface-expressed growth factors or bioactive lipids, transfer of membrane receptors, or delivery of proteins to target cells. Additionally, the presence of mRNA and microRNA, termed “exosomal shuttle RNA,” in exosomes suggests that genetic material exchange could be an additional level of exosome-mediated intercellular communication [10] (Fig. 2).

The most well-known mechanism of intercellular communication is via signaling molecules such as proteins to interact with the surface receptors of target cells. The communication role of exosomes deemphasizes signal molecular diffusion in the body fluid, and ensures that the easily inactivated or degraded components in extracellular fluid (e.g., mRNAs, miRNAs) can be transferred to target cells safely and are involved in the regulation of target cells. Furthermore, exosomes can carry a wide range of active molecules, including proteins, RNAs and lipids and regulate the recipient cells in multiple pathways and multiple sites, thus greatly improving the accuracy of regulation and conforming more to the needs of the organ. Because exosomes are extensively distributed in vivo, and the formation of hydrogen bonds between lipid compositions in exosome membranes increases stability, the information regulated by exosomes is wide and persistent. To some extent, exosome secretion by cells may be similar to endocrine regulation in the organism.

Section snippets

The immunogenicity of TD-exosomes

Exosomes secreted from tumor cells are called tumor-derived (TD) exosomes. The proteins in an exosome are exactly similar to the proteins in its parallel cells and are cell-type-specific. TD-exosomes contain tumor-specific antigens that are expressed in the parent cells. Compared with the total cell lysates, the tumor antigens in exosomes, such as melan-A, Silv, carcinoembryonic antigen (CEA), and mesothelin, are more abundant. Currently, TD-exosomes are being used as a source of tumor antigen

Exosomal shuttle microRNAs (esmiRNAs) in genetic exchange

MicroRNAs are small non-coding RNA molecules with diverse functions [53]. They can regulate many genes by binding to non-coding regions of target mRNA, causing disorders in the target genes [54]. One miRNA can affect a plurality of genes in a cell, or even the expression of genes adjacent to the target cells in the tumor microenvironment. Because miRNAs can coexist in original sites (e.g., inside the cell) and in blood circulation, they can affect distant cells [55]. Conventionally, the output

Conclusions and future directions

Successful treatment of cancer depends on the understanding of complex interactions between tumor components. Exosomes, as small particles, can function as key communication facilitators between cells. The functions of exosomes in interactions between distant cells and their complex role in tumorigenesis and progression have been gradually recognized. Exosomes can secrete a variety of biological molecules, including viruses, miRNAs, proteins and their complexes. Some researchers are trying to

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgments

The work is supported by grants from the National Natural Science Foundation of China: No. 81101737 (to Jing Yu), No. 81301912 (to Qin Li), and No. 81272615 (to Bangwei Cao), by Grant No. 12JL33 from the Capital Medical University Sciences-Clinical Research Cooperation Foundation (to Qin Li), by Grant No. 2011-3-007 from the Beijing Municipal Health System High-level Health Person Foundation Project (to Bangwei Cao), and by a grant from the Beijing Municipal “Ten, Hundred, Thousand” Person

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