Cell-to-cell communication is an essential component in multicellular organisms, allowing for rapid, coordinated responses to changes within the environment. Classical signaling mediators include direct cell-cell contact as well as secreted factors, such as cytokines, metabolites, and hormones. In the past decade, extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, have emerged as important mediators of intercellular communication. EVs are double-membrane vesicles containing cargoes of multiple proteins, lipids, and nucleic acids, which are derived from their cells of origin, and EV cargoes can change depending on the status of their originating cells. Importantly, EVs are found in all body fluids and can carry their cargoes to distant sites within the body as well as neighboring cells. Reviews in this series discuss the role of EV-mediated signaling in physiological and pathophysiological conditions, including infection, host immune responses, and cancer. Additionally, these reviews cover the potential clinical use of EVs as therapeutics and diagnostic biomarkers.
Intercellular signaling via extracellular vesicles (EVs) is an underappreciated modality of cell-cell crosstalk that enables cells to convey packages of complex instructions to specific recipient cells. EVs transmit these instructions through their cargoes of multiple proteins, nucleic acids, and specialized lipids, which are derived from their cells of origin and allow for combinatorial effects upon recipient cells. This Review series brings together the recent progress in our understanding of EV signaling in physiological and pathophysiological conditions, highlighting how certain EVs, particularly exosomes, can promote or regulate infections, host immune responses, development, and various diseases — notably cancer. Given the diverse nature of EVs and their abilities to profoundly modulate host cells, this series puts particular emphasis on the clinical applications of EVs as therapeutics and as diagnostic biomarkers.
Jonathan M. Pitt, Guido Kroemer, Laurence Zitvogel
New biomarkers are needed to improve the diagnosis of prostate cancer. Similarly to healthy cells, prostate epithelial cancer cells produce extracellular vesicles (prostasomes) that can be isolated from seminal fluid, urine, and blood. Prostasomes contain ubiquitously expressed and prostate-specific membrane and cytosolic proteins, as well as RNA. Both quantitative and qualitative changes in protein, mRNA, long noncoding RNA, and microRNA composition of extracellular vesicles isolated from prostate cancer patients have been reported. In general, however, the identified extracellular vesicle–associated single-marker molecules or combinations of marker molecules require confirmation in large cohorts of patients to validate their specificity and sensitivity as prostate cancer markers. Complications include variable factors such as prostate manipulation and urine flux, as well as masking by ubiquitously expressed free molecules and extracellular vesicles from tissues other than the prostate. Herein, we propose that the most promising methods include comprehensive combinational screening for (mutant) RNA in prostasomes that are immunoisolated with antibodies targeting prostate-specific epitopes.
Carla Zijlstra, Willem Stoorvogel
Two broad categories of extracellular vesicles (EVs), exosomes and shed microvesicles (sMVs), which differ in size distribution as well as protein and RNA profiles, have been described. EVs are known to play key roles in cell-cell communication, acting proximally as well as systemically. This Review discusses the nature of EV subtypes, strategies for isolating EVs from both cell-culture media and body fluids, and procedures for quantifying EVs. We also discuss proteins selectively enriched in exosomes and sMVs that have the potential for use as markers to discriminate between EV subtypes, as well as various applications of EVs in clinical diagnosis.
Rong Xu, David W. Greening, Hong-Jian Zhu, Nobuhiro Takahashi, Richard J. Simpson
Numerous studies have shown that non–cell-autonomous regulation of cancer cells is an important aspect of tumorigenesis. Cancer cells need to communicate with stromal cells by humoral factors such as VEGF, FGFs, and Wnt in order to survive. Recently, extracellular vesicles (EVs) have also been shown to be involved in cell-cell communication between cancer cells and the surrounding microenvironment and to be important for the development of cancer. In addition, these EVs contain small noncoding RNAs, including microRNAs (miRNAs), which contribute to the malignancy of cancer cells. Here, we provide an overview of current research on EVs, especially miRNAs in EVs. We also propose strategies to treat cancers by targeting EVs around cancer cells.
Nobuyoshi Kosaka, Yusuke Yoshioka, Yu Fujita, Takahiro Ochiya
Almost all cell types release extracellular vesicles (EVs), which are derived either from multivesicular bodies or from the plasma membrane. EVs contain a subset of proteins, lipids, and nucleic acids from the cell from which they are derived. EV factors, particularly small RNAs such as miRNAs, likely play important roles in cell-to-cell communication both locally and systemically. Most of the functions associated with EVs are in the regulation of immune responses to pathogens and cancer, as well as in regulating autoimmunity. This Review will focus on the different modes of immune regulation, both direct and indirect, by EVs. The therapeutic utility of EVs for the regulation of immune responses will also be discussed.
Paul D. Robbins, Akaitz Dorronsoro, Cori N. Booker
Exosomes and other extracellular microvesicles (ExMVs) have important functions in intercellular communication and regulation. During the course of infection, these vesicles can convey pathogen molecules that serve as antigens or agonists of innate immune receptors to induce host defense and immunity, or that serve as regulators of host defense and mediators of immune evasion. These molecules may include proteins, nucleic acids, lipids, and carbohydrates. Pathogen molecules may be disseminated by incorporation into vesicles that are created and shed by host cells, or they may be incorporated into vesicles shed from microbial cells. Involvement of ExMVs in the induction of immunity and host defense is widespread among many pathogens, whereas their involvement in immune evasion mechanisms is prominent among pathogens that establish chronic infection and is found in some that cause acute infection. Because of their immunogenicity and enrichment of pathogen molecules, exosomes may also have potential in vaccine preparations and as diagnostic markers. Additionally, the ability of exosomes to deliver molecules to recipient cells raises the possibility of their use for drug/therapy delivery. Thus, ExMVs play a major role in the pathogenesis of infection and provide exciting potential for the development of novel diagnostic and therapeutic approaches.
Jeffrey S. Schorey, Clifford V. Harding
Stroke is one of the leading causes of death and disability worldwide. Stroke recovery is orchestrated by a set of highly interactive processes that involve the neurovascular unit and neural stem cells. Emerging data suggest that exosomes play an important role in intercellular communication by transferring exosomal protein and RNA cargo between source and target cells in the brain. Here, we review these advances and their impact on promoting coupled brain remodeling processes after stroke. The use of exosomes for therapeutic applications in stroke is also highlighted.
Zheng Gang Zhang, Michael Chopp
Extracellular vesicles (EVs, including exosomes) are implicated in many aspects of nervous system development and function, including regulation of synaptic communication, synaptic strength, and nerve regeneration. They mediate the transfer of packets of information in the form of nonsecreted proteins and DNA/RNA protected within a membrane compartment. EVs are essential for the packaging and transport of many cell-fate proteins during development as well as many neurotoxic misfolded proteins during pathogenesis. This form of communication provides another dimension of cellular crosstalk, with the ability to assemble a “kit” of directional instructions made up of different molecular entities and address it to specific recipient cells. This multidimensional form of communication has special significance in the nervous system. How EVs help to orchestrate the wiring of the brain while allowing for plasticity associated with learning and memory and contribute to regeneration and degeneration are all under investigation. Because they carry specific disease-related RNAs and proteins, practical applications of EVs include potential uses as biomarkers and therapeutics. This Review describes our current understanding of EVs and serves as a springboard for future advances, which may reveal new important mechanisms by which EVs in coordinate brain and body function and dysfunction.
Valentina Zappulli, Kristina Pagh Friis, Zachary Fitzpatrick, Casey A. Maguire, Xandra O. Breakefield
Humans circulate quadrillions of exosomes at all times. Exosomes are a class of extracellular vesicles released by all cells, with a size range of 40–150 nm and a lipid bilayer membrane. Exosomes contain DNA, RNA, and proteins. Exosomes likely remove excess and/or unnecessary constituents from the cells, functioning like garbage bags, although their precise physiological role remains unknown. Additionally, exosomes may mediate specific cell-to-cell communication and activate signaling pathways in cells they fuse or interact with. Exosomes are detected in the tumor microenvironment, and emerging evidence suggests that they play a role in facilitating tumorigenesis by regulating angiogenesis, immunity, and metastasis. Circulating exosomes can be used as liquid biopsies and noninvasive biomarkers for early detection, diagnosis, and treatment of cancer patients.
Tumor-derived exosomes (TEX) are harbingers of tumor-induced immune suppression: they carry immunosuppressive molecules and factors known to interfere with immune cell functions. By delivering suppressive cargos consisting of proteins similar to those in parent tumor cells to immune cells, TEX directly or indirectly influence the development, maturation, and antitumor activities of immune cells. TEX also deliver genomic DNA, mRNA, and microRNAs to immune cells, thereby reprogramming functions of responder cells to promote tumor progression. TEX carrying tumor-associated antigens can interfere with antitumor immunotherapies. TEX also have the potential to serve as noninvasive biomarkers of tumor progression. In the tumor microenvironment, TEX may be involved in operating numerous signaling pathways responsible for the downregulation of antitumor immunity.
Theresa L. Whiteside
DC-derived exosomes (Dex) are nanometer-sized membrane vesicles that are secreted by the sentinel antigen-presenting cells of the immune system: DCs. Like DCs, the molecular composition of Dex includes surface expression of functional MHC-peptide complexes, costimulatory molecules, and other components that interact with immune cells. Dex have the potential to facilitate immune cell–dependent tumor rejection and have distinct advantages over cell-based immunotherapies involving DCs. Accordingly, Dex-based phase I and II clinical trials have been conducted in advanced malignancies, showing the feasibility and safety of the approach, as well as the propensity of these nanovesicles to mediate T and NK cell–based immune responses in patients. This Review will evaluate the interactions of Dex with immune cells, their clinical progress, and the future of Dex immunotherapy for cancer.
Jonathan M. Pitt, Fabrice André, Sebastian Amigorena, Jean-Charles Soria, Alexander Eggermont, Guido Kroemer, Laurence Zitvogel