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Journal of Molecular Biomarkers & Diagnosis
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Enigmatic Exosomes: Role in health and disease with significance in cancer

Nandini DB1*, Deepak BS2, Nachiammai1 and Madhushankari GS1

1Department of Oral Pathology and Microbiology, Dental College, Regional Institute of Medical Sciences, India

2Department of Conservative Dentistry and Endodontics, Dental College, Regional Institute of Medical Sciences, India

*Corresponding Author:
Nandini DB
Department of Oral Pathology and Microbiology, Dental College
Regional Institute of Medical Sciences, Imphal, Manipur, India
Tel: 09448404214
E-mail: [email protected]

Received Date: November 24, 2016; Accepted Date: December 24, 2016; Published Date: December 26, 2016

Citation: Nandini BD, Deepak BS, Nachiammai, Madhushankari GS (2016) Enigmatic Exosomes: An Insight with Emphasis on Their Role in Cancer. J Mol Biomark Diagn S2:024. doi: 10.4172/2155-9929.S2-024

Copyright: © 2016 Nandini BD, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Exosomes are small membrane derived vesicles secreted by a variety of mammalian cells during normal and pathologic conditions which are actively involved in conferring intercellular signals. They are enriched with mRNA, micro RNA, lipids and other cellular proteins which can be isolated from various body fluids. Recently their role as potential biomarkers is gained a lot of attention. Exosomes can reveal the cell of origin and the condition of the cell as well. Their role as biomarkers in diseases like Alzheimer’s, brain tumors, chronic kidney disease, salivary gland diseases, breast cancer has been already established. Role of tumor derived exosomes in cancer progression, metastasis and drug resistance is widely discussed at present times. In contrast, exosomes from healthy cells of the immune system appear to have anti-tumor characteristics. Anti-tumor therapies based on exosomes, for example, by blocking the formation of tumor-derived exosomes or having exosomes release therapeutic agents at specific sites is being explored. The use of exosomes from dendritic cells in tumor vaccination, the safety of which has been demonstrated in phase I studies. Salivary exosomes can be relevant diagnostic, prognostic and predictive biomarkers in oral diseases especially oral cancer. Exosomes isolated from cells infected with various intracellular pathogens, including Mycobacterium tuberculosis and Toxoplasma gondii, have been shown to contain microbial components and can promote antigen presentation and macrophage activation, suggesting that exosomes may function in immune surveillance. Their role in forensic analysis is also being explored. On the other hand, exosome mediated drug expulsion has led to drug resistance thus hindering the therapy.

Keywords

Biomarker; Body fluid; Cancer diagnosis; Drug resistance; Exosomes; Micro vesicles; Stromal remodeling; Tumor microenvironment; Vaccine

Introduction

Exosomes are membrane bound vesicles carrying a large array of macromolecules like proteins, lipids, nucleic acids, viruses or any other pathogens derived from their originating cell [1]. These are nanosized bioactive vesicles derived from the fusion of external membrane of multivesicuar bodies with plasma membrane and then released extracellularly [2]. Exosomes vary from microvesicles in that the latter are larger sized measuring 200 nm to 1000 nm and also vary from apoptotic bodies which are 0.5 μm to 3 μm [3]. Exosomes are nano sized with a diameter of 30 nm to 200 nm [3] or 40 nm to 100 nm [4] and a density of 1.13 g/mL to 1.21 g/mL in a sucrose gradient [4] and can be sedimented at 100,000 xg [5,6].

Exosomes sometimes show a ‘cup shaped’ or ‘saucer like’ morphology when viewed under electron microscopy [7,8]. Exosomes have emerged as mediators of cellular intercommunication both in health and disease conditions.

Exosomes are released by all types of cells haemopoietic and nonhaemopoietic, normal as well as tumor cells [9]. The phenotype of the exosomes depends on the cell of origin [2,10]. They are released during normal physiologic as well as pathologic conditions. They are released by reticulocytes, dendritic cells, B and T lymphocytes, platelets, mast cells and macrophages. Epithelial cells, fibroblasts, astrocytes and neurons also secrete exosomes. Release or secretion of exosomes in these cells can be modulated by ligand cognition or stress conditioned [11,12]. Release of exosomes can be triggered by other stimuli like ceramide, changes in membrane pH, hypoxia, and microbial attack [13].

Biosynthesis composition, and regulation of these vesicles have gained a lot of attention in recent times. The term exosome was first coined by Trams et al. [14]. Release of exosomes from live cells was first observed in early 1980s in maturing mammalian reticulocytes [15,16] and was proposed to be a mechanism through which cells discard their inert debris [8,14].

Exosomes may be found in most of the body fluids like plasma, breast milk, saliva, tears and urine [17]. Tumor derived exosomes are present in supernatant of tumor cells, malignant effusions of tumor patients, broncho-alveolar lavage fluid, and cerebrospinal fluid as well [2]. They are durable for travel through the body fluids and are capable of causing metastasis [11]. The contents of exosomes can be transferred from the cell of origin to their target cells in local microenvironment or even at distant site that can possibly give rise to an exponential intercellular communication networks [13].

Exosomes released from different cells share a common set of molecules that are needed for their biogenesis, structure and trafficking-as well as cell‐type specific components which, presumably, reflect the biological function of the parent cell. Ubiquitous proteins in exosomes include cytoplasmic proteins, such as tubulin, actin and actin-binding proteins, the heat shock proteins Hsp70 and Hsp90, and trimeric G proteins, as well as membrane proteins, such as members of the tetraspanin family (CD9, CD63, CD81, CD82) [4]. These proteins are said to be involved in cell adhesion, activation, proliferation, and antigen presentation. Cell‐type specific proteins have shown to reflect the specialized function of the original cells [4]. For example, dendritic cell derived exosomes were also found to express high levels of MHC class I and class-II peptides that trigger T-cell responses leading to tumor rejection [18].

“Exosomes predominantly contain lipids, such as cholesterol, diglycerides, sphingolipids (including sphingomyelin and ceramide), phospholipids, glycerophospholipids (including phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol and polyglycerophospholipids (i.e. bisphosphate) [12]. Exosomes have also been reported to contain bioactive lipids, such as prostaglandins and leukotrienes, and active enzymes of lipid metabolism that may generate these lipids” [19,20].

Exosomes in Health

Exosomes are involved in normal physiologic processes like lactation, immune response and neuronal function and diseases like liver disease, neurodegenerative disease, and cancer [21-29]. Exosomes released from healthy normal cells of immune system appear to have antitumor characteristics. Use of exosomes from dendritic cells in tumor vaccination and its safety has been demonstrated in phase 1 studies and is proved in brain cancer therapy [30]. Exosomes have been used in immune therapy of cancer to improve the overall survival [31].

Exosomes in infectious diseases

Exosomes have also been examined for their therapeutic potential in the treatment of infections such as toxoplasmosis, diphtheria [32], tuberculosis [33] and atypical severe acute respiratory syndrome [34]. Exosomes as a vaccine has also been explored in infection with the SARS‐associated coronavirus (SARS‐CoV) known to induce an atypical pulmonary disease with a high lethality rate [34].

Exosomes isolated from cells infected with intra cellular pathogens like Mycobacterium tuberculosis and Toxoplasma gondii have been shown to contain microbial components and can promote antigen presentation and macrophage activation suggesting that they may function in promoting immune surveillance [10].

Exosomes in allergic and autoimmune diseases

Exosomes may be potential candidates as vaccines for allergic diseases. The role of exosomes and microflora in establishing mucosal tolerance and protection against allergic diseases was studied by few authors [35]. They concluded that exosomes induced antigen specific tolerance and thus provided protection against allergy which was possibly mediated by plasmacytoid dendritic cells. They further stated that certain microbial stimuli like S. aureus effects tolerogenic processing as a result of activated immune system in the gut [35]. Exosomes have also proved useful in treatment of autoimmune diseases in animal models.

Exosomes in salivary gland diseases

Salivary exosomal miRNAs may be valuable not only as a diagnostic tool but may also provide an insight into the role miRNAs in the underlying pathophysiology of various salivary gland diseases like Sjogren’s syndrome [36]. Isolation of exosomal microRNAs from the salivary gland holds the promise of focused biomarker discovery for pathologies that directly or indirectly affect the salivary glands including cancer.

Exosomes in cancer

Interaction of tumor cells and surrounding microenvironment is essential for tumor establishment and progression. “It has been suggested to be through various mechanisms, including (a) cell and cell-matrix interactions, (b) local release of soluble factors promoting survival and tumor growth (crosstalk between stromal and tumor cells), (c) direct cell-cell interactions with tumor cells, i.e. trogocytosis, (d) generation of specific niches within the tumor microenvironment that facilitate the acquisition of drug resistance, or (e) conversion of the cancer cells to cancer-initiating cells or cancer stem-like cells” [13]. Tumor derived exosomes usually exhibit protumorigenic role but some anti-tumorigenic properties have also been described. Role of exosome-mediated transport in diverse mechanisms, such as metastasis and angiogenesis, hypoxia, epithelial mesenchymal transition (EMT) signaling, tumor growth factor-β (TGF β) signaling, and Wnt-β-catenin signaling that collectively support the tumor microenvironment niche is widely studied at present [13]. Tumor cells interact with the fibroblasts, endothelial cells and immune cells in surrounding stroma. Tumor cells of many different cancer types have been shown to secrete exosomes in greater amounts than normal cells [37].

Anti-Tumorigenic Role of Exosomes

Immunogenic properties or tumor exosome based cancer vaccine

Indirect application: Exosome pulsed dendritic cells (DC), exosomes contain antigenic proteins specific to parental tumor cell. Thus, these are used to pulse dendritic cells resulting in transfer of T-antigens to DC which result in cytotoxic T-cell dependent antitumor effects in mice and human ex vivo models [38,39]. Dendritic cellderived exosomes stimulate T-cell mediated anti-tumor immune responses. Exosomes also contain antigens that are capable of triggering a biological immune response by activating T-lymphocytes, natural killer cells, and dendritic cells exosomes have also emerged as an exciting potential candidate for immunotherapy and vaccination modalities [10], as well as a novel vector for gene therapy [40].

Direct application: When parental tumor cells were genetically modified to express proinflammatory cytokines/enriched chemokines such as IL 18,12,2 [41-43] or when cells were subjected to stress conditions/heat shock proteins, exosomes were released which could induce specific antitumor response [44].

Inducing tumor cell apoptosis

Exosomes are shown to exhibit pro apoptotic properties on tumor cells directly. Pancreatic cancer cells were shown to release exosomes which induced apoptosis in tumor cells by increasing Bax and decreasing Bcl2 expression [45].

Exosomes are abundantly present in tumor environment in patients with advanced cancer. However effective antitumor effects are rarely seen. It is also unclear whether the constant production of exosomes by tumor cells is useful or harmful for their own survival in vivo.

Protumorigenic Role of Tumor Exosomes

By inducing immunosuppression

Tumor exosomes can either directly induce apoptosis of activated cytotoxic T-cells or down regulate the T-cell/NK cell functions in addition to direct killing thus promoting tumor growth [46]. They can also target myeloid cells to modulate their differentiation into dendritic cells towards formation of myeloid-derived suppressor cells and exert TGFβ1 mediated suppression on T-cells thus favoring tumor growth [47]. Transfer of genetic material between exosomes and bone marrow (BM) cells can influence the function of future population of BM cells [48]. Tumor exosomes support function of Regulatory T (Treg) cells by maintaining the number and enhancing resistance to apoptosis of Treg cells via TGF β and IL-10 dependent mechanism [49].

By promoting tolerance to tumor specific antigens

Tumor exosomes provide tumor antigens to dendritic cells as well as condition dendritic cells towards a suppressive tolerogenic phenotype resulting in down regulation of antigen specific immune response [50].

Facilitation to tumor invasion and metastasis

Exosomes act as central mediators of the tumor microenvironment by expressing molecules involved in angiogenesis promotion, remodeling of stromal cells, remodeling of extracellular matrix through matrix metalloproteinases (MMPs), signaling pathway activation through growth receptor/factor transfer, providing hypoxic environment for increased aggressiveness, chemoresistance and intercellular genetic exchange [51,52]. Exosomes help the tumor cells to survive immune surveillance and evasion thus promoting tumor growth and metastasis. They also contribute to the establishment of a pre-metastatic niche thus creating a suitable microenvironment in distant metastatic sites [52].

Hypoxia promotes the sustenance and spread of epithelial tumors [53]. “The hypoxic environment (a niche within tumor) is recognized to harbor cells that are drug resistant (compared with the bulk of the tissue) carrying markers that are reminiscent of Epithelial Mesenchymal Transition” [54]. Hypoxia facilitates the secretion of various tumor-promoting factors that influence adjacent tissues in the tumor microenvironment with enhanced angiogenic and metastatic potential suggesting that tumor cells adapt to a hypoxic microenvironment [55,56]. Therefore, either directly targeting hypoxia or the factors promoting this important phenomenon is an emerging form of therapy under investigation [57,58]. In breast cancer hypoxia induced more aggressive cell phenotype as observed by King et al. [59].

Tetraspanin and D6.1A enriched exosomes upregulated angiogenesis by inducing endothelial proliferation, migration, sprouting and maturation of endothelial cell progenitors [60,61]. Exosomes from mesenchymal stem cells (MSC) can also promote tumor growth by enhancing vascular endothelial growth factor expression in tumor cells by activating the ERK1/2 pathway [62]. Platelet-derived exosomes have also been shown to stimulate mRNA expression of angiogenic factors such as Matrix Metallo proteinases-9 [63].

Epithelial mesenchymal transition is considered one of the hallmarks of aggressive tumors [6]. Cells undergoing EMT have enhanced plasticity and propensity to migrate out from the site of origin, resulting in tumor spread [64]. These cells secrete factors that affect adjacent cells and tissues and contribute to resistance by maintaining the overall tumor microenvironment [65]. The role of exosomes in EMT promotion has been delineated recently.

TGF-β plays an important role in the promotion and maintenance of tumor stroma as well as in the induction of EMT [66,67]. Certain cancer cells produce TGF-β enriched exosomes which are capable of causing differentiation of fibroblasts into myofibroblasts thus altering the stroma. This in turn supports tumor growth, vascularization and metastasis. Exosomal TGFβ induced more production of FGF2 than soluble TGFβ [68]. “TGF-β1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative response and fibrosis [69]. The fibroblast activation was found to be dependent on the success of exosomes to primarily deliver TGF-β1 mRNA to the site of fibrosis” [57]. Clayton and colleagues showed that exosomes rich in TGF-beta can suppress the lymphocytes response to interleukin 2 [70].

Wnt signaling plays central role in tissue development, and aberrations in this evolutionary conserved pathway has been shown to be linked with the development of cancers [71]. β-catenin protein acts as an intracellular signal transducer and functions as a dual function protein, regulating the coordination of cell-cell adhesion and gene transcription, processes that are essential for early embryonic development [72]. Increased nuclear β-catenin, a major component in Wnt signaling pathway has been shown in various cancers [73]. Wnt signaling either induces exosome secretion or the components in the Wnt signaling pathway that can be exported to distant sites through exosomal transport. However, mechanism is elusive.

Tumor-associated macrophages, which are known to promote invasion and metastasis, have been shown to secrete microvesicles containing microRNAs that could be taken up by breast cancer cells [12].

“In a co-culture system, it was demonstrated that uptake of IL-4 activated macrophage secreted exosomes could promote the invasion of breast cancer cells, due to uptake of miR-223 (a microRNA specific for IL-4 activated macrophages) and disruption of the Mef2c-β-catenin pathway” [74].

“Through pathogen recognition receptors, such as Toll-like receptors (TLRs), and their associated downstream signaling pathways, such as nuclear factor kappaB (NF-κB) and MAPK, exosomal microRNAs may also play a large role in the regulation and homeostasis of the innate immune response by fine-tuning the mechanisms responsible for the production and release of cytokines/chemokines, adhesion and co-stimulatory molecules in epithelial cells” [75]. These mechanisms, in the context of cancer, could be disrupted, thereby promoting an immune-evasion response and cancer promotion.

Exosomes from certain cancers like ovarian were found to contain matrix metalloproteinases which were proteolytic thus resulting in increased extracellular matrix degradation and augment tumor invasion into the stroma. CD44 is said to serve as exosome carrier or a reservoir for growth factors, chemokines, and proteases required for tumor cell embedding and growth [76-78]. Heat shock proteins like Hsp 90 secreted via exosomes can activate MMP-2 thus promoting the invasion of tumor cells [79]. Platelet derived exosomes in lung cancer cell lines have shown to promote tumor progression [63].

“Tumor exosomes were shown to target non-transformed cells in pre-metastatic organs and modulate pre-metastatic organ cells predominantly through transferred miRNAs by mostly targeting metastasis-related pathways, such as proteases, adhesion molecules, chemokine ligands, cell cycle and angiogenesis promoting genes, and genes engaged in oxidative stress response” [13].

Transport of RNAs and proteins for tumor survival and growth

Tumor exosomes promote tumor progression mainly through the transfer of RNA and proteins from tumor cells to other neighboring cells, resulting in stimulation of angiogenesis and suppression of immune surveillance [30]. Exosomes can be utilized by human tumor virus for disseminating viral materials especially Epstein-Barr virus (EBV) infected nasopharyngeal carcinoma. Epstein-Barr virus (EBV)-derived miRNAs can be delivered via exosomes and regulate target genes in the recipient non-viral cells [80]. Valadi et al. discovered the presence of small RNAs and mRNAs (but not DNA) from approximately 1300 genes present in exosomes that are not present in the parental cell and proposed that these RNAs be referred to as exosomal shuttle RNAs (esRNAs) to distinguish them from circulating microRNAs [81].

Drug interference

De novo and acquired resistance to chemo-, radiation, and targeted therapies has resulted in a major barrier in effective cancer drug delivery and failure of cancer treatment. Certain tumor derived exosomes show active participation in drug resistance by several mechanisms. They help the tumor cells by exporting tumoricidal drugs or by neutralizing antibody-based drugs (Yang et al.). “The development of resistance is multifactorial that includes switching of cancer cells to secondary salvage pathways when the primary hallmark is shut [82], epigenetic suppression of tumor suppressor protein activation by miRNAs [83], presence of a subpopulation of highly resistant cancer stem-like cells with enhanced plasticity, such as epithelial-to-mesenchymal transition (EMT) phenotype [84], low drug penetrance (due to desmoplastic reaction (DR) in the tumor microenvironment) and others” [85]. Exosome-released factor can promote (a) EMT cell morphology, resulting in stemness; (b) promote fibroblast-like cell formation that causes desmoplatic reaction (stromal reaction); (c) promote immune escape mechanisms; and (d) promote angiogenesis and metastasis. The miRNAs expelled by exosomes can regulate multiple signaling pathways that cumulatively promote resistant phenotype of most tumors [13]. “Cancer cells exposed to drugs are recognized to expel drugs in extracellular compartments using specialized transporters of the multidrug resistance (MDR)-ATP binding-cassette transporter (ABC transporters) system that are found to be activated in different malignancies” [86].

Thus, the predominant regulatory role of exosomes depends on their molecular phenotype and cell specificity. In addition, the environmental factors also play an important role in determining the behavior and immunological impact of tumor derived exosomes. Further, different types of tumor and possibly different tumor growth patterns may affect the accumulation of tumor derived exosomes in peripheral circulation. Thus, careful interpretation is needed when using them as diagnostic biomarkers [11]. Although these clinical approaches appear to be safe, there has been a lack of clinical efficacy of exosome-based vaccines in contrast to the promising results obtained in many animal tumor models. Still, the limited number of clinical trials and patients recruited prevents a conclusive evaluation of their efficacy and prospect.

Techniques for isolation, and identification of exosomes

Isolation of exosome is usually done by multiple centrifugation and ultracentrifugation steps with a rotational force up to 100,000 × g for sedimentation as they are smaller sized and have low density. Centrifugation is also sometimes combined with 0.1 μm to 0.22 μm filtration in order to separate the nano-sized particles and to exclude larger particles and cellular debris [87]. For reduction of protein aggregate contamination and for obtaining a purer exosome preparation, sucrose, iodixanol [88], deuterium oxide density gradients (also called cushions) or proprietary reagents, such as ExoQuick (System Biosciences), have also be utilized [89,90].

Immunoaffinity capture methods using magnetic beads coated with antibodies against presumably any exosome-specific surface marker, such as the tetraspanins, CD63 or CD82, can be used to isolate exosomes from cancer cells or patient serum [87].

Electron microscopy with negative staining [7], immunoblot procedures [1], mass spectrometry [91], various RNA isolation techniques like phenol-based techniques (TRIzol®), silica column [e.g. RNeasy® (Qiagen) or miRCURY (Exiqon)] and combined phenol and silica column approaches [e.g. TRIzol® followed by RNeasy (Qiagen), miRNeasy (Qiagen) or mirVana (Ambion)] have been utilized and compared [92-94].

“The RNA yield can be determined by spectrophotometric analysis at 260 nm, and a profile of the exosomal RNAs can be determined using the Agilent 2100 Bioanalyzer Lab-on-a-Chip instrument system (Agilent Technologies). Typical profiles of RNA extracted from exosomes contain a size distribution of 25-2000 nucleotides and are characteristically absent of ribosomal RNAs” [92].

“Typical profiles of RNA extracted from exosomes contain a size distribution of 25-2000 nucleotides and are characteristically absent of ribosomal RNAs [92]. Detection of specific small RNA or microRNA species can be determined by real-time reverse-transcription PCR assay and oligonucleotide microarray analysis (51 Xiao 2012-hanna), or more in-depth analysis next-generation RNA sequencing can be applied” [95-97].

Quantification of exosomal protein is challenging due to their nanosize. Currently it can be done using enzyme-linked immunosorbent assays (ELISA) or by immunoblotting. cell lines stably “expressing GFP tagged CD63 (a specific marker of exosomes), thus generating exosomes with a traceable marker that can be easily measured by fluorescent spectrometry [98]. New nanoparticle/exosome tracking analysis technologies have recently been developed by Nanosight Ltd. [99].

The protein composition of exosomes has been characterized using immunoblotting [100], peptide mass spectroscopy mapping [5,6] and affinity extraction into magnetic beads, followed by phenotyping by flow cytometry [70].

Several studies have demonstrated that the RNA present in exosomes is very different from the parental cell RNA content, with the apparent lack of ribosomal RNA [81,95]. In contrast, the exosomal microRNA content is similar to that in the original tumor, thus peaking researchers’ interests in the use of exosomal microRNA profiles for cancer diagnostics [12]. However, an abundance of certain microRNAs that are not present or present at very low levels in the parental cells has recently been observed [101,102]. These results suggest that certain microRNAs may be preferentially secreted. However, the mechanisms for selective packaging and release of exosomal microRNAs are currently unknown, and whether these microRNAs may serve as reliable markers of disease is yet to be determined.

On the contrary Hannafon et al. found that microRNA expression signatures were not significantly different between TD-exosomes and tumor cells, with the exception of miR-1246, suggesting that these circulating TD-exosome microRNAs could be utilized as a surrogate for biopsymicroRNA profiling [12]. In addition, a database called miRandola has been created to catalog all extracellular circulating microRNAs and currently contains 2312 entries with 581 unique mature microRNAs identified in circulation from 21 different types of samples [103].

Conclusion and Future Directions

Exosomes play a very important role in health as well as disease. Tumor derived exosomes with their anti or pro-tumorigenic properties suppress or promote cancer development through modulation of intercellular communication within the tumor microenvironment. Further research related to exosome secretion and identification may allow the development of novel diagnostic, preventive and therapeutic approaches. Possible creation of synthetic exosomes and utilization of exosome mediated drug delivery targeting specific cancer cells may be future possibilities.

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