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Table of Contents
REVIEW
Year : 2018  |  Volume : 1  |  Issue : 5  |  Page : 159-167

Advances in exosome-related biomarkers for glioblastoma: Basic research and clinical application


1 Department of Pathology, Peking University Third Hospital, Peking University School of Basic Medical Science, Peking University Health Science Center, Beijing, China
2 Department of Neurosurgery, Peking University Third Hospital, Peking University School of Basic Medical Science, Peking University Health Science Center, Beijing, China
3 Department of Pathology, Tianjin Huan Hu Hospital, Nankai University, Tianjin, China
4 Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

Date of Web Publication25-Oct-2018

Correspondence Address:
Dr. Qing Chang
Department of Pathology, Peking University Third Hospital, Peking University School of Basic Medical Science, Peking University Health Science Center, Xue Yuan Road 38#, Beijing 100191
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_35_18

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  Abstract 

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The median survival rate of GBM patients is approximately 14 months and tumor recurrence is almost inevitable. With the increased use of immunotherapy, immune response and edema found on posttreatment magnetic resonance imaging (MRI) may be misinterpreted as tumor progression. Distinguishing the true radiographic progression from pseudo-progression by MRI is often difficult. Peripheral biomarkers are needed to identify the true tumor recurrence and evaluate therapy response. Exosomes isolated from both blood and cerebrospinal fluid are cargo containers utilized by eukaryotic cells to exchange biomolecules such as proteins, mRNA, and microRNA (miRNA). These biomolecules participate in cell-cell communication, cell migration, angiogenesis, and tumor growth. Isolation of RNA (including miRNA) from exosomes can yield a greater concentration compared with circulating mRNA directly taken from body fluid as molecules within exosomes are not degraded by nucleases and proteases. Not only are exosomes a novel approach to biomarker detection, but they may also provide potential therapeutic interventional targets. In addition, exosomes are critical in miRNA replacement therapy as they can act as a carrier for anticancer drug delivery. This review focuses on the advances in basic research of exosome-related potential biomarkers and discusses their potential application in the diagnosis, prognosis, and treatment of GBM.

Keywords: Biomarker, clinical application, exosome, glioblastoma, tumor microenvironment


How to cite this article:
Jiang Y, Qian J, Yang J, Yan X, Xue X, Chang Q. Advances in exosome-related biomarkers for glioblastoma: Basic research and clinical application. Glioma 2018;1:159-67

How to cite this URL:
Jiang Y, Qian J, Yang J, Yan X, Xue X, Chang Q. Advances in exosome-related biomarkers for glioblastoma: Basic research and clinical application. Glioma [serial online] 2018 [cited 2022 Dec 7];1:159-67. Available from: http://www.jglioma.com/text.asp?2018/1/5/159/244193

Yuzhen Jiang and Jiaying Qian contributed equally to this work.



  Introduction Top


Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults.[1] Despite surgical resection with subsequent radio-chemotherapy, the median survival is approximately 14 months.[2] GBM recurrence is almost inevitable, and therefore monitoring by magnetic resonance imaging (MRI) must be done bimonthly.[3] However, distinguishing the true radiographic progression from pseudo-progression by MRI is often difficult; some studies suggest that pseudo-progression rates are close to 20%.[4] The increased use of immunotherapy also confounds posttreatment monitoring; immune response and edema seen on MRI can be misinterpreted as tumor progression.[3] All of the aforementioned challenges call for an improvement in the methodology for therapy response evaluation. We present the use of peripheral biomarkers to help identify early tumor recurrence.

Circulating biomarkers in conjunction with MRI can be used to distinguish pseudo-progression from true tumor progression. Proteins, DNA, and RNA, which are secreted by tumor cells (TCs) or by the tumor microenvironment (TME) due to active secretion or cell death,[5] can be detected in blood, urine, and cerebrospinal fluid (CSF) and studied.[6],[7],[8],[9] These pieces of tumor nucleic acids are called cell-free circulating tumor DNA (ctDNA) and circulating microRNA (miRNA).[10] However, both proteins and ctDNA are at risk of being degraded by enzymes in the plasma; therefore, identifying more stable biomarkers is desirable.

Extracellular vesicles (EVs) are nanometer-sized membrane-enclosed particles that are released from the fusion of an endosome (intracellular membrane-bound compartment) with exosomes (plasma membrane) or via microvesicles (MVs) directly from the cell membrane.[11] EVs are vehicles which allow communication between the TC and its microenvironment.[12],[13] EVs isolated from both blood and CSF are a rich source of tumor-derived molecules,[12],[13],[14],[15],[16] containing DNA, mRNA, miRNA, proteins, lipids, and metabolites; these molecules can be identified because components within EVs are not degraded by nucleases and proteases.[17] A greater yield of RNA (including miRNA) can be isolated from EVs compared with circulating mRNA directly taken from body fluid, rendering it an advantageous approach.[18]


  Characteristics of Extracellular Vesicles Top


EVs need to fuse with target cell membranes, either directly with the plasma membrane or with the endosomal membrane after endocytic uptake. MVs are larger vesicles (>200 nm in diameter) which arise from outward budding of the plasma membrane. This process may be related to a mode of purging damaged membrane regions from the cell in response to a sublethal complement attack and is considered a form of debris associated with cellular damage.[19] Exosomes correspond to the intraluminal vesicles of endosomal MV bodies (MVBs) that fuse with the cell surface in an exocytic manner. The role of the endosomal sorting complex required for transport (ESCRT) machinery in this process is well studied.[20],[21] ESCRTs consist of approximately twenty proteins that assemble into four complexes (ESCRT-0, -I, -II, and -III) with associated proteins (VPS4, VTA1, and ALIX) which are conserved from yeast to mammals.[22],[23] The ESCRT-0 complex recognizes and sequesters ubiquitylated proteins in the endosomal membrane, whereas ESCRT-I and -II complexes appear to be responsible for membrane deformation into buds with sequestered cargo, and ESCRT-III components subsequently drive vesicle scission.[24],[25],[26],[27] In addition, some studies have provided evidence that some exosomal proteins are released in an ESCRT-independent manner, such as an alternative pathway for sorting cargo into multivesicular endosomes, which seems to depend on raft-based microdomains for the lateral segregation of cargo within the endosomal membrane.[28],[29] Endocytosis appears to be the primary method of entry by exosomes, with five types of endocytic mechanisms including clathrin-dependent, caveolin-dependent, micropinocytosis, phagocytosis, and lipid raft-mediated uptake [Figure 1]. These differences reflect the heterogeneity in both exosome populations and cell types being studied. It is possible that a population of EVs can simultaneously trigger a number of different gateways into a cell, with primary points of entry dependent on the cell type and EV constituents.[30],[31],[32]
Figure 1: Mechanisms of biogenesis, secretion, and uptake of exosomes by eukaryotic cells. Exosomes are formed as ILVs by budding into early endosomes and MVBs. Several molecules are involved in the biogenesis of ILVs, such as ESCRT machinery consisting of four complexes. The fate of MVBs is fusion with the plasma membrane, which allows the release of their content to the extracellular milieu. Other types of EVs bud directly from the plasma membrane and are often called MV. Exosomes have been shown to be internalized by cells through endocytosis and cell membrane fusion. Intraluminal exosomes may fuse with the endosomal-limiting membrane following endocytosis to elicit a phenotypic response. ILVs: Intraluminal vesicles, MVBs: Multivesicle bodies; ESCRT: Endosomal sorting complex required for transport, EV: Extracellular vesicles, MV: Microvesicles

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Exosome vesicles are generally smaller (30–150 nm diameter)[33] and have a characteristic density of 1.1–1.2 g/mL.[34] They can have a characteristic cup-shaped morphology or are round as observed by transmission and cryo-electron microscopy. These vesicles can be found in many fluids within mammalian organisms including blood, urine, and ascitic fluid, as well as in the medium of cell culture.[35] Exosomes were originally considered to assist in cellular waste disposal.[33] However, recent data support the idea that exosomes are actually cargo containers utilized by eukaryotic cells to exchange biomolecules such as proteins, mRNA, and miRNA, facilitating cell-cell communication, cell migration, angiogenesis, and tumor growth.[36]

While all cells can produce exosomes, tumor-derived exosomes (TEX) appear to have properties distinct from exosomes secreted by normal cells and are strongly immunosuppressive.[37],[38] TEX can deliver intercellular signals or transfer bioactive materials to recipient cells, thus altering the cellular characteristics of these cells.[37],[38],[39] Because of these properties, TEX have received increasing attention as potential clinical biomarkers.


  Methods for Isolation and Quantification of Tumor-Related Exosomes Top


There are efficient methods for obtaining high yields of pure exosomes from cell culture supernatant and complex biological fluids such as plasma. Ultracentrifugation, ultrafiltration, OptiPrep™ density gradient purification, and immunoprecipitation (IP) have all proven to be effective methods for exosome separation. Among these methods, ultracentrifugation is the most widely applied and has long been considered the gold standard for isolation of relatively homogeneous-sized populations of exosomes.[40],[41],[42] However, the specificity for plasma exosome purification is limited. The steps which are taken for differential centrifugation also have an impact on the input to density gradient purification, a problem that may bias subsequent analysis and this problem is avoidable with ultrafiltration. Modern ultrafiltration devices provide a more rapid and higher yield of exosomes compared to ultracentrifugation.[43] IP enables preparation of highly enriched exosomes with greater specificity compared to differential centrifugation and density gradient isolation methods. However, due to the availability of exosome membrane markers, the use of the density-based separation method provides significant advantages for exosome isolation.[44]

There are also some new technologies for the isolation of exosome including two-stage microfluidic platform (ExoPCD-chip), which integrates on-chip isolation and in situ electrochemical analysis of exosomes from serum. To promote exosomes capture efficiency, an improved staggered Y-shaped micropillars mixing pattern was designed to create anisotropic flow without any surface modification.[45]

Some novel methods for exosome detection have been reported recently, for example, surface plasmon resonance of ordered nanopore arrays, which was applied to detect TEX.[46] A novel system introduces ectopic or CRISPR/Cas9-mediated knock-in luciferase-fusion exosome markers such as CD63 for quantifying exosomes. This luciferase-based method makes it possible to measure exosomes secreted into the culture medium in a high-throughput manner.[47] ExoCounter is another novel device to determine the exact number of exosomes in the sera of patients with various types of cancer without any enrichment procedures.[48]


  Clinical Applications for Exosome Biomarkers for Glioblastoma Multiforme Top


Exosomes isolated from both blood and CSF are cargo containers utilized by eukaryotic cells to exchange biomolecules such as DNA, mRNA, protein, and noncoding RNA[Table 1].
Table 1: Clinical applications for exosome biomarkers for glioblastoma multiforme

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These biomolecules participate in cell-cell communication, cell migration, angiogenesis, and tumor growth.

DNA

Recently, DNA sequences from peripheral blood EVs isolated from patients with brain tumors were reported to successfully detect the presence of specific molecular alterations, for example, IDH1G395A. In addition, NANOGP8, which has been shown with increased expression levels in glioblastoma cancer stem cells, was found in exosomes secreted by cancer cells and has been regarded as a potential biomarker for higher tumor occurrence.[49],[51] The utility of tumor-derived DNA within circulating EVs as potential biomarkers can potentially improve diagnosis and prognosis for gliomas.[50]

mRNA and protein

Exosomes may carry characteristic glioblastoma protein markers such as the epidermal growth factor receptor (EGFR), the EGFR variant III, and IDH1-R132H.[52] DNM3 and p65 are upregulated in both mRNA and protein levels in GBM xenograft exosomes, while p53 is downregulated at the same time, and this suggests that expression of DNM3, p65, and p53 may be utilized as clinical markers for monitoring the diagnosis and treatment of GBM patients.[53] At the same time, expression levels of 14 GBM-derived EV proteins (PSMD2, ACTR3, APP, ANXA1, CALR, CTSD, IGF2R, extracellular matrix [ECM]1, GAPDH, IPO5, ITGB1, MVP, PSAP, and PDCD6IP) were significantly correlated with cell invasion. Several proteins, such as PDCD6IP and ACTR3, interact with molecules responsible for regulating invadopodia formation, which is associated with more aggressive disease and is a site of EV release.[63] Recently, a positive correlation between polymerase I and transcript release factor (PTRF) expression in serum exosomes and tumor grade was found, suggesting that serum exosomal PTRF serves as a promising biomarker and a potential therapeutic target.[54]

Noncoding RNA

microRNA

miRNAs are small noncoding RNAs that regulate the translation of mRNAs and have been found to function accordingly in different types of cancer.[64] These miRNAs may play important roles in multiple processes associated with cancer initiation and progression by functioning as either oncogenes or tumor suppressors.[65],[66],[67],[68] The recent identification of exosomal miRNAs in the serum of cancer patients has opened up new and attractive possibilities for the development of noninvasive diagnostic/prognostic biomarkers.[69] Some miRNAs which can serve as potential GBM biomarkers are described below.

miR-320 and miR-574-3p

Polymerase chain reaction (PCR)-based TaqMan low-density arrays followed by individual quantitative reverse transcriptase PCR were used to test the differences in miRNA expression levels of serum MVs in 25 GBM patients and healthy controls. miR-320/miR-574-3p/RNU6-1 combined signatures found in exosomes isolated from the serum of GBM patients could serve as diagnostic biomarkers, and they can help distinguish GBM patients from healthy controls.[55],[56],[57]

miR-301a

Serum exosomal samples were collected from 60 patients with histologically proven glioma prior to surgery and 43 control samples were collected from healthy volunteers. Serum exosomal miR-301a levels may reflect the cancer-bearing status and pathologic changes in glioma patients. Expression of serum exosomal miR-301a may serve as a novel biomarker for glioma diagnosis and as a prognostic factor for advanced grade disease. It may activate the AKT and FAK signaling pathways by downregulating PTEN.[59]

miR-151a

Based on data from 156 high-grade glioma patients, it had been discovered that the downregulation of miR-151a correlates with a poor prognosis in GBM patients receiving temozolomide (TMZ) therapy, whereas restored miR-151a expression sensitized TMZ-resistant GBM cells. This result was restricted to exosomal miR-151a in CSF, while no difference was detected in serum.[60]

miR-148a

A study recruiting 30 GBM patients and 30 healthy volunteers showed that exosomal miR-148a significantly increased in GBM patients' serum compared with that of controls. They found that exosomal miR-148a may promote cancer cell proliferation and metastasis via targeting CADM1 to activate signal transducer and activator of the transcription 3 (STAT3) pathway, suggesting its role as a predictor in GBM patients.[58]

miR-21

Various studies indicated that miR-21 could effect on a variety of molecular pathways such as IGF-binding protein-3, RECK, and TIMP3, which could be used as diagnostic and therapeutic biomarkers for GBM patients. A meta-analysis based on 81 studies showed that exosomal miR-21 is a potential biomarker, and CSF-based miR-21 detection had the highest diagnostic and prognosis efficiency.[61]

Long noncoding RNA

Recent studies suggest that long noncoding RNAs (lncRNAs) can be utilized as peripheral biomarkers in several cancers due to their stable secondary structures. lncRNAs are 200 nucleotide or greater in length and do not encode for any protein.[70] lncRNAs act as an interface between DNA and specific chromatin remodeling activities. They are transcribed from intergenic regions, translocated to different genomic loci (transaction), and regulate the expression of oncogenes and tumor suppressor genes in tissue- and cell-specific manners.[71]

HOTAIR is an example of lncRNA in GBM. HOTAIR expression was measured in serum from 43 GBM patients and 40 controls using quantitative real-time PCR. HOTAIR levels in serum samples from GBM patients were significantly higher than that in the corresponding controls. HOTAIR expression was significantly correlated with high-grade brain tumors. In addition, Pearson's correlation analysis indicated a medium correlation of serum HOTAIR levels and corresponding tumor HOTAIR levels. As a result, serum HOTAIR can be used as a prognostic and diagnostic biomarker for GBM.[62]

Circular RNA

Circular RNAs (circRNAs) have recently been established as a comprehensive class of RNAs generated by nonlinear back-splicing.[72] circRNAs are characterized by covalently joined 5′- and 3′-ends. This peculiarity renders them intrinsically resistant to degradation mediated by exonucleases, and thus they are more stable than their linear isoform counterparts, both intra- and extra-cellularly.[73] circRNAs show species, cell type, and developmental stage-specific expression patterns in animals. These molecules are highly enriched in neural tissues[74] and are detectable in several biological fluids, and are therefore useful as noninvasive biomarkers.[75]


  Exosome and Tumor Microenvironment Top


TME is the cellular environment in which the tumor exists.[76] Subtle changes in the cellular microenvironment may stimulate malignant transformation of cells, and the cellular microenvironment has been implicated in tumor initiation, proliferation, and metastasis. Cell-to-cell, or cell-to-microenvironment communication, in a tumor may be achieved by direct contact or over longer distances by secreted molecules and secreted membranous vesicles.[42] Apart from the TCs, the TME includes surrounding blood vessels, ECM, other nonmalignant cells, and signaling molecules.[77] These nonmalignant cells include stromal cells, fibroblasts, immune cells (such as T-lymphocytes, B-lymphocytes, natural killer cells and natural killer T-cells, and tumor-associated macrophages [TAMs]), as well as pericytes and sometimes adipocytes. In addition to the stromal cells, fibroblasts, and immune cells which are noted above, there are many unique tissue-resident cell types located in the central nervous system including astrocytes, neurons, and microglia.

Extracellular vesicles and astrocytes

Exosomes released by GBM have a special role in glial cells in the TME. Researchers suggest that GBM EVs are capable of modifying their local environment by enhancing cytokine production of normal human astrocytes (NHAs) and promoting NHA migration. GBM EVs may drive molecular changes in cancer signaling pathways in NHAs, thereby enhancing NHA growth in a semi-solid matrix, which is indicative of cellular transformation.[78]

Extracellular vesicles and microglia

Macrophages which constitute 20% of all myeloid cells that infiltrate glioblastoma are designated as M1 and M2 phenotypes. M1 macrophages are capable of phagocytosis, antigen presentation, and inflammation promotion. In contrast, M2 macrophages lose their pro-inflammatory and antitumor immune functionalities; they have also been shown to increase tumor invasion and promote angiogenesis.[79] It was recently shown that glioblastoma-infiltrating monocyte cells are aligned in a continuum from a nonpolarized M0 macrophage to an M2 phenotype. These cells typically engage in significant bidirectional crosstalk with TCs in the brain; brain TCs release cytokines and chemo-attractants to recruit TAMs to the microenvironment, and TAMs in turn supply pro-tumorigenic, pro-survival factors.

TEX may modulate the immune system and are immunosuppressive.[80] GBM-derived exosomes secrete specific factors including members of the STAT3 pathway[81] and transforming growth factor-β (TGF-β), which are potent modulators of the GBM-associated immunosuppressive microenvironment.[80] PD-L1 has been shown to be induced in macrophages by STAT3.[82] The upregulation of PD-L1 in exosome-treated monocytes correlates with increased phosphorylation of STAT3.[71] Recently, another research group showed that binding of PD1 with PD-L1 on EVs secreted by GBM leads to suppression of antitumor immunity via inhibition of T-cell function.[83] Interestingly, according to their study, only EVs from PD-L1high glioblastoma cells function in this manner, whereas PD-L1low glioblastoma cells must be stimulated by interferon-γ (IFN-γ) in order to express observable levels of PD-L1-dependent T-cell inhibition [Figure 2].
Figure 2: EVs derived from GBM cells modulate the immune system by upregulating PD-L1 in macrophages and downregulating the activation of T-cells. Glioma-derived exosomes secreted GBM-released factors, including members of STAT3 pathway and TGF-β. PD-L1 has been shown to be induced in macrophages by pSTAT3 in GSC exosome-treated monocytes. Binding of PD1 with PD-L1 on EVs, which is secreted by GBMs, leads to suppression of antitumor immunity via inhibition of T-cell function. Only EVs from PD-L1high glioblastoma cells function constitutively in this manner, whereas PD-L1low glioblastoma cells must be stimulated by IFN-γ in order to express observable levels of PD-L1-dependent T-cell inhibition. STAT3: Signal transducer and activator of the transcription 3, pSTAT3: Phosphorylated STAT3, GSC: Glioma stem cell, EVs: Extracellular vesicles, IFN-γ: Interferon-γ, GBM: Glioblastoma multiforme, TGF-β: Transforming growth factor-β

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Extracellular vesicles and angiogenesis

Tumor vasculature is abnormal in both structure and function, exhibiting aberrant organization and poor structural integrity.[84] As a consequence of this leakiness, gliomas exhibit deregulated perfusion, high interstitial fluid pressure, edema, extensive hypoxia, and necrosis.[85] Tumor-released EV cargo may play a role in tumor-induced angiogenesis and vascular permeability in GBM.[86] Molecules derived from EVs, such as pro-angiogenic (vascular endothelial growth factor [VEGF] and interleukin [IL]-8) and pro-inflammatory mediators (IL-6), have been found to be related to tumor growth in a noncell autonomous manner and stimulation of cultured endothelial cells and microglia [Figure 3].[87],[88] EV-harbored VEGF-A targets brain endothelial cells and may impact their ability to form new vessels.[86]
Figure 3: EVs derived from GBM cells modulate angiogenesis, especially under hypoxic conditions. The contents of GBM-derived EVs, such as pro-angiogenic (VEGF and IL-8) and pro-inflammatory mediators (IL-6), have been found to be related to intriguing biological activities in tumor growth in a noncell autonomous manner, including stimulating cultured endothelial cells. Exosomes derived from GBM cells grown under hypoxic conditions are potent inducers of angiogenesis through phenotypic modulation of endothelial cells by secreting several potent growth factors and cytokines, such as CXCL1, IL-6, and IL-8 and stimulating pericyte PI3K/AKT signaling activation and migration. A significantly increased content of TF was identified in glioblastoma cell-derived EVs under hypoxic conditions, which induces angiogenesis. EVs: Extracellular vesicles, GBM: Glioblastoma multiforme, VEGF: Vascular endothelial growth factor, IL: Interleukin, TF: Tissue factor

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Tumor vasculature is always inadequate to meet the demands of the growing tumor mass, and this leads to the presence of hypoxic and acidotic regions within the tumor. When a quiescent blood vessel senses an angiogenic signal from the hypoxic conditions in the TME, angiogenesis is stimulated and heterogeneous new vessels with chaotic branching structures sprout from the existing vasculature.[89] Oxygen concentration is also an important factor in the tumor growth process. Compared with GBM cells grown in normoxic conditions, exosomes derived from GBM cells grown under hypoxic conditions are potent inducers of angiogenesis through phenotypic modulation of endothelial cells, and the latter secrete several potent growth factors and cytokines, such as CXCL1, IL-6, IL-8, etc., and stimulate pericyte PI3K/AKT signaling activation and migration. Notably, VEGF and other growth factors secreted via EVs can also induce hypoxia-dependent intercellular signaling, which is the main inducer of necrosis and blood–brain barrier (BBB) alteration.[90] It has also been reported that there is a significantly increased content of tissue factor (TF) in glioblastoma cell-derived EVs under hypoxic conditions,[91] and the former induces angiogenesis. Notably, emission of TF-containing EVs was suggested as a possible mechanism which results in the procoagulant effects associated with cancer [Figure 3].[37]


  Exosomes' Potential Therapeutic Carriers or Targets of Glioblastoma Multiforme Top


Exosome as a carrier for anticancer drugs

Recently, an increasing number of studies have demonstrated that directly targeting primary tumor masses or even metastatic lesions by genetically modified mesenchymal stem cells (MSCs) with therapeutic agents holds promise as a therapeutic approach.[92] Wharton's jelly (WJ)-MSCs can easily be obtained in large quantities with a high proliferation rate and have stem cell-like characteristics.[93] WJ-MSCs can effectively deliver exogenous miR-124 to GBM cells, impact cell migration, and reduce proliferation. Therefore, the use of exogenous miRNAs delivered by WJ-MSCs may provide a novel approach for miRNA replacement therapy for GBM cancers or other types of tumor.[94]

TMZ is the first-line chemotherapy agent for the treatment of GBM and has improved the prognosis of GBM patients significantly.[95] However, the development of TMZ resistance during the therapy period is common among GBM patients, which is one of the main causes of treatment failure. TMZ treatment leads to the enrichment of exosomes dedicated to cell adhesion processes and increases the release of pro-tumoral information.[96] Recently, a research team investigated the role of miR-9 in the development of resistance toward TMZ in GBM cells. The delivery of anti-miR-9 by MSC-derived exosome to the resistant GBM cells reversed the expression of multidrug transporters and sensitized the GBM cells to TMZ; this was demonstrated by increased cell death and caspase activity, indicating a potential role of MSCs in the functional delivery of synthetic anti-miR-9 to reverse the chemoresistance of GBM cells.[97]

In addition to the choice of donor cell type for vesicle production, drug loading can be more efficient by electroporation where small pores are created in the membrane of the EVs, hereby allowing for free diffusion of the drug compound into the interior of the vesicle. A group investigated the utility of adipose-derived stem cells (ASCs) as an efficient exosome donor cell type, with a particular focus on the treatment of GBM. They found that electroporation of ASC exosomes mediates aggregation of the exosomes. In order to address this issue, they have successfully optimized the use of a trehalose-containing buffer system as a way of maintaining the structural integrity of the exosomes.[98]

Exosome as a therapeutic target

Exosomes are carriers of pro-tumorigenic factors and many fusion genes with strong driver mutations participate in GBM tumorigenesis. PTPRZ1-MET (ZM) fusion in GBM cells promotes TC proliferation, epithelial–mesenchymal transition (EMT), migration, invasion, neurosphere formation, and angiogenesis in vitro and in vivo. Hence, ZM exosomes containing MET and p-MET are not only be a novel approach to biomarker detection, but may also provide therapeutic interventional targets in aggressive GBM.[99]

Exosomes also contain some regulatory factors that affect the secretion of exosomes, which may become potential targets for the treatment of GBM. PTRF, also known as Cavin1, has previously been described as a critical factor in caveola formation, one of the four endocytic mechanisms. PTRF is a tumor promoter during gliomagenesis.[55] A positive correlation between tumor grade and PTRF expression was identified in both tumor tissues and exosomes isolated from the blood of glioma patients. Furthermore, exosomes induced by PTRF regulate intercellular communication and exert a malignant effect. PTRF expression in exosomes is decreased after surgery. Thus, PTRF is a promising biomarker in both tumor samples and serum exosomes as it facilitates the detection of glioma and potentially serves as a therapeutic target for glioblastoma.[55]

LRRC4 is a member of the LRR superfamily and is decreased in WHO Grades II and III astrocytomas and is consistently absent in GBM.[100] A research team demonstrated that LRRC4 promotes the expansion of CD4+ CCR4+ T-cells and enhances the chemotaxis of CD4+ CCR4+ T-cells in the GBM microenvironment by promoting cytokine secretion and affecting GBM cell-derived exosomes (containing PD-1 without cytokine). miR-101 – as a potential novel therapeutic agent for GBM – modulated tumor-infiltrating lymphocyte accumulation by reversing LRRC4 promoter hypermethylation and induced LRRC4 re-expression in GBM cells. In fact, their study reveals a novel mechanism underlying the GBM microenvironment and provides a new therapeutic strategy using the re-expression of LRRC4 in GBM cells to create a permissive intratumoral environment.[101]

Exosomes released by GBM have significance for the efficacy of GBM vaccine. Recent research showed that co-delivery of TEX with α-galactosylceramide (α-GalCer) in a dendritic cell-based vaccine is effective in improving the TME by balancing the release of immunoinhibitory and immunostimulatory factors. TEX show a stronger antitumor immune effect than tumor lysate. When combined with invariant natural killer T-cells that have direct antitumor effects as an effective cellular adjuvant activated by α-GalCer, exosomes can synergistically break immune tolerance and induce a strong antigen-specific cytotoxic T-lymphocyte response against GBM cells and are highly effective in immunotherapy for GBM.[102]


  Outlook Top


Specific oncogenic pathways may impact EV-mediated intercellular connectivity in several different ways which are yet have not been clarified. Such mechanisms may include effects on EV biogenesis, uptake and emission, as well as the incorporation of mutant molecules into the EV cargo.[87],[103] TME, cellular differentiation programs (stemness, EMT), therapeutic stress, and other factors may clearly modify these effects.[104],[105]

Not only are EVs permeable to the BBB and thus found in abundance when entering the circulating plasma, their special intravesicle composition can also now be used as brain tumor biomarkers. These biomarkers will help with diagnosis, prognosis, and may contribute to a new route for drug delivery. Identification of additional mechanisms by which EVs modulate TCs may lead to further study of their clinical application in glioblastoma.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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