Review article
The emergent role of exosomes in glioma

https://doi.org/10.1016/j.jocn.2016.09.021Get rights and content

Highlights

  • A systematic review on the emerging role of exosomes in glioma.

  • Currently known composition of exosomes is outlined.

  • The potential role of exosomes as diagnostic biomarkers or markers of chemotherapeutic resistance is presented.

  • Exosomal based therapeutic approaches are also discussed.

Abstract

Extracellular vesicles (EVs) are known mediators of intercellular communication for both normal and tumour cells. With the capability to transfer nucleic acids, proteins and lipids, EVs are able to influence numerous functional and pathological aspects of both donor and recipient cells. The tumour microenvironment possesses a high level of complex heterogeneity, particularly within the most prominent brain malignancy, glioblastoma multiforme (GBM). This complexity relies on a network-based communication between many different components of the local niche, including the various cell types, stroma, blood vessels, secreted factors and surrounding matrix. Exosomes are one type of EV which facilitates this intercellular communication and cross-talk within the tumour microenvironment. Exosomes secreted by tumour cells are increasingly recognized in a number of processes underlying tumour progression including facilitating the transport of receptors, signalling molecules, oncogenic genes and miRNA. They are emerging as a key component in the biogenesis of glioma, in addition to contributing to the modification of the surrounding microenvironment to support tumour progression. In this review we describe advancements in the understanding of the biology of exosomes, as well as their roles in tumour progression, as a tumour biomarker for tracking cancer progression, and as a potential therapeutic target/delivery system, with a contextual emphasis on GBM.

Introduction

Glioma tumours that arise from glia or glial precursor cells are the most prevalent brain tumour, with an estimated 23,000 new cases and 16,000 deaths in the USA in 2016 [1]. According to the CBTRUS Statistical report (2008–2012), gliomas account for over 32% of all central nervous system (CNS) tumours and approximately 80% of malignant primary CNS tumours [2]. The most prevalent form of glioma with the most dismal prognosis is the grade IV glioblastoma multiforme with an incidence rate of 3.2 per 100,000 population [2] and evidence suggesting that it is increasing every year [3].

With a median survival rate of only 14.6 months [4], GBM is the most intractable and lethal primary brain malignancy [5]. The customary treatment protocol usually involves surgery followed by post-operative fractionated radiation therapy and concomitant chemotherapy [4], [5]. However, with near universal recurrence, this approach provides only a degree of palliation [6], [7]. The invasive nature of GBM prevents total resection, making them surgically incurable. In 2005, a pivotal study was published showing that concurrent radiotherapy and temozolomide-based chemotherapy led to a modest 2.5 month increase in the dismal median survival of GBM patients and improvement in their health-related quality of life. This combinatorial treatment also led to a significant increase from 10% to 26% of patients who survived beyond two years [8]. The treatment, now referred to as the Stupp protocol, has been universally adopted as the standard of care for them [9]. Even alternative adjuvant therapies such as photodynamic therapy have only achieved similar median survival figures (14.8 months) as the Stupp treatment protocol for GBM patients [10], [11], [12].

GBM tumours are both morphologically and molecularly complex. Not only do they display properties indicative of diverse cellular phenotypes [13], [14], [15], [16], [17], they are also significantly heterogeneous at the inter-tumour and intra-tumour levels [18]. As a result, the classification and subsequent treatment of GBM are made considerably more difficult as a result of this heterogeneity [19]. Regional diversity observed in molecular pathways, cellular communication and tumour stem cell signalling may also contribute to the varied therapeutic response observed in GBM patients. Such diversity has driven the efforts in refining existing classification systems focus on the sub-typing of GBM by utilizing genomic and expression data [20], [21]. Categorization of GBM based on distinct gene sets and particular signalling pathways yields potential for more specific and targeted therapeutics [22], [23]. Further complicating the aspect involving the heterogeneous nature of GBM, single cell sequencing has recently identified that different regions within an individual GBM lesion may exhibit several subtype-specific signatures [24], [25]. With this taken into consideration, selection of particular sub-populations of GBM patients in the future could enable the design of personalized molecularly–targeted therapies for them [26], [27], [28].

Tumour cells possess the ability to communicate between the different compartments of the tumour microenvironment and ultimately influence neighboring cells. This effect can be varied with respect to the different subtypes of GBM, depending on the composition of the molecules they secrete. Mesenchymal cells have been shown to promote an invasive microenvironment by manipulating surrounding cells via the involvement of miRNA [29], [30]. The molecules which are secreted by tumour cells and are subsequently utilized for communicative purposes are often encapsulated in structures known as extracellular vesicles (EVs). EVs are small portions of organelle-free cytosol enclosed by a spherical lipid bilayer. EVs can be categorized further depending upon their site of origin and their size, which can range from 30 to 2000 nm. Vesicles that are derived from multi-vesicular bodies (MVBs) are referred to as exosomes, whilst those produced directly from the plasma membrane are known as microvesicles [31]. Cells can also shed contents into the microenvironment in moments of stress or cell death and this involves the process of blebbing by apoptotic bodies [31]. It has now become evident that exosomes are particularly important structures as they are involved in a variety of physiological processed including the intercellular exchange of proteins and RNA [32], [33], induction of angiogenesis [34] and immune regulation [35], [36], [37]. However, given the expanding and complex research field on EVs, this review will only focus on a brief overview of the current literature that has investigated the potential roles of exosomes in brain tumours.

Section snippets

Exosomal composition

Exosomes can be defined via a number of main morphological and physical characteristics. Firstly, they range in size between 40 and 120 nm in diameter, are of endocytic origin and sediment at approximately 100,000 g (sucrose density gradient of 1.13–1.19 g/ml) [38]. Morphologically they appear as spherical structures with a well-defined lipid bilayer when viewed with an electron microscope [37]. Contained within their aqueous core or in the lipid membrane, are various proteins, nucleic acids and

Inhibiting exosome biogenesis, uptake and secretion

It is evident that exosomes may play a role in a range of biological processes within the progression of GBM and therefore targeting exosome-mediated cellular interactions is an area of interest for therapeutics. Studies are revealing the mechanisms which are involved in the trafficking, targeting and secretion of exosomes, however, many aspects still remain unclear and additional research is required to strengthen the knowledge base in the field. Nonetheless, areas of potential exosomal

Conclusion

It is known that exosomes, along with other EVs are utilized for long distance communication by donor and acceptor cells for the delivery of numerous molecules and molecular messages. There is evidence to show that exosomes can be involved in the regulation of many tumour based processes and their response to immune-based and therapeutic agents. The exosomes secreted by tumour cells can be utilized in the process of tumour progression, but also in the modification of the surrounding

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