Review
Extracellular vesicles as modulators of the cancer microenvironment

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Abstract

The tumour microenvironment is a highly complex and dynamic tissue. It comprises not only neoplastic cells, but also other resident cells within the milieu such as stroma and vascular cells in addition to a variable cellular infiltrate from the periphery. A host of soluble factors such as growth factors, chemokines, eicosanoids soluble metabolites and extracellular matrix components have been extensively documented as factors which modulate this environment. However, in recent years there has also been growing interests in the potential roles of extracellular vesicles (EV) in many of the processes governing the nature of cancerous tissue. In this brief review, we have assembled evidence describing several distinct functions for extracellular vesicles in modulating the microenvironment with examples that include immune evasion, angiogenesis and stromal activation. Whilst there remains a great deal to be learnt about the interplay between vesicles and the cancerous environment, it is becoming clear that vesicle-mediated communication has a major influence on key aspects of cancer growth and progression. We conclude that the design of future therapeutics should acknowledge the existence and roles of extracellular vesicles, and seriously consider strategies for circumventing their effects in vivo.

Introduction

Like most cell types, neoplastic cells release small lipid-bounded vesicles into the extracellular space, but they may do so extensively compared to their non-neoplastic counterparts [1]. Genotoxic, hypoxic, metabolic and other forms of cellular stress [2], [3], [4] lead to heightened levels of vesicle secretion, together with alterations in vesicle-cargo molecules. In cancer therefore, where such conditions are particularly rife, the vesicle secretion pathway appears to be a major feature.

Cells can release different types of vesicles, which have been difficult to categorise in a definitive manner [5]. There are fundamentally two principal vesicle types under discussion. Microvesicles, which are considered large (>200 nm diameter) and dense, and arise from outward budding of the plasma membrane. Traditionally this process may have been related to a mode of purging regions of damaged membrane from the cell in response to sub-lethal complement attack for example, and is considered by many therefore as a form of debris associated with cellular damage [6]. Exosome vesicles are generally smaller (30–150 nm diameter) [7], have a characteristic density of 1.1–1.2 g/ml [8], and are manufactured within multivesicular endosomes of the late endocytic tract [8]. Small (∼100 nm) plasma-membrane derived vesicles have also been reported [9]. Categorising vesicles based on their size or subcellular origin therefore remains problematic. Furthermore defining them on the basis of molecular cargo is not straightforward due to the likely overlap between different types of vesicles. Methods such as nano-particle tracking that facilitate the counting of small particulate material invariably demonstrate the predominance of the smaller types of vesicles present in biological fluids or in cell-conditioned media [10]. Whether or not one type of vesicle is biologically more significant than another is simply unclear from our current understanding, hence, the term extracellular vesicles (EV) has been adopted by the field as these questions continue to be investigated.

The transmission of EV from cancer cells to other cell types has been the subject of intensive studies in recent years. It is a process which offers a sophisticated form of cellular communication through the delivery of highly complex and dynamic cargo, packaged within a readily captured vesicle. Recipient cells usually uptake EV through endocytic processes [11], and/or for microvesicles through membrane fusion events [12], [13]. Cells receive not only classical receptor–ligand interactions from EV, but do so in the context of co-delivered factors including proteins, lipids and RNA. Hence the biological effects of EV delivery can be profound, as well as difficult to study and characterise. Nevertheless there are many well characterised examples of EV functions in cancer, many of which may indeed become viewed as a coordinated set of mechanisms that act to promote disease.

Section snippets

Immune activating EV

A key discovery by Raposo et al. described the first biological effect of EV interaction with a recipient cell [8]. The study showed the capacity for EV to mimic the function of the parent cell, in this case B-lymphocytes, by stimulating T cell proliferation in an antigen and MHC-restricted manner. Hence the concept of EV-based vaccine therapeutics in cancer was born, and several studies followed demonstrating the potential for EV principally of dendritic cell origin to prime T cell responses

Delivery of angiogenic proteins by EV

Among the major hallmarks of cancer is the capacity for growing tumours to generate their own vasculature; an essential element in progressive disease [50], [51], [52]. It is increasingly clear that cancer derived EV can exert complex effects on endothelial cells, their progenitors and on supporting cells, contributing to vessel formation within tumours (Fig. 2).

The expression of tetraspanin proteins is a characteristic feature of exosomes, where this complex family of proteins is often very

Cancer associated stroma and EV

Fibroblasts are the predominant cellular component of interstitial connective tissue (or stroma) and they play a matrix homeostasis function in health. This compartment however undergoes significant alterations in response to neoplasia in adjacent tissue, akin to a non-resolving wound healing-like response [72]. Cancer associated fibroblasts (CAFs) almost invariably accompany tumourigenesis, and are associated with differentiation towards a myofibroblastic phenotype [73]. Such cells are

Cancer EV and metastasis

An important paradigm in the complexities of metastatic tumour spread is that tissues receive long distance signals from primary tumour sites in order to prepare for the eventual landing and seeding by tumour cells. This “pre-metastatic niche” formation is an aspect of considerable interest to EV researchers as cancer vesicles which are known to be present in the circulation may be an ideal modality for long-range signal dissemination.

Among the earliest reports of EV playing a role in this

Conclusions and future perspectives

As the EV-research field continues to mature, the evidence for the important roles of vesicles in microenvironment modulation is compelling. EV clearly exert multiple, and highly complex effects involving many distinct molecular mediators and pathways. There is currently enormous enthusiasm and research activity involving profiling the RNA content of EV, but direct evidence for a causal relationship between RNA-delivery by EV and microenvironmental alterations is not yet fully convincing. Given

Acknowledgements

The Cardiff Exosome group is funded principally by a Programme Grant from Cancer Research Wales, awarded to AC, and also by the Life Science Research Network Wales, an initiative funded through the Welsh Government's Ser Cymru programme (Studentship (to VY), by the Movember Global Action Plan-1 (AC), by Prostate Cancer UK (grants G2012-03 and CDF13-001) (AC & JW), and by the British Lung Foundation (grant APG13-8) (AC)).

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