Microvesicles As Mediators of Intercellular Communication in Cancer—The Emerging Science of Cellular ‘Debris’

Semin Immunopathol (2011) 33:455–467 DOI 10.1007/s00281-011-0250-3 REVIEW Microvesicles as mediators of intercellular communication in cancer—the emerging science of cellular ‘debris’ Tae Hoon Lee & Esterina D’Asti & Nathalie Magnus & Khalid Al-Nedawi & Brian Meehan & Janusz Rak Received: 11 January 2011 /Accepted: 13 January 2011 /Published online: 12 February 2011 # Springer-Verlag 2011 Abstract Cancer cells emit a heterogeneous mixture of Ongoing studies explore the molecular mechanisms and vesicular, organelle-like structures (microvesicles, MVs) mediators of MV-based intercellular communication (cancer into their surroundings including blood and body fluids. vesiculome) with the hope of using this information as a MVs are generated via diverse biological mechanisms possible source of therapeutic targets and disease biomarkers triggered by pathways involved in oncogenic transforma- in cancer. tion, microenvironmental stimulation, cellular activation, stress, or death. Vesiculation events occur either at the Keywords Angiogenesis . Biomarker . Cancer . Exosomes . plasma membrane (ectosomes, shed vesicles) or within Intercellular communication . Microvesicles . Oncogenes endosomal structures (exosomes). MVs are increasingly recognized as mediators of intercellular communication due Abbreviations to their capacity to merge with and transfer a repertoire of MVs Microvesicles bioactive molecular content (cargo) to recipient cells. Such TF Tissue factor processes may occur both locally and systemically, con- EGFR Epidermal growth factor receptor tributing to the formation of microenvironmental fields and EGFRvIII Mutant EGFR (variant III) niches. The bioactive cargo of MVs may include growth GBM Glioblastoma multiforme factors and their receptors, proteases, adhesion molecules, IL-6 Interleukin-6 signalling molecules, as well as DNA, mRNA, and micro- IL-8 Interleukin-8 RNA (miRs) sequences. Tumour cells emit large quantities mRNA Messenger ribonucleic acid of MVs containing procoagulant, growth regulatory and PS Phosphatidylserine oncogenic cargo (oncosomes), which can be transferred RTK Receptor tyrosine kinase throughout the cancer cell population and to non- VEGF Vascular endothelial growth factor transformed stromal cells, endothelial cells and possibly to VEGFR-2 VEGF receptor 2 the inflammatory infiltrates (oncogenic field effect). These events likely impact tumour invasion, angiogenesis, metas- tasis, drug resistance, and cancer stem cell hierarchy. Modes of intercellular communication—the emerging Tae Hoon Lee and Esterina D'Asti equally contributed to this article. role of microvesicles This article is published as part of the Special Issue on Small Vesicles as Immune Modulators. In a multicellular organism, biological functions are executed T. H. Lee : E. D’Asti : N. Magnus : K. Al-Nedawi : B. Meehan : by complex assemblies of cells, the actions of which must be J. Rak (*) coordinated by intercellular communication. In this regard, Montreal Children’s Hospital Research Institute, the exchange of signals is usually ascribed to specific McGill University, molecules (soluble or immobilized) and their corresponding 4060 Ste Catherine West, Montreal, QC H3Z 2Z3, Canada cognate receptors. This exchange may entail a direct cell-to- e-mail: [email protected] cell contact (adhesion, juxtacrine interactions), or gradients 456 Semin Immunopathol (2011) 33:455–467 formed by soluble (paracrine) mediators, which may also exonucleotidase associated with glioma cells [15]; further- circulate in blood and body fluids and act in a regional or more, the groups of Johnstone [41]andStahl[17] systemic (endocrine) manner. Such information translates into established exosomes as a mechanism involved in the activation of intracellular signalling networks and changes in removal of spent transferrin receptors from differentiating the behaviour of individual cells and their populations [1, 2]. reticulocytes [6, 41]. Indeed, molecular pathways of cell–cell communication play Different biological circumstances under which formation an important role in development, health and disease of MVs (vesiculation) has been observed reflect the diversity including cancer [9, 86]. of their biogenesis, structure and function (Fig. 1). Thus, It is increasingly clear, however, that cells may also cellular activation, transformation, stress, or programmed communicate via supramolecular complex mechanisms cell death are associated with a different output and nature of involving the exchange of cellular fragments, membranes vesicular structures [9]. Indeed, it is clear that MVs are or specialized organelles. The latter could be vesicular heterogeneous, and this has led to the usage of multiple (microvesicles, MVs) [3, 13], tubular (nanotubes/TNTs) [9], names for their designation under different experimental or filopodial (cytoneme) [4] in nature depending on their settings [9, 18]. Some of the most frequently encountered biogenesis and whether they are separated or contiguous descriptors are MVs, microparticles, ectosomes, exosomes, with the emitting cell. The underlying process of the exosome-like vesicles, shed vesicles and most recently intercellular transmission of proteins, lipids or nucleic acids oncosomes [6, 18, 41]. Other names have also been used encapsulated in plasma membranes is often referred to as in various specific settings including argosomes, prominino- trogocytosis, or cellular synapse [5, 8]. Notably, this somes, P4 particles, prostasomes, and several others [6, 9, transfer entails ‘pre-programmed’ combinations of soluble 41]. To some extent, this diversity reflects the culture of or insoluble molecules, which are uniquely protected from different fields in which MVs have been studied, but also degradation and dispersion in the extracellular space [18]. substantial biological diversity of the underlying biological Of particular interest are mechanisms involving MVs, process. Indeed, MVs originate through at least three distinct spherical or cup-shaped membrane structures that originate mechanisms: (a) breakdown of dying cells into apoptotic from ‘donor’ cells and may travel considerable distances in bodies, (b) blebbing of the cellular plasma membrane the interstitial space until they undergo uptake, fusion or (ectosomes) and (c) the endosomal processing and emission interaction with a range of ‘acceptor’ cells [3, 6, 7, 10–14]. of plasma membrane material in the form of exosomes [6, MVs can also reach cells located at a distance by being 18, 22, 41]. released into the circulating blood, lymph, cerebrospinal Apoptotic bodies are relatively large (up to 4,000 nm in fluid (CSF), urine, glandular secretions and other fluids. diameter) and contain genomic DNA and intact organelles. The effects MVs exert on various ‘acceptor’ (target) cells Since they result from cellular breakdown, their generation are rather diverse and may include sharing of interactive, has self-limiting dynamics, but is not devoid of biological signalling and enzymatic activities that would otherwise be compartmentalized to individual cells by their gene expres- sion patterns [87]. This mechanism may explain a level of coordination and molecular integration within multicellular populations, as is often observed in heath and disease. In this article, we will consider the various possible roles of MVs in intercellular communication in general and espe- cially as it relates to pathogenesis, progression, and therapeutic responses in cancer, recognizing that profound qualitative and quantitative differences may exist between various specific disease contexts [9]. Biogenesis and heterogeneity of microvesicles MVs have long been regarded as ‘cellular debris’, but this Fig. 1 Pathways of cellular vesiculation. Two main types of micro- view is rapidly changing [10–13, 18, 22, 66]. The release of vesicles, ectosomes and exosomes, emerge from cellular membrane MVs was first described by Wolf in 1967 who noted and endosomal system, respectively (see text). Ectosomes are thought procoagulant particulate matter around activated blood to be associated with lipid rafts and are larger in size. Exosomes originate within endosomal multivesicular bodies (MVBs), which are platelets [20]. Subsequently, similar organelles, referred to redirected to the cellular surface from the lysosomal degradation as exosomes, were implicated by Trams as carriers of 5′ pathway Semin Immunopathol (2011) 33:455–467 457 influences [19]. Indeed, the cargo of apoptotic MVs monly associated with membrane regions containing high remains protected from degradation and is often ingested levels of cholesterol and signalling complexes, often by tissue phagocytes or neighbouring cells. referred to as lipid rafts [18, 25]. Indeed, certain lipid raft- Ectosomes are MVs that emerge from the outward associated molecules can be found in the cargo of these blebbing of the cellular plasma membrane [13, 18]. These MVs including tissue factor (TF) and flotillin-1 [25]. MVs (also known as shed vesicles or microparticles) may Depending on the cell type, membrane MVs may be rich range in sizes between 100 and 1,000 nm in diameter and in cellular lineage markers, β1 integrin, matrix metal- are characterized by the prominent exposure of phosphati- loproteases (MMPs) and their activators (EMMPRIN), P- dylserine (PS) residues on their outer surfaces, among other selectin glycoprotein ligand 1 (PGSL1), cytokines and markers (Table 1). Ectosome-like MVs have been com- chemokines (e.g. interleukin-1β (IL-1β) and IL-8), vascu- Table

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