Microvesicles and Exosomes in Cancer

Cancer microvesicles (MVs) were first described in 1978 when they were detected in the spleen nodules and lymph nodes of a patient with Hodgkin’s lymphoma.1 Over the last several decades the mechanistic activities of extracellular vesicles (EVs) have been investigated, including their role in cell-to-cell communication via direct stimulation by surface-expressed ligands; the transfer of receptors, proteins, and ribonucleic acid (RNA); the delivery of various infections (prions, human immunodeficiency virus [HIV], etc.); and perhaps the transport of whole cell parts such as mitochondria.2-5 EVs in the malignant state are now implicated as playing a central role in the biology of malignancy, including mechanisms that regulate metastasis, angiogenesis, and immune signaling. Recently, populations of EVs expressing tissue factor (TF) have been identified as a biomarker to predict thrombotic events in patients with malignant disease. The term “extracellular vesicle” is a general label used to describe vesicular, membrane-bound particles secreted by a whole host of cells ranging from leukocytes aiding in the generation of a fibrin clot to tumor cells implicated in the propagation of a malignant clone.6-8 EVs were first described in 1967 by Peter Wolf, who referred to “minute particulate material” derived from platelets, which he termed “platelet dust.” However, since that time, our knowledge of the diversity, complexity, and significance of EVs has expanded exponentially.9 In addition to cancer, EVs have been studied in relation to HIV, complement fixation, sepsis, acute coronary syndromes, and even the normal physiologic state.10-12 There still exists much controversy as to an appropriate nomenclature for these vesicles, with microparticles or MVs being used interchangeably regardless of the cell of origin, mode of production, or cargo contained.3,13,14 However, there is marked heterogeneity among EVs: an MV formed during apoptotic cell death is distinct, both in structure and in function, from a vesicle carefully packaged and released by a malignant cancer cell. In this chapter, the term “EVs” will be used broadly to refer to all types of membrane-bound vesicles.