Abstract
Cells release membrane enclosed nano-sized vesicles termed extracellular vesicles (EVs) that function as mediators of intercellular communication by transferring biological information between cells. Tumor-derived EVs have emerged as important mediators in cancer development and progression, mainly through transfer of their bioactive content which can include oncoproteins, oncogenes, chemokine receptors, as well as soluble factors, transcripts of proteins and miRNAs involved in angiogenesis or inflammation. This transfer has been shown to influence the metastatic behavior of primary tumors. Moreover, tumor-derived EVs have been shown to influence distant cellular niches, establishing favorable microenvironments that support growth of disseminated cancer cells upon their arrival at these pre-metastatic niches. It is generally accepted that cells release a number of major EV populations with distinct biophysical properties and biological functions. Exosomes, microvesicles, and apoptotic bodies are EV populations most widely studied and characterized. They are discriminated based primarily on their intracellular origin. However, increasing evidence suggests that even within these EV populations various subpopulations may exist. This heterogeneity introduces an extra level of complexity in the study of EV biology and function. For example, EV subpopulations could have unique roles in the intricate biological processes underlying cancer biology. Here, we discuss current knowledge regarding the role of subpopulations of EVs in cancer development and progression and highlight the relevance of EV heterogeneity. The position of tetraspanins and integrins therein will be highlighted. Since addressing EV heterogeneity has become essential for the EV field, current and novel techniques for isolating EV subpopulations will also be discussed. Further dissection of EV heterogeneity will advance our understanding of the critical roles of EVs in health and disease.
Highlights
Extracellular vesicles (EVs) are heterogeneous populations of naturally occurring nano to micro-sized membrane vesicles released by essentially all cell types
Findings by Yue et al provide more in vivo evidence for the link between EV composition and biological functions [134], in this case the specific involvement of EV tetraspanins CD151 and Tspan8, two major metastasis-promoting tetraspanins that play a role in metastasis formation in several tumor systems
The authors were able to show that knockdown of CD151 and Tspan8 resulted in loss of metastatic capacity of rat pancreatic adenocarcinoma tumor cells, which was regained after pre-treatment with EVs derived from highly metastatic wild-type pancreatic cells
Summary
Extracellular vesicles (EVs) are heterogeneous populations of naturally occurring nano to micro-sized membrane vesicles released by essentially all cell types. EVs are enclosed by a lipid bilayer and range in size from 30 to 10,000 nm in diameter. They have emerged as a novel and important player in intercellular communication, mainly through their ability to transfer their biological content, consisting of proteins, lipids, and nucleic acids, to recipient cells [1,2,3]. In terms of pathophysiological processes, EVs have established as important players in diseases such as cancer [7], neurodegenerative disease [8], and viral infection [9]
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