Asymmetric RNA Distribution among Cells and Their Secreted Exosomes: Biomedical Meaning and Considerations on Diagnostic Applications

Abstract

Over the past few years, exosomes and their RNA cargo have been extensively studied because of the fascinating biological roles they play in cell-to-cell communication, including the signal exchange among cancer, stromal, and immune cells, leading to modifications of tumor microenvironment. RNAs, especially miRNAs, stored within exosomes, seem to be among the main determinants of such signaling: their sorting into exosomes appears to be cell-specific and related to cellular physiopathology. Accordingly, the identification of exosomal miRNAs in body fluids from pathological patients has become one of the most promising activity in the field of biomarker discovery. Several analyses on the qualitative and quantitative distribution of RNAs between cells and their secreted exosomes have given rise to questions on whether and how accurately exosomal RNAs would represent the transcriptomic snapshot of the physiological and pathological status of secreting cells. Although the exact molecular mechanisms of sorting remain quite elusive, many papers have reported an evident asymmetric quantitative distribution of RNAs between source cells and their exosomes. This phenomenon could depend both on passive and active sorting mechanisms related to: (a) RNA turnover; (b) maintaining the cytoplasmic miRNA:target equilibrium; (c) removal of RNAs not critical or even detrimental for normal or diseased cells. These observations represent very critical issues in the exploitation of exosomal miRNAs as cancer biomarkers. In this review, we will discuss how much the exosomal and corresponding donor cell transcriptomes match each other, to better understand the actual reliability of exosomal RNA molecules as pathological biomarkers reflecting a diseased status of the cells.

TNFα and IL-1β modify the miRNA cargo of astrocyte shed extracellular vesicles to regulate neurotrophic signaling in neurons

“…The mechanisms for differential enrichment of particular miRNAs into ADEVs following ATP, TNFα, or IL-1β are less clear. Previous studies have reported differential sorting of miRNA into EVs 43 , and several mechanisms for miRNA loading into EVs including lipid-mediated RNA loading, RNA-binding protein-assisted RNA loading, loading by non-templated 3′-end uridylation of microRNAs 44 – 46 . However, mechanisms regulating stimulus-dependent inclusion/exclusion of particular miRNA cargo are currently unknown.…”

LncRNA UCA1, Upregulated in CRC Biopsies and Downregulated in Serum Exosomes, Controls mRNA Expression by RNA-RNA Interactions

“…This opposite deregulation would suggest that the oncogenic function of UCA1 is crucial for tumor progression, inducing tumor cells to retain the lncRNA by limiting its secretion through exosomes. 58 …”

Caveolin-1 selectively regulates microRNA sorting into microvesicles after noxious stimuli

“…Cell stressors not only promote the release of EVs, but more importantly, also promote highly specific EV-containing microRNAs (miRNAs; Gray et al, 2015 ; Lee et al, 2016 , 2017 ). Accumulating evidence indicates that a specific repertoire of miRNAs is actively selected and loaded into EVs ( Skog et al, 2008 ; Xu et al, 2013 ; Momose et al, 2016 ; Ragusa et al, 2017 ). This process involves an ATP-dependent, active sorting mechanism ( Xu et al, 2013 ) and involves RNA-binding proteins that are enriched in EVs ( Laffont et al, 2013 ; Villarroya-Beltri et al, 2013 ; Cha et al, 2015 ; McKenzie et al, 2016 ; Santangelo et al, 2016 ; Shurtleff et al, 2016 ; Teng et al, 2017 ).…”