Cell-to-cell communication: microRNAs as hormones

Abstract

Mammalian cells can release different types of extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies. Accumulating evidence suggests that EVs play a role in cell-to-cell communication within the tumor microenvironment. EVs' components, such as proteins, noncoding RNAs [microRNAs (miRNAs), and long noncoding RNAs (lncRNAs)], messenger RNAs (mRNAs), DNA, and lipids, can mediate paracrine signaling in the tumor microenvironment. Recently, miRNAs encapsulated in secreted EVs have been identified in the extracellular space. Mature miRNAs that participate in intercellular communication are released from most cells, often within EVs, and disseminate through the extracellular fluid to reach remote target cells, including tumor cells, whose phenotypes they can influence by regulating mRNA and protein expression either as tumor suppressors or as oncogenes, depending on their targets. In this review, we discuss the roles of miRNAs in intercellular communication, the biological function of extracellular miRNAs, and their potential applications for diagnosis and therapeutics. We will give examples of miRNAs that behave as hormones.

Keywords: cell-cell communication; circulating miRNAs; exosomes; extracellular vesicles; microRNAs; tumor microenvironment.

Figure 1

MicroRNAs release and uptake mechanism between donor and recipient cells. Biogenesis of exosomes. Early endosomes originate from the cell membrane via endocytosis. Multivesicular bodies originate by invagination of the plasma membrane. Multivesicular bodies fuse with the plasma membrane and exosomes are released into the extracellular space. Some types of miRNAs are generally localized in membrane‐derived vesicles (exosomes, microvesicles, apoptotic bodies), while some miRNAs are found mainly in miRNA‐binding protein complexes, such as Ago‐2, or high‐density lipoproteins (HDL). Finally, miRNAs enter into recipient cells and interact with specific target genes.

Figure 2

Schematic illustration of the interaction between primary tumor cells and tumor microenvironment through miRNAs. miRNAs can play a key role in cell–cell communication in several physiological and pathophysiological processes associated with many human diseases, including cancer. Selected examples of paracrine miRNA signaling between primary tumor cells, immune cells, and endothelial cells are shown.