Intercellular communication by exosome-derived microRNAs in cancer

Abstract

The development of human cancers is a multistep process in which normal cells acquire characteristics that ultimately lead to their conversion into cancer cells. Many obstacles must be overcome for this process to occur; of these obstacles, is the ability to survive an inhospitable microenvironment. It is recognized that the intercommunication between tumor cells and their surrounding microenvironment is essential to overcoming this obstacle and for the tumor to progress, metastasize and establish itself at distant sites. Exosomes are membrane-derived vesicles that have recently been recognized as important mediators of intercellular communication, as they carry lipids, proteins, mRNAs and microRNAs that can be transferred to a recipient cell via fusion of the exosome with the target cell membrane. In the context of cancer cells, this process entails the transfer of cancer-promoting cellular contents to surrounding cells within the tumor microenvironment or into the circulation to act at distant sites, thereby enabling cancer progression. In this process, the transfer of exosomal microRNAs to a recipient cell where they can regulate target gene expression is of particular interest, both in understanding the basic biology of cancer progression and for the development of therapeutic approaches. This review discusses the exosome-mediated intercellular communication via microRNAs within the tumor microenvironment in human cancers, with a particular focus on breast cancer exosomes.

Figure 1

Biogenesis, secretion and uptake of tumor-derived exosomes in the tumor microenvironment. Exosomes are formed by the inward budding of the multivesicular body (MVB) membrane in the form of intraluminal vesicles (ILVs). Exosome formation and cargo sorting into lysosomes involves the endosomal sorting complex required for transport (ESCRT), which recognizes ubiquitinated proteins. Exosome production and secretion also occurs through an ESCRT-independent process involving the sphingolipid, ceramide, and the enzyme neutral, sphingomyelinase (the enzyme that converts sphingomyelin to ceramide). Exosomes secretion can be stimulated by various chemical, environmental and mechanical stimuli, such as gamma-irradiation, hypoxia (low oxygen), low pH, matrix detachment, etc. Exosomes are secreted in exocytic MVBs following fusion of MVBs with the cell membrane, a process that depends on Rab GTPases (Rab27A, Rab27B). Exosomes released from a primary tumor cell will display similar membrane components as their cell of origin, such as receptor ligands or antigens. Endocytosis of exosomes may occur through activation of cell surface receptors or bioactive lipid ligands. Upon endocytosis by a secondary recipient cell, such as fibroblasts or vascular endothelial cells, exosomes can release their microRNA cargo. The transferred microRNAs are functionally active and can regulate gene expression in the recipient cell through post-translational regulation of target mRNA expression, leading to mRNA degradation or de-stabilization. microRNA-dependent gene regulation can activate various processes involved in tumor development and progression. Abbreviations: TAK1, transforming growth factor β activated kinase-1; MMPs, matrix metalloproteinases; MAPK, mitogen activated protein kinase; NFκB, nuclear factor kappa-light-chain-enhancer of activated B-cells; EZH2, enhancer of zeste homolog 2; VEGF/VEGF, vascular endothelial growth factor/receptor; ECM, extracellular matrix.