Function of extracellular vesicle-associated miRNAs in metastasis

Extracellular RNA (exRNA) is functionally transferrable from donor to recipient cells and is protected from RNAses by electrostatic interactions with proteins or by membrane encapsulation. In addition to bioactive RNA, extracellular vesicles (EVs) contain intraluminal and membrane-associated proteins. The cellular context and fitness affect the composition of EVs and thus the outcome of the communication between the EV-producer and recipient cells. Adaptive communication through EVs is particularly important between cancer cells and their local and distant environment and drives life-threatening metastatic progression. Small noncoding RNAs (miRNAs) have been reported in EV isolations and play a role in local invasion, angiogenesis, immune modulation, metastatic niche preparation, colonization and dormancy. The metastasis-related functions attributed to EV-associated miRNAs are currently increasing exponentially in the scientific literature. We must be aware that the correct and efficient separation of non-vesicular entities (soluble proteins, RNA-protein complexes and RNA-lipoprotein complexes) from EVs is necessary to determine the true contribution of EVs in any experiment that describes the molecular content or the functional consequences of the isolated material.

Role of extracellular vesicle (EV)-derived small noncoding RNAs
(miRNAs) at the primary tumor site

Cancer cells (CCs) make use of EV-mediated autocrine signaling to promote proliferation and migration (1). CCs release EVs enriched in miRNAs to target endothelial cells, promoting intravasation of CCs(2). Paracrine transfer of EV-derived miR-214 between endothelial cells promotes angiogenesis (3). CCs release EVs enriched in miRNAs, promoting angiogenesis after uptake by endothelial cells (4). Mesenchymal stem cells (MSCs) and bone-marrow-derived-MSCs (BM-MSCs) transfer miRNAs to CCs via EVs, stimulating proliferation and migration (5). CCs discard EVs containing tumor-suppressing miRNAs to increase their aggressiveness (6). Monocyte-derived EVs enriched in miR-223 drive breast cancer invasion (7). CCs transfer EV-derived miRNA to immune cells; miR-21 and miR-29b released from a primary lung tumor are able to bind to the Toll-like receptor-4 (TLR4) of macrophages to drive an interleukin-6 (IL-6)-mediated inflammatory response through nuclear factor kappa B (NF-κB) signaling (8). EV-derived miRNAs released from PC cells (TNF-α tumor necrosis factor-alpha, MHCII major histocompatability complex II) induce an immune tolerance (9). EV-mediated miR-409 transfer from cancer-associated fibroblasts (CAFs) to CCs promotes proliferation and epithelial to mesenchymal transformation (EMT) in prostate cancer (10). Cancer types are given as follows: BC breast cancer, CC colorectal cancer, HC hepatocellular carcinoma, LC lung cancer, LK leukemia, MM multiple myeloma, OC ovarian cancer, PC pancreatic cancer, PCa prostate cancer, TC thyroid cancer