LAUSR

Cholangiocarcinoma (CCA) is a lethal malignancy originating from the biliary tree. Because CCA is usually detected in advanced stages, patients are infrequently eligible for surgery, which is the only curative intervention. Unfortunately, there are currently no other efficient therapeutic options, and these tumors are particularly resistant to chemotherapy. Therefore, new strategies for the treatment of CCA are needed. In this issue of HEPATOLOGY, Li et al. provide the basis for a potential new approach based on the use of extracellular vesicles (EVs). Their study addresses two important topics in CCA biology: the bidirectional intercellular communication between tumor and stromal cells by means of EVs and the potential therapeutic use of these vesicles for delivering molecules of interest such as microRNAs (miRNAs) into tumor cells. EVs are bilayered membrane vesicles released from a variety of cell types, and they can be found in almost any biological fluid. In addition to apoptotic bodies, which are measured in micrometers, EVs can be divided in two groups based on their size, but more importantly on their origin—namely, microvesicles (also known as ectosomes or microparticles, 0.2-1 lm in diameter) and exosomes (0.04-0.1 lm in diameter). Microvesicles are originated by budding from the plasma membrane, whereas exosome biogenesis starts from the multivesicular bodies that are redirected to and fuse with the plasma membrane, delivering the exosomes by way of exocytosis into the extracellular media. In addition to lipids and proteins, EVs contain cytokines, hormones, transcription factors, and nucleic acids, including miRNAs. In recent years, it has become evident that EVs may be integral components of the tumor developmental process, from the communication between tumor and stromal cells to the colonization of new niches during metastasis. For example, exosomes derived from CCA cells are capable of transferring oncogenic proteins to normal cholangiocytes and induce migration and invasion, and also induce the differentiation of mesenchymal stem cells into fibroblasts, which may contribute to stromal generation. Furthermore, the characterization of EVs in bile suggests their potential use as a diagnostic tool. MiRNA dysregulation is a common feature of tumor cells. These short noncoding RNAs act as critical regulators of gene expression by specifically binding to messenger RNAs and blocking translation and/or inducing RNA degradation. To date, there is much evidence to show that EVs are able to transport signals from a donor cell and communicate with adjacent or more distant cells by fusing with the plasma membrane and delivering their cargo inside the target cell. Moreover, transported miRNAs are capable of targeting messenger RNAs or activate receptors in recipient cells, suggesting that the use of artificially overloaded vesicles with a particular therapeutic miRNA may be of utmost interest. Li et al. report that the coculture of a hepatic stellate cell line (LX2, a human cell line extensively used for in vitro modeling of CCA stroma) with a CCA cell line (HuCCT-1) induced the down-regulation of several miRNAs, including miR-195, in stellate cells by Abbreviations: CCA, cholangiocarcinoma; EV, extracellular vesicle; miRNA, microRNA.