Nonetheless, patients with metastatic CRC exhibit low miR-126 expression levels which are associated with poor survival, confirming the tumor suppressive role of miR-126 in CRC (167). Tumor-derived exosomes have long been known to harbor microRNAs (miRNAs or miRs) that help prepare secondary sites for metastasis; however, their roles in the early and intermediate steps of the metastatic cascade are only beginning to be characterized. The present review article presents a summary and discussion of the miRNAs that form part of colorectal cancer (CRC)-derived exosomal cargoes and which play distinct roles in epithelial to mesenchymal plasticity and metastatic organotropism. First, an overview of epithelial-to-mesenchymal transition (EMT), metastatic organotropism, as well as exosome biogenesis, cargo sorting and uptake by recipient cells is presented. Lastly, the potential of these exosomal miRNAs as prognostic biomarkers for metastatic CRC, and the blocking of these as a possible therapeutic intervention is discussed. (114) isolated exosomes from B lymphocytes and demonstrated their involvement in antigen presentation, capable of inducing an immune response. Exosomal messenger RNAs were then found to be internalized and translated into functional proteins (9,92), while exosomal miRNAs and lncRNAs can regulate (Z)-MDL 105519 the translation of target mRNAs (75,107,115,116) in recipient cells, concretely establishing a role in intercellular communication. This links exosomes to several biological processes as well as disease pathogenesis. In the context of cancer, cumulative evidence suggests that exosomes can promote tumorigenesis through the horizontal transfer of oncogenic material to recipient cells. Likewise, cancer cells can utilize exosomes to discard tumor-suppressive genetic (Z)-MDL 105519 material not beneficial for tumor growth so as to increase their own oncogenicity (117). For instance, in CRC, miR-100 is a tumor suppressor that inhibits cellular migration and invasion by targeting Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) (118). Mutant KRAS CRC cells have been reported to secrete exosomes enriched in miR-100 as a strategy to sustain low intracellular levels (117). Tumor-derived exosomes have been shown to induce (119) or suppress (120) the immune response, promote the formation of a pre-metastatic tumor niche (7,121), regulate angiogenesis (122), enhance migration (76) and cell proliferation (77), and induce epithelial to mesenchymal transition (123), among others (Fig. 2). Open in a separate window Figure 2 Tumor-and stroma-derived exosomes as major drivers (Z)-MDL 105519 of EMT and pre-metastatic niche formation. Exosomes are formed via the endocytic pathway. In the primary tumor site, both cancer cells and stromal cells in the tumor microenvironment release exosomal miRNA to promote cancer metastasis. Tumor-derived exosomes can reprogram fibroblasts, macrophages, mesenchymal stem cells, and endothelial cells, as well as induce epithelial to mesenchymal transition to enable cell migration and invasion. At the metastatic site, the exosomes participate in pre-metastatic niche formation through immune modulation and angiogenesis, and induce EMT reversal or mesenchymal to epithelial transition to facilitate colonization of the foreign environment. EMT, epithelial-mesenchymal transition; miRNA, microRNA. Exosomes can also promote tumor resistance by encapsulating drugs and their metabolites into exosomes for export, as a drug efflux mechanism (124). Similarly, drug-resistant cancer cells can induce chemoresistance in other cancer cells through exosome-mediated transfer of efflux transporters (78). 4. CRC exosomal CDH1 miRNAs implicated in EMT and organotropism Various miRNAs can inhibit EMT progression by directly targeting components of the EMT regulatory pathways. CRC exosomes may be enriched with oncogenic miRNAs that downregulate EMT inhibitors. Alternatively, tumor suppressive miRNAs that downregulate inducers of EMT may themselves be downregulated or disposed of in CRC exosomes. Exosomal cargo can both originate from and be delivered to either tumor cells or cells in the tumor microenvironment, enhancing the capacity for metastasis by both driving EMT in tumor cells and influencing the properties of the microenvironment. Moreover, miRNAs carried by serum exosomes can be delivered to sites distant from the originating tumor, further extending metastatic potential. The promotion of EMT by altered regulation of exosomal miRNAs results in.