Non-Coding RNAs of Extracellular Vesicles: Key Players in Organ-Specific Metastasis and Clinical Implications

Simple Summary Metastasis refers to the progressive dissemination of primary tumor cells and their colonization of other tissues, and is a major cause of treatment failure in cancer patients. Most cancers metastasize to specific organs with a non-random distribution pattern through a process known as "organ-specific metastasis". Extracellular vesicles (EVs), mediating intercellular communication, can deliver ncRNAs to regulate cancer phenotypes at distant organs or sites in multiple cancers, thereby contributing to organ-specific metastasis. This review summarizes the underlying mechanisms and functions of EV-ncRNA-mediated metastatic organotropism in bone, liver, lung, brain, and lymphatic metastasis, and highlights the clinical applications of EV-ncRNAs serving as potential biomarkers and therapeutic targets. The aim of this review is to provide a perspective on the novel therapeutic strategies of organ-specific metastasis and hope for improving the survival outcome of cancer patients. Extracellular vesicles (EVs) are heterogeneous membrane-encapsulated vesicles released by most cells. They act as multifunctional regulators of intercellular communication by delivering bioactive molecules, including non-coding RNAs (ncRNAs). Metastasis is a major cause of cancer-related death. Most cancer cells disseminate and colonize a specific target organ via EVs, a process known as "organ-specific metastasis". Mounting evidence has shown that EVs are enriched with ncRNAs, and various EV-ncRNAs derived from tumor cells influence organ-specific metastasis via different mechanisms. Due to the tissue-specific expression of EV-ncRNAs, they could be used as potential biomarkers and therapeutic targets for the treatment of tumor metastasis in various types of cancer. In this review, we have discussed the underlying mechanisms of EV-delivered ncRNAs in the most common organ-specific metastases of liver, bone, lung, brain, and lymph nodes. Moreover, we summarize the potential clinical applications of EV-ncRNAs in organ-specific metastasis to fill the gap between benches and bedsides.