Renal cell cancer (RCC) is the most common kidney cancer and has a poor prognosis (1). Although some achievements have been made to date, radical therapy for RCC remains challenging (2). It is now generally accepted that recurrence and metastasis are the main cause of reducing survival of RCC patients attributed to causing tumor resistance for conventional therapies. Recently, sunitinib is an important therapeutic option for advanced RCC patients. However, it is reported that 10–20% of advanced RCC patients are resistant to sunitinib therapy because of the patient’s inherent drug resistance (3). Emerging evidence have shown that the acquisition of sunitinib resistance was associated with the activation of compensatory signaling pathways (4), but the underlying mechanisms remain unclear. Further investigations of the mechanisms of resistance in RCC are necessary to clarify the pathogenesis and development of novel combination therapies (5).
Exosomes generally refer to a mixed population of small extracellular vesicles (sEVs) that display a diverse range of sizes (40 to 100 nm in diameter) (6). They can transfer information (e.g., proteins, RNAs, and DNAs) to target cells by a manner of specific cell-to-cell communication. This process was completed through three main mechanisms: endocytosis by phagocytosis, direct fusion with the plasma membrane and receptor–ligand interactions (7). The weight of evidence supports that exosomes can transfer noncoding RNAs (ncRNAs) (e.g., miRNAs, lncRNAs, and circRNA) to achieve the cell-to-cell communication (8). These exosome-associated ncRNAs play pivotal roles in a variety of human diseases, including cancer (9,10). However, it is not clear whether resistant cancer cells can confer drug resistance to sensitive cells via exosomes, and whether EV-associated lncRNAs have therapeutic potential in cancer.
In a recently published study by Qu et al. (11) demonstrated an insight to search for novel targets for sunitinib resistance. In this study, the authors identified lncARSR (lncRNA Activated in RCC with Sunitinib Resistance, ENST00000424980) plays important role in mediating sunitinib resistance in RCC cells. It acts as a competing endogenous RNA for binding to miR-34/miR-449, thereby facilitating the expression of their targets AXL and c-MET to reactivate the receptor tyrosine kinase (RTK), while sunitinib is a novel multitargeted PTK inhibitor. Recently, studies have reported that drug resistance can be disseminated to sensitive cells by exosomes that transmit these regulatory RNAs (12,13). Interestingly, Qu et al. clearly illustrated that when lncARSR was bio-activated, could be encapsulated by exosomes and released into the extracellular environment, thereby conferring sunitinib resistance to neighbouring sensitive cells. These findings indicated that exosome-transmitted lncARSR may be as a novel therapeutic target for sunitinib resistance in RCC, thereby improving the clinical benefits in the future.
In summary, Qu et al. clearly established that sunitinib resistance can be disseminated to sensitive cells by exosomes that transmit these regulatory RNAs, and exosome-transmitted lncARSR could act as a diagnostic biomarker as well as a therapeutic target for sunitinib resistance. Exosomes were previously regarded functionally as “junk” to remove from cells; however, it is now clear that they play important roles in tumorigenesis and drug resistance in specific cell-to-cell communication via the transfer of a series of small molecules, including lncRNAs. Because of exosome-associated lncRNAs stability and abundance in serum, they show a strong potential to act as new molecular biomarkers and therapeutic targets for cancer. The application of next-generation sequencing and RNA-seq technology has enabled the identification of an increasing number of exosome-transmitted lncRNAs. However, exosome-associated lncRNA functions in vivo remain an outstanding question, and additional research need to utilize suitable in vivo model systems. In addition, it is necessary to explore functional exosome-associated lncRNAs to establish whether they are specifically associated with one or more diseases and to determine the molecular mechanisms underlying these associations. In brief, further research is urgently needed to enable clinical applications. Although our current knowledge of exosome-associated lncRNAs only represents the tip of the iceberg, novel methods and technologies will eventually clarify these processes, thereby providing a novel strategy for the prevention, early diagnosis, and treatment of cancer.
Funding: This work was supported by the Student Innovation Project of Central South University (2017zzts010).
Conflicts of Interest: The authors have no conflicts of interest to declare.
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