Extracellular Vesicle-Associated miRNAs and Chemoresistance: A Systematic Review

SIMPLE SUMMARY: There is an urgent need for a non-invasive, specific biomarker to identify patients at risk of chemoresistance, which it is the ability of cancer cells to escape the effect of chemotherapy drugs. Extracellular vesicles contain an abundance of miRNAs that demonstrate expression across a range of cancers including breast cancer, renal cell carcinoma, lung cancer, multiple myeloma, and lymphoma. Interestingly, miRNAs encapsulated within extracellular vesicles (EVs) including exosomes display an association with chemoresistance. Here, we performed a systematic revision to evaluate the association between miRNAs within EVs and chemotherapy resistance. The summarized graphical abstract indicates that several exosome-derived miRNAs involved in chemotherapy resistance can be found among different types of cancers, such as colorectal, ovarian, breast, and lung cancer, and lymphoma. ABSTRACT: Cancer is a leading public health issue globally, and diagnosis is often associated with poor outcomes and reduced patient survival. One of the major contributors to the fatality resultant of cancer is the development of resistance to chemotherapy, known as chemoresistance. Furthermore, there are limitations in our ability to identify patients that will respond to therapy, versus patients that will develop relapse, and display limited or no response to treatment. This often leads to patients being subjected to multiple futile treatment cycles, and results in a reduction in their quality of life. Therefore, there is an urgent clinical need to develop tools to identify patients at risk of chemoresistance, and recent literature has suggested that small extracellular vesicles, known as exosomes, may be a vital source of information. Extracellular vesicles (EV) are membrane bound vesicles, involved in cell-cell communication, through the transfer of their cargo, which includes proteins, lipids, and miRNAs. A defined exploration strategy was performed in this systematic review in order to provide a compilation of key EV miRNAs which may be predictive of chemoresistance. We searched the PubMed, Science Direct, and Scopus databases using the following keywords: Extracellular vesicles OR exosomes OR EVs AND miRNA AND Chemotherapy OR Chemoresistance OR Cancer Recurrence from 2010 to 2020. We found 31 articles that reported key EV-associated miRNAs involved in cancer recurrence related to chemoresistance. Interestingly, multiple studies of the same tumor type identified different microRNAs, and few studies identified the same ones. Specifically, miR-21, miR-222, and miR-155 displayed roles in response to chemotherapy, and were found to be common in colorectal cancer, ovarian cancer, breast cancer, and diffuse large B cell lymphoma patients (DLBCL). miR-21 and miR-222 were found to favour the development of chemoresistance, whereas miR-155 exhibited a contrasting role, depending on the type of primary tumor. Whilst high levels of miR-155 were found to correlate with chemotherapy resistance in DLBCL, it was found to be predictive of an effective response towards chemotherapy in breast cancer. Thus, further research regarding the roles of these miRNAs would be beneficial in terms of designing novel tools to counteract the progression of cancer in a not-to-distant future.