ReviewFunctional roles of exosomal miRNAs in multi-drug resistance in cancer chemotherapeutics
Introduction
An uncontrolled proliferation and inappropriate survival of defective cells could lead to tumor formation (Esquela-Kerscher and Slack, 2006). According to World Health Organization (WHO), cancer is recognized as an important global health threatening and the second leading cause of human deaths worldwide. Tumor microenvironment (TME) is a heterogeneous dynamic system whose cells are surrounded by an extracellular matrix, which mainly comprises of fibroblasts, endothelial cells, mesenchymal cells, and immune cells. The microsystem provides cell proliferation factors and facilitates tumor cells to escape cancer treatments (Nouraee et al., 2016). Multi-drug resistance (MDR) development is one of the main challenges in cancer therapy. In this process, cancer cells treated with a given drug acquire cross-resistance to a spectrum of other structurally and mechanically different chemotherapeutics (Annereau et al., 2004). MDR arises by either decreased drug uptake or increased drug efflux. However, other mechanisms are also involved such as activation of detoxifying and DNA repair pathways (An et al., 2017). Recently, a differential pattern in the secretion of specialized vesicles named “exosomes” by TME cells have received much attention. Most cells could release bilayer membrane-bound vesicles into extracellular space and body fluids. They are a class of vesicles whose size ranges from 40 to 150 nm and release their cargo molecules upon fusion with the plasma membrane of target cells (Bach et al., 2017). Studies in recent years have introduced exosomes as an important signaling vehicle for intercellular communications. Several molecules are contained in exosomes, such as short peptides, proteins, lipids, and nucleic acids (Fig. 1A) (Théry, 2011). The cargo of these exosomes can promote drug resistance in all types of TME cells via modulating multiplex cellular and molecular pathways. Additionally, TME cells (such as macrophages and fibroblasts) could also release factors that cause drug resistance in neighboring cells (Santos and Almeida, 2020). In addition, many publications have considered the different patterns of circulating exosomal miRNAs as predictive markers for chemoresistance in various cancer types. In the current review, we have focused on exosomal miRNAs and described the mechanisms by which they can modulate drug resistance in tumors.
Section snippets
Biogenesis of exosomes
Exosomes are defined as micro-vesicles released by many cells, which are formed from an endosomal origin. Accumulating evidence indicates that the molecules are packaged into exosomes via two main well-known sorting mechanisms; 1- endosomal sorting complex for transport (ESCRT) process, 2- ESCRT-independent process(Guay and Regazzi, 2017). Both mechanisms begin with a vesicular early endosome, which forms intraluminal vesicles (ILVs) and further it becomes a late endosome called multivesicular
Exosomes composition
The content of secreted exosomes is different between various cells or tissue types. Additionally, changes in the cellular condition (such as hypoxic microenvironment) can influence the exosomal content and the number of exosomes secreted (Henderson and Azorsa, 2012; Perez-Gonzalez et al., 2012). According to exocarta database, data from different cell types of multiple organisms show that proteins are the most enriched molecules in exosomes. Interestingly, miRNAs, and lipids are the next two
miRNAs biogenesis and their role in chemo-resistance
microRNAs (miRNAs) are identified as short non-coding RNAs, with a length of 21–22 nucleotides, which post-transcriptionally regulate gene expression by mostly by base-pairing with the 3’untranslated region (3’-UTR) of their target messenger RNAs (mRNAs) (Hausser and Zavolan, 2014). miRNA genes are mostly transcribed by RNA polymerase II (Pol II), which forms pri-miRNAs in the nucleus. pri-miRNA is then cleaved into pre-miRNA, by an RNase III enzyme named Drosha, and then exported to the
Roles of Exo-miRs in drug resistance
Recent studies have suggested that cancer-derived exo-miRs are released in a different pattern, which are assumed to display MDR through the mechanisms described above. Secreted exo-miRs prepare the microenvironment cells for cancer evolution and hence chemotherapy resistance by affecting all types of TME cells. On the other hand, TME cells (such as macrophages and fibroblasts), themselves are considered to transmit MDR manner to sensitive neighboring cells. In all scenarios, it is believed
Concluding remarks
Drug resistance is the main obstacle in clinical oncology. In recent years, the molecular basis of drug resistance has been widely investigated. Treatment failure during chemotherapy is closely relevant to the cross-talk between tumor chemo-resistant cells, tumor non-resistant cells, CSCs, and TME cells. miRNAs have been found to play a central role in mediating these cancer extracellular communications. The miRNA-drug resistant pattern can be transferred to other neighbor cells via signaling
Funding
None.
Ethical approval
Not applicable.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgements
This work was supported by the research deputy of Shahid Beheshti University of Medical Sciences in Tehran, Iran.
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