1.1.1.3. Exosomal miRNAs and autophagy
Autophagy is a catabolic process that removes damaged or redundant macromolecules and organelles to maintain homeostasis and metabolic adequacy [78]. This process is involved in escalating tumor resistance against therapy and increasing tumor growth, as well as upregulating autophagy frequently occurring leading to cell survival and high energy supply during cancer initiation [36, 79, 80]. During a phenomenon called cytoprotective autophagy a process caused by high levels of autophagy and the creation of hypoxic TME, resulting in oxidative stress, ultimately delays apoptosis and subsequently contributes to treatment resistance [81, 82]. Upregulation of exosomes and autophagy can act to induce an adaptive response under cellular stress conditions in cancer cells [36]. Exosomes released from cancer cells can induce the construction of reactive oxygen species (ROS) and stimulate the secretion of tumor growth factors by upregulation of autophagy in target cells [83]. Moreover, during a drug treatment regimen, exosomes derived from cancer cells cause a resistant phenotype in target cells by upregulation of cytoprotective autophagy [84]. Exosomal miRNAs can control autophagy and play a role as mediators in therapeutic resistance [36, 85, 86]. For example, cisplatin-resistant non-small cell lung cancer (NSCLC) cells secreted exosomal miR-425-3p, which targeted the AKT1/mTOR signaling pathway and subsequently led to the upregulated autophagy activity and reduced cisplatin treatment outcomes [87].