1.1.1. Exosomal miRNAs
miRNAs, or microRNAs, are a type of short ncRNAs that regulate various important biological functions such as apoptosis, migration, proliferation, differentiation, drug resistance, and invasion by regulating gene expression [5, 43]. Cancer cells create an abnormal expression of miRNAs through genetic or epigenetic changes, which subsequently leads to abnormal expression of their target genes [44-49]. miRNAs act as elements that promote the formation and biological changes of TME [50-53]. Exosomal miRNAs derived from tumors cause heterogeneity and phenotypic changes in TME and subsequently promote uncontrolled tumor growth [20, 36, 54-58]. Exosomal miRNAs derived from tumors by matrix reprogramming in TME create a context for resistance to chemotherapy, tumor growth, immune system escape, and metastasis [5]. Exosomal miRNAs secreted by cancer stem cells that target immunosuppressive and anti-apoptotic pathways can impart and develop drug resistance in susceptible neighboring cells [36]. Exosomal miRNAs derived from cancer stem cells (CSCs) cause inhibition of pro-apoptotic FOXO3a property and activation of mTOR signaling pathway in sensitive cancer cells and they can inhibit apoptosis and subsequently promote tumor progression, therefore, drug-induced apoptosis is inhibited [36]. Horizontal transfer of exosomal miRNAs derived from cancer cells can induce a resistant phenotype of drug-resistant cells in sensitive cancer cells and create resistance to a wide range of anticancer drugs, moreover, miRNAs can be delivered from cancer cells to TME cells by exosomes and modulate the process of drug resistance response in TME [59-61]. Exosomal miRNAs derived from cancer stem cells and non-cancerous cells help to drug resistance by creating different effects on target cells in TME, in addition, exosomal miRNAs play a role in inducing resistance to specific molecular target drugs and cytotoxic drugs [36]. Due to the key role of miRNAs in cancer and their regulation of drug resistance in a tumor-specific manner by some miRNAs, exosomal miRNAs can be considered and used as potential cancer biomarkers for prediction and diagnosis in a broad or specific tumor approach [36]. Exosomal miRNAs derived from cancer cells and transferred to fibroblasts in the tumor microenvironment (TME) promote differentiation of cancer-associated fibroblasts (CAFs), subsequently, exosomal miRNAs secreted by CAFs induce drug resistance in cancer cells through induction of proliferation, metastasis, and inhibition of anti-tumor effects of cytotoxic drugs such as cell cycle arrest and apoptosis [36]. For example, the transfer of exosomal miR-21 derived from CAFs to ovarian cancer cells led to inhibition of apoptosis and downregulation in the expression of apoptotic peptidase activating factor 1 (APAF1), as a result, resistance to treatment with paclitaxel was increased [62]. Alterations in the Extracellular matrix promote the widespread growth of cancer cells, angiogenesis, metabolic reprogramming, and inflammatory response [5]. Primary tumor cells release exosomal miRNAs such as miR-21, miR-155, miR-210, miR-1247-30, and miR-124 that are transferred to normal fibroblasts (NFs), then, by targeting proteins such as SPHK1, PTEN, and SOCS1, as well as activating molecules such as FGF-2, FAP, TGF-\(\beta\), and bFGF induce NFs conversion into CAFs, ultimately, ECM undergoes reshaping [5, 36].