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].