1.1. Extracellular vesicles (EVs)
Extracellular vesicles (EVs) act as intermediaries in intercellular
communication and are secreted by various types of cells [25]. These
vesicles are composed of a lipid bilayer that protects their contents
from enzymatic degradation [26]. They carry diverse biological
active molecules such as lipids, proteins, and various nucleic acids
including miRNA and lncRNA, and can regulate cellular processes and
functions, leading to changes in gene expression and activation of
multiple signaling pathways [25, 27-29]. Tumor-derived EVs can
modulate the tumor microenvironment [30]. EVs by transferring
surface markers and signaling molecules, nucleic acids, and oncogenic
proteins to stromal cells, can prepare the tumor microenvironment for
tumor growth, invasion, and metastasis [31-33]. Stromal and tumor
cells, by releasing EVs, cause heterogeneity and complexity in the tumor
microenvironment [25]. EVs create favorable conditions in the tumor
microenvironment for tumor growth and resistance to anti-cancer drugs by
transferring bioactive materials [25]. EVs contribute to drug
resistance through various mechanisms, including drug export and
sequestration, reduction of drug concentration in target sites,
transferring drug efflux pumps, mediating communication between cancer
and stromal cells, transfer of survival factors, apoptosis inhibitors,
and non-coding RNAs [25]. EVs not only play a role in metastasis and
drug resistance but also in immune suppression and angiogenesis, and
also, by providing growth factors such as TGF-\(\beta\) (transforming
growth factor-\(\beta\)) and various miRNAs, they can convert
mesenchymal stem cells and other bone marrow-derived cells into
tumor-supporting cells [25, 34, 35].
One class of EVs is exosomes, which are involved in various cancer
events such as apoptosis escape, immune suppression/evasion, cell
proliferation, inflammatory responses, angiogenesis, invasion,
metastasis, and chemotherapeutic sensitivity [5, 36-39]. Not only
are exosomes involved in acquired drug resistance through various
cellular and molecular processes in the tumor microenvironment
(including DNA repair, epithelial-mesenchymal transition (EMT), immune
surveillance, and cell cycle), but also they contribute to drug
resistance through various pathways, including transporting drug efflux
pumps, direct drug export, and miRNA signaling [40-42]. By
transferring ABC transporters (drug efflux pumps) through exosomes, drug
resistance is promoted in sensitive cells [36].