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].