Role of Exosomal miRNAs and the Tumor Microenvironment in Drug Resistance

Abstract

Tumor microenvironment (TME) is composed of different cellular populations, such as stromal, immune, endothelial, and cancer stem cells. TME represents a key factor for tumor heterogeneity maintenance, tumor progression, and drug resistance. The transport of molecules via extracellular vesicles emerged as a key messenger in intercellular communication in the TME. Exosomes are small double-layered lipid extracellular vesicles that can carry a variety of molecules, including proteins, lipids, and nucleic acids. Exosomal miRNA released by cancer cells can mediate phenotypical changes in the cells of TME to promote tumor growth and therapy resistance, for example, fibroblast- and macrophages-induced differentiation. Cancer stem cells can transfer and enhance drug resistance in neighboring sensitive cancer cells by releasing exosomal miRNAs that target antiapoptotic and immune-suppressive pathways. Exosomes induce drug resistance by carrying ABC transporters, which export chemotherapeutic agents out of the recipient cells, thereby reducing the drug concentration to suboptimal levels. Exosome biogenesis inhibitors represent a promising adjunct therapeutic approach in cancer therapy to avoid the acquisition of a resistant phenotype. In conclusion, exosomal miRNAs play a crucial role in the TME to confer drug resistance and survivability to tumor cells, and we also highlight the need for further investigations in this promising field.

Drug Resistance in Glioblastoma: The Two Faces of Oxidative Stress

“…These EVs transport a diverse selection of molecules, including proteins, lipids, or nucleic acid cargoes. Tumor cells exclude EVs to the non-tumor cells, resulting in molecular, transcriptional, and translational modifications that cause these cells to fabricate factors required for tumor growth and at the same time alter the function of these cells (Santos and Almeida, 2020 ). TME stromal cells would, in turn, generate their own EVs containing and transferring molecules not only to the tumor but also to other cells in the TME, enhancing their pro-tumorigenic activity (Kalluri, 2016 ).…”

Role of Exosomal miRNA in Bladder Cancer: A Promising Liquid Biopsy Biomarker

“…ExomiRs released from cancer cells or noncancerous cells, which have different effects on target cells in the tumor microenvironment, can affect the development of drug resistance [ 88 ]. ExomiRs can induce resistance to cytotoxic and molecular target-specific drugs [ 89 ].…”

miR-9-Mediated Inhibition of EFEMP1 Contributes to the Acquisition of Pro-Tumoral Properties in Normal Fibroblasts

“…This event could be the result of either an uptake or/and an induction of the miRNA upon cell conditioning and contributes to the observed resistant phenotype. Indeed, a recent review reports a list of CAF-secreted miRNAs responsible of conferring cisplatin resistance in different tumor models, even though miR-9 was not reported [ 34 ]. However, the reduction of sensitivity in conditioned tumor cells can also be caused by other multiple secreted factors rather than by a single molecule.…”