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.
Highlights
Primary human tumors consist of a mixture of genetically and phenotypically distinct cellular subpopulations
Tumor heterogeneity comes from different interactions as well as intra- and extracellular alterations, resulting in a dynamic and reactive environment that promotes tumor growth and suppresses therapeutic approaches
We presented a plethora of evidence that exosomes are key extracellular mediators of the communication between tumor cells and the tumor microenvironment (TME) during different cancer stages, including cancer progression and metastasis
Summary
Primary human tumors consist of a mixture of genetically and phenotypically distinct cellular subpopulations. The initial conversion of a non-malignant cell to a malignant one is driven by genetic, epigenetic, and phenotypic changes that lead to cellular overgrowth, suppression of death signals, induction of angiogenesis, and resistance to therapy. Exosomal miRNAs released by cancer cells can directly induce drug resistance in the tumor angiogenesis and to suppress the antitumor oforTcancer cells.exosomes can interact surroundings from a drug-resistant cell toimmune a sensitiveresponse counterpart, and deliver miRNAs to TME cells that will modulate a drug resistance response in the area [18]. Exosomal miRNAs released by cancer cells can directly induce drug resistance in the tumor surroundings from a drug-resistant cell to a sensitive counterpart, or cancer exosomes can interact and deliver miRNAs to TME cells that will modulate a drug resistance response in the area [18]. We discuss the recent developments in mechanisms mediated by tumoral exosomes, focusing on miRNA interactions and signaling in the TME that confer survivability and a therapy-resistant phenotype upon tumor cells
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