Abstract

Simple SummaryDrug resistance still represents the main reason for therapy failure in cancer patients. In the last decade, extracellular vesicles (EVs), a heterogeneous group of particles implicated in cell-to-cell communication, have been shown to substantially contribute to this phenomenon. This review summarizes the molecular mechanisms underlying the EV-mediated development of chemoresistance, shedding light on the potential role of these vesicles as both diagnostic/prognostic markers and therapeutic targets.Extracellular vesicles (EVs) have recently emerged as crucial modulators of cancer drug resistance. Indeed, it has been shown that they can directly sequester anti-tumor drugs, decreasing their effective concentration at target sites. Moreover, they facilitate the horizontal transfer of specific bioactive cargoes able to regulate proliferative, apoptotic, and stemness programs in recipient cells, potentially conferring a resistant phenotype to drug-sensitive cancer cells. Finally, EVs can mediate the communication between the tumor and both stromal and immune cells within the microenvironment, promoting treatment escape. In this context, clarifying the EV-driven resistance mechanisms might improve not only tumor diagnosis and prognosis but also therapeutic outcomes. Detailed cellular and molecular events occurring during the development of EV-mediated cancer drug resistance are described in this review article.

Highlights

  • Extracellular vesicles (EVs) are a heterogeneous population of nano-sized, membranedelineated vesicles involved in cell-to-cell communication [1]

  • They can vary in size, function, and biogenesis, and are mostly classified as: exosomes, 30–100 nm particles which originate from the endosomal compartment and are secreted upon fusion of multivesicular bodies (MVBs) with the cell membrane; microvesicles, which are 100 nm–1 μm in diameter and formed via outward budding and fission of the cell membrane; apoptotic bodies, ranging from 50 nm to 5 μm and released as blebs of cells undergoing apoptosis [2]

  • EVs can be found in various body fluids, including blood, urine, and saliva, and can be used for the transfer of DNA, mRNA, microRNAs, long non-coding RNAs, and proteins from the originating cells to both neighboring and distant cells [3]

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Summary

Introduction

Extracellular vesicles (EVs) are a heterogeneous population of nano-sized, membranedelineated vesicles involved in cell-to-cell communication [1]. EVs can be found in various body fluids, including blood, urine, and saliva, and can be used for the transfer of DNA, mRNA, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and proteins from the originating cells to both neighboring and distant cells [3]. They have been shown to modulate different tumorigenic processes, such as cancer proliferation, migration, and angiogenesis, and are implicated in the horizontal transmission of biological cargo and in the interactions between malignant and non-malignant cells in the tumor microenvironment [4,5,6]. The EV-mediated sequestration of anti-tumor agents and transfer of drug efflux pumps, as well as the EV-related transmission of pro-survival, anti-apoptotic, and stemness-associated genetic and protein cargo appear to crucially contribute to the emergence of chemoresistance (Figure 1)

EVs and Drug Sequestration at Intracellular and Extracellular Levels
EVs and Acquisition of a Multidrug Resistant Phenotype
EVs and Horizontal Transfer of Pro-Survival Proteins and RNAs
EVs and Modulation of Cancer Stem Cell-Like Features
EVs as Tools to Monitor Response to Cancer Treatment
Strategies to Overcome EV-Related Cancer Drug Resistance
Findings
Conclusions and Future Perspectives
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