Mechanisms of Drug Resistance in Cancer: The Role of Extracellular Vesicles

Abstract

Drug resistance remains a major barrier to the successful treatment of cancer. The mechanisms by which therapeutic resistance arises are multifactorial. Recent evidence has shown that extracellular vesicles (EVs) play a role in mediating drug resistance. EVs are small vesicles carrying a variety of macromolecular cargo released by cells into the extracellular space and can be taken up into recipient cells, resulting in transfer of cellular material. EVs can mediate drug resistance by several mechanisms. They can serve as a pathway for sequestration of cytotoxic drugs, reducing the effective concentration at target sites. They can act as decoys carrying membrane proteins and capturing monoclonal antibodies intended to target receptors at the cell surface. EVs from resistant tumor cells can deliver mRNA, miRNA, long noncoding RNA, and protein inducing resistance in sensitive cells. This provides a new model for how resistance that arises can then spread through a heterogeneous tumor. EVs also mediate cross-talk between cancer cells and stromal cells in the tumor microenvironment, leading to tumor progression and acquisition of therapeutic resistance. In this review, we will describe what is known about how EVs can induce drug resistance, and discuss the ways in which EVs could be used as therapeutic targets or diagnostic markers for managing cancer treatment. While further characterization of the vesiculome and the mechanisms of EV function are still required, EVs offer an exciting opportunity in the fight against cancer.

MicroRNAs in cancer drug resistance: Basic evidence and clinical applications

“…Therefore, these miRNAs provide an intercellular network in the tumor microenvironment in different types of tumors. Transfer of miRNAs between cancerous cells can influence parenchymal and endothelial cells of the tumor microenvironment, leading to angiogenesis or drug resistance or tumor progression, and suppressing the immune responses, and at the same time may be involved in communications with exogenous miRNA in the exosomes that may result in metastasis of tumor (Evans‐Knowell, LaRue, & Findlay, ; Samuel, Fabbri, & Carter, ; Tomasetti, Lee, Santarelli, & Neuzil, ). However, in hematological malignancies, the tumor microenvironment is different from that in solid tumors.…”

A new role for extracellular vesicles: how small vesicles can feed tumors' big appetite

“…For clarity, in this review, the term "exosome" used in many of the cited by guest, on June 8, 2019 www.jlr.org Downloaded from proven the involvement of EVs in transfer of metastatic potential between tumor cells in vitro (19)(20)(21) and in vivo (22). Moreover, EVs can mediate drug resistance through the sequestration, transport and/or expulsion of chemotherapeutic drugs from tumor cells [for recent reviews concerning this point, see (23,24)]. …”

Extracellular vesicles, news about their role in immune cells: physiology, pathology and diseases

“…This combination, however, is not always successful. Therapy in this case consists of the prevention or elimination of the EV mechanisms of action [62,74]. These effects are at least potentially critical because, together with the cross-talk of cancer cells with stromal cells, they play substantial roles in the establishment of cancer.…”

“…These effects are at least potentially critical because, together with the cross-talk of cancer cells with stromal cells, they play substantial roles in the establishment of cancer. Therapy in this case consists of the prevention or elimination of the EV mechanisms of action [62,74].…”