Extracellular vesicles-mediated intercellular communication: roles in the tumor microenvironment and anti-cancer drug resistance

Abstract

The tumor microenvironment represents a complex network, in which tumor cells not only communicate with each other but also with stromal and immune cells. Current research has demonstrated the vital role of the tumor microenvironment in supporting tumor phenotype via a sophisticated system of intercellular communication through direct cell-to-cell contact or by classical paracrine signaling loops of cytokines or growth factors. Recently, extracellular vesicles have emerged as an important mechanism of cellular interchange of bioactive molecules. Extracellular vesicles isolated from tumor and stromal cells have been implicated in various steps of tumor progression, such as proliferation, angiogenesis, metastasis, and drug resistance. Inhibition of extracellular vesicles secretion, and thus of the transfer of oncogenic molecules, holds promise for preventing tumor growth and drug resistance. This review focuses on the role of extracellular vesicles in modulating the tumor microenvironment by addressing different aspects of the bidirectional interactions among tumor and tumor-associated cells. The contribution of extracellular vesicles to drug resistance will also be discussed as well as therapeutic strategies targeting extracellular vesicles production for the treatment of cancer.

Keywords: Drug resistance; Extracellular vesicles; Metastasis; Stroma; Tumor microenvironment.

Fig. 1

Role of the extracellular vesicles-mediated intercommunication in tumor development and progression. Tumor and stromal cells release extracellular vesicles as a mean of communication contributing to the complexity and heterogeneity of the tumor microenvironment. Extracellular vesicles-mediated transport of bioactive materials can induce a tumor microenvironment favorable for tumor growth and resistance to anti-cancer drugs

Fig. 2

Mechanisms of extracellular vesicles-mediated transfer of anti-cancer drug resistance. Extracellular vesicles can mediate drug resistance by directly exporting or sequestering cytotoxic drugs reducing their effective concentration at target sites. Extracellular vesicles can also compete with bona fide target cells for the binding of immunotherapeutic agents targeting cellular antigens. Extracellular vesicles also mediate transfer of drug resistance to drug-sensitive cancer cells through the horizontal transfer of specific bioactive cargoes including drug efflux pumps, prosurvival factors, inhibitors of apoptosis, and non-coding RNAs