Extracellular Vesicles and Resistance to Anticancer Drugs: A Tumor Skeleton Key for Unhinging Chemotherapies

Abstract

Although surgical procedures and clinical care allow reaching high success in fighting most tumors, cancer is still a formidable foe. Recurrence and metastatization dampen the patients' overall survival after the first diagnosis; nevertheless, the large knowledge of the molecular bases drives these aspects. Chemoresistance is tightly linked to these features and is mainly responsible for the failure of cancer eradication, leaving patients without a crucial medical strategy. Many pathways have been elucidated to trigger insensitiveness to drugs, generally associated with the promotion of tumor growth, aggressiveness, and metastatisation. The main mechanisms reported are the expression of transporter proteins, the induction or mutations of oncogenes and transcription factors, the alteration in genomic or mitochondrial DNA, the triggering of autophagy or epithelial-to-mesenchymal transition, the acquisition of a stem phenotype, and the activation of tumor microenvironment cells. Extracellular vesicles (EVs) can directly transfer or epigenetically induce to a target cell the molecular machinery responsible for the acquisition of resistance to drugs. In this review, we resume the main body of knowledge supporting the crucial role of EVs in the context of chemoresistance, with a particular emphasis on the mechanisms related to some of the main drugs used to fight cancer.

Keywords: chemoresistance; extracellular vesicles; metastasis; tumor microenvironment; tumor recurrence.

Figure 1

Schematization of the biogenesis of the three classes of EVs. Small EVs arise from the shedding of MVBs fusing with the plasma membrane (PM). Three main paths are described for the formation of MVBs, entrapping in the cytoplasmatic components of ILVs. Medium and large EVs are derived for the budding of PM, pulling the constituent of PM. Apoptotic bodies (APOBs) are released after an irreversible injury to the cell, triggering apoptotic cell death and the perturbation of PM. MVBs, multivesicular bodies; ILVs, intraluminal vesicles; ESCRT, endosomal sorting complexes required for transport.

Figure 2

Cartoon summarizing the main mechanisms involved in the induction of the phenomenon of tumor drug resistance. Upon the influence of these pathways, drug-resistant cancer cells acquire an enhanced invasive ability, break away from the original tumor site, and finally metastasize to other organs through the blood or lymphatic systems. This figure was drawn with the support of the bioicons website (https://bioicons.com/).

Figure 3

Cartoon illustrating the involvement of EVs in the spreading of chemoresistance among the cells of the tumor microenvironment (TME). The drugs induce the modification of the gene expression of primary tumor cells or TME cells. These cells release EVs enriched in the molecular players involved in the acquisition of drug resistance in the EV-donor cells, finally taken up by the sensitive tumor cells acquiring the insensitiveness toward the chemotherapeutic. Bottom-right box: molecular effectors involved in drug resistance shuttled through the EVs. ncRNAs, non-coding RNAs; mRNAs, messenger RNAs. This figure was drawn with the support of the bioicons website.

Figure 4

Scheme summarizing the mechanism of drug resistance activated by EVs. Examples of molecular players for each category, as described in Figure 2 , are reported. Only molecules shuttled by EVs are reported.