Fig. 2

Drug-resistant cells can transfer the resistant phenotype through EVs. EVs released by drug-resistant cells contain proteins and miRNAs, which partake in propagating resistance. Drug-sensitive cells become gradually resistant when they incorporate ”resistant EVs”: Resistant cells (1) then over-express efflux pumps (P-gp) to eliminate anti-cancer drugs and produce more EVs, which again reflect the resistant phenotype of the secreting cell. Once in the extracellular environment, these EVs can be taken up by sensitive recipient cells (2) through fusion, endocytosis or binding to surface receptors. The released content acts on these cells, which in turn might also become drug-resistant (3). The lower part shows example trends of dose–response curves to a cytotoxic drug, representative of drug-resistant cells (1), drug-sensitive cells (2) and the same sensitive cells, which are becoming resistant after incubation with “resistant EVs” (3). The effectiveness of the drug to inhibit a specific biological function in the cells (exemplified by the inhibition of cell growth) is expressed by the IC₅₀ value. The higher this value, the more resistant the cells. The IC₅₀ value of cells which are acquiring the resistant phenotype would be in between the IC₅₀ values of the other two conditions: IC₅₀ (1) > IC₅₀ (3) > IC₅₀ (2)