**9. The role of EV proteins and RNA transfers in cancer drug resistance**

Although cargoes of EVs are passively packaged into EVs, evidence have shown the existence of selective packaging as well [163]. Major components of EVs include protein that contribute to determining the destination of EVs and also influence the phenotype of recipient cells [163]. Vesicular protein transfers between cells constitute a potential mechanism of action of these effects. An example is the transfer of an ATP binding cassette called P-glycoprotein (P-gp), which has been reported to mediate resistance in recipient cells during their transfer between cells. In other instances, it is the expression of P-gp that becomes induced in receiver cells after a different kind of protein is delivered [164]. For example, the transfer of TrpC5 protein to recipient cells by adriamycin resistant MCF7 cells through EVs is known to stimulate the translocation of NFATc3 protein resulting in the transcriptional activation of MDR1 (ABCB1) promoter [165]. The characteristics and pathways by which drug-sensitive cells acquire resistance from EVs containing P-gp have been investigated quite extensively. The process of transfer of cancer traits from drug resistant cells to drug sensitive cells is dependent on characteristics of donor cell. While EVs from cells of leukemia transfer P-gp to malignant and non-malignant cells, those from drug resistant breast cancer cells transfer P-gp to malignant recipient cells only [166]. These findings demonstrated that P-gp transfer by EVs are potentially tissue selective and are likely associated with the cell of origin of EVs rather than their possible relation to a particular feature of recipient cell membrane [166]. In another study, de-Souza et al., [167] explored the selectivity of P-gp transfer and found no discrimination in relation to cell-type. In their study, EVs from drug-resistant leukemia cells could transfer P-gp to drug-sensitive lung and breast cancer cells. Altogether, these findings indicate the debatable issue of the selectivity of EV cargo and therefore require further investigation.

EVs can also carry non-coding RNAs such as miRNAs, IncRNAs, and circRNAs which are noted to mediate cell to cell transfer of resistance [164, 168]. These RNAs have been found to be associated with cancer progression and their deregulation is noted to support drug resistance in tumors of diverse origins [169–171]. Through the transmission of active biomolecules to neighboring cells, these various RNAs induce drug resistance in recipient cells. The transmitted biomolecules regulates certain genes together with their corresponding signaling pathways [168].

miRNAs contributes to the progress of chemoresistance by influencing the genes that are involved in cell cycle, cell proliferation and survival, apoptosis and immunity [172]. They regulate the genes by inhibiting the translation of mRNA. miRNAs have been reported in several studies to play a role in EV mediated chemoresistance. For instance, several miRNAs have been identified to be involved in the transfer of gemcitabine resistance. Gemcitabine is a chelator of DNA that gets activated by deoxycytidine kinase. EVs secreted by macrophages associated with tumors and having miR-365 cargoes have been identified to induce resistance of pancreatic ductal adenocarcinoma cells in the treatment of gemcitabine. The concentration of triphosphate nucleotides (NTPs) in the recipient cells become increased by miRNAs and the result is competitive interaction between activated gemcitabine and the increased levels of NTPs which efficiently reduces the efficacy of gemcitabine [173]. In another study, abundance of miR-1246 was observed to have been present in EVs secreted by paclitaxel resistant ovarian cancer cells. The transfer of this miRNA upregulated the expression of ABCB1 and inhibited the expression of Cav1 to facilitate paclitaxel efflux and in the process promoting drug resistance phenotype in recipient cells [174]. Conversely, EVs secreted by cancer-associated fibroblasts were found to contain miR-106 when exposed to gemcitabine. Resistance of pancreatic cancer cells (AsPC-1) against the treatment of gemcitabine has been found to be associated with the uptake of miR-106 enriched EVs [175].

Several studies have also made efforts to demonstrate the link between specific EV-transferred miRNAs and drug resistance. Through the EV-mediated transfer of miR-21, drug resistance has been found to be induced in MCF7 cells after they

*Extracellular Vesicles as Biomarkers and Therapeutic Targets in Cancers DOI: http://dx.doi.org/10.5772/intechopen.101783*

were co-cultured with EVs from multidrug-resistant chronic myeloid leukemia cell lines [167], Again, cisplatin resistance in lung cancer cells by miR-96 [176], Adriamycin resistance in breast cancer by miR-222 [148], and EVs' miR-155 mediated gemcitabine resistance in pancreatic cancer cells [177] have been reported. Further studies found exosomal miR-19b mediated oxaliplatin-resistance in SW480 colorectal cancer cells [178], tamoxifen-resistance in ER-positive breast cancer MCF7 cells by miR221/222 [179].
