Exosome-mediated drug resistance in cancer: the near future is here

Drug resistance exerts a crucial role in several cancer treatments. Understanding the resistance mechanisms against different therapeutic agents can be helpful to determine the prognosis, but remains a tricky task. In this context, tumor-derived exosomes (TDEs) may give crucial answers about these resistance mechanisms. Exosomes are biological nanovesicles with an average size around 30–100 nm of diameter (Figure 1) that originate from the endocytic pathway by the inward budding of multivesicular bodies (MVB), and they function as cell-free messengers, involved in the cell–cell communication [Kowal et al. 2014]. It has been demonstrated that both cells in physiological and pathological conditions release exosomes and that exosomes are easily detected in several body fluids, such as plasma, serum, urine, saliva, etc. [Rolfo et al. 2014]. It has been demonstrated that TDEs contain different proteins, lipids, mRNAs and miRNAs and have pleiotropic functions in the tumor microenvironment, tumor growth and progression, immune escape, angiogenesis, invasion, and drug resistance [Kowal et al. 2014; Rolfo et al. 2014; Fontana et al. 2013].

Figure 1.

Image of exosomes, released in the plasma of a non-small cell lung cancer patient, performed through transmission electron microscopy analysis.

Currently, there are three frequently described exosome-mediated drug resistance mechanisms: drug export via the exosome pathway, neutralization of antibody-based drugs and exosome-mediated transfer of miRNAs (Figure 2) [Chen et al. 2014b; Ciravolo et al. 2012; Corcoran et al. 2012; Safaei et al. 2005; Wei et al. 2014].

Figure 2.

Overview of three well-described exosome-mediated drug-resistance mechanisms.

In a preclinical study, it was demonstrated that exosomes released from cisplatin-resistant ovarian carcinoma cells contained 2.6-fold more cisplatin respect to exosomes released from cisplatin-sensitive ovarian carcinoma cells, suggesting that cancer cells exploited the endocytic compartment as drug export vector [Safaei et al. 2005]. In addition, it was also described that cancer cells can release drugs or their metabolites through exosomal pathway mediated by ABC transport. In this context, it was demonstrated in prostate cancer that exosomal transfer of multidrug resistance proteins such as multidrug resistance protein 1 (MDR-1/P-gp) could be related to docetaxel resistance [Corcoran et al. 2012]. Interestingly, an exosome-mediated transfer of MDR-1 from nonsensitive to sensitive breast cancer cells to docetaxel was observed, transferring docetaxel drug resistance to sensitive cells [Lv et al. 2014]. It was also described that mesenchymal stem cells derived exosomes could induce, both in vivo and ex vivo, 5-fluorouracil drug resistance in gastric cancer cells enhancing the expression of MDR-1, lung resistance protein (LRP) and multidrug resistance-related protein (MRP) through CaM-Ks/Raf/MEK/ERK pathway activation [Ji et al. 2015].

The idea to discover the mechanisms that lead to early antibody-based drug resistance in cancer cells is very attractive. In this field, Ciravolo and colleagues described that, both in vitro and in vivo, TDEs are involved into neutralizing antibody-based drugs: HER2-overexpressing breast carcinoma cell lines released TDEs containing HER2 protein that could bind the anti-HER2 antibody trastuzumab. This interaction leads to a decrease in the real amount of antibody-based drug that can interact with cancer cells and eventually decreased the overall effect of trastuzumab [Ciravolo et al. 2012].

During the last few years, there is a lot of interest in drug resistance by exosome-mediated transfer of miRNAs. Currently, several studies indicate that TDEs function also as a genetic exchange vector in the tumor microenviroment. Several in vitro studies suggest that breast cancer cells resistant to different drugs (docetaxel–adriamycin–tamoxifen) may transfer the resistance to sensitive cells in part by exosomal miRNAs exchange [Chen et al. 2014a, 2014b; Wei et al. 2014]. Similar results were obtained in ovarian cancer preclinical studies, it was demonstrated that a cisplatin-resistant ovarian cancer cell line transfers the resistance to sensitive cells by exosomal exchange of biologically active miR-21-3p, which targeted the NAV3 gene [Pink et al. 2015]. Moreover, the role of exosomal miRNAs in drug resistance mediated by the cross-talk with the tumor microenviroment in neuroblastoma (NBL) was investigated. In a preclinical study, Challagundla and colleagues demonstrated that exosomes released from the NBL cell line transferred the oncomiR-21 to human monocytes. This genetic information exchange led monocytes to transcribe oncomiR-155 in a NF-κB-dependent pathway and, interestingly, monocytes released exosomes containing miR-155 that was, in turn, internalized by NBL cells. One of described target of miR-155 is TERF1, a telomerase inhibitor; silencing of TERF1 mRNAs caused alterations of telomerase activity, which could lead to an increased resistance to DNA-damage induced by cisplatin [Challagundla et al. 2015]. Furthermore, other exosomal proteins lead to a drug-resistant phenotype changes in the target cells, for example, it has been demonstrated that PTEN is released in exosomes thus exerting biological functions in target cells [Putz et al. 2012]. Moreover, it has been described that the loss of function of PTEN increases resistance to chemotherapeutic and sensitivity to mTOR inhibitors in breast cancer and, then, PTEN exosomal transfer could be exploited as a transfer mechanism of drug resistance changes [Steelman et al. 2008].

Altogether, these findings suggest a crucial role for exosomes in drug resistance in several tumor types. Notable, in the liquid biopsy research field, it could be an attractive idea to analyze selected exosome groups among the total population in different body fluids. Regrettably, especially in cancer patients, the challenge for a good discrimination of TDEs among the total exosome population in body fluids (such as in blood) is still open. However, it seems that the amount of TDEs is prevalent in the total exosome population [Milane et al. 2015]. The new era of liquid biopsies is growing very fast, and less-known components, such as exosomes, may also be exploited as a source of biomarkers. Could exosomal drug resistance biomarkers finally be used in clinical practice? Probably the near future is here, and after more research and validation, exosomal drug resistance biomarkers could lead to a more defined insight into resistance mechanisms against several targeted therapies in cancer.