**6. Extracellular vesicles as therapeutic targets in cancers**

Communication between cells in a tumor microorganism is largely via chemokines, cytokines, or growth factors [10]. These notwithstanding, EVs from cells in the tumor microenvironment are also noted to facilitate such communications owing to their role in tumor progression [103]. EVs are endogenous vesicles whose composition and function makes them attractive vehicles for the delivery of therapeutic agents to target cells. They have experienced increasing attention in recent years since studies into their roles demonstrated their importance as therapeutic nanomaterials. Compared to some existing synthetic or traditional carriers, EVs are considered more suitable for use as nanovesicles due to their characteristic properties of being intrinsically biocompatible, low immunogenicity and toxicity and their ability to cross-physiological barriers such as the blood-brain barrier. In addition, they have biodegradable and modification abilities and have the capability to escape clearing actions of the immune system [104, 105]. The first report of a successful therapeutic application of EVs was reported by Alvarez-Erviti et al. [106] in 2011. In that study, modified exosomes were exploited and a transfer of siRNAs was made into the brain of mice, which resulted in a knock down of the targeted gene. Supporting this hypothesis, a study by Saari et al. observed the delivery of chemotherapeutics to recipient cells and these were subsequently released into intracellular milieu to give rise to an increased cytotoxic bioactivity. The chemotherapeutics were noted to have been loaded by tumor-cell derived EVs [107]. There are three main approaches that are utilized by EVs in their role as therapeutic agents that include elimination of EVs in circulation, inhibition of secretion and disruption of the absorption of EVs.

The elimination of EVs secreted by cancer cells has been one of EV-targeting therapeutic strategies. The first report of the use of this target therapeutic approach was by Marleau et al., [108]. In the study, a hemofiltration system that was capable of targeting EVs from cancer cells by specifically aiming at human epidermal growth factor receptor 2 (HER-2) on the surface of EVs was proven [108]. This targeting of HER-2 which results in the selective elimination of cancer derived-EVs could be very valuable for cancer treatment [109].

A number of studies have focused on other strategies that block EV secretion. Inhibition of intraluminal vesicles formation and release of EVs by the fusion of MVBs to the plasma membrane have been achieve by the use of a sphingomyelinase inhibitor drug, GW4869 [110, 111]. Again, the inhibition of EV production and the transfer of miR-210-3p have reportedly been achieved by the attenuation of neutral sphingomyelinase 2 (nSMase2). nSMase2 is known to control the synthesis of ceramide and suppresses angiogenesis and metastasis in breast cancer xenograft model [112]. Conversely, EV secretion from prostate cancer cells was not inhibited by the downregulation of nSMase2. Meanwhile, nSMases have been revealed in normal neural cells [113, 114]. Their presence in these normal cells indicates the inhibition of some other fundamental pathways. Cancer specific mechanisms of EV secretion are therefore very crucial in the establishment of the role of EVs as cancer therapeutic targets. Quite recently, a group of researchers have identified a number of activators and inhibitors of EV production from prostate cancer cells [115]. This implies a clear understanding of cancer specific mechanism of EV production is required in identifying cancer-specific therapies mediated by targeted EVs.

Reports into the role of EVs have shown that the process of anti-melanoma is facilitated by EVs released by natural killer cells [116]. Similarly, the abundance of histocompatibility complex classes I and II from dendritic cells are capable of *Extracellular Vesicles as Biomarkers and Therapeutic Targets in Cancers DOI: http://dx.doi.org/10.5772/intechopen.101783*

triggering other immune system cell types and also activate antitumour immune responses [117]. The use of these traditional methods in obtaining EVs for direct use as cancer therapeutic targets are not without challenges. Indistinct production mechanisms, low product yield, and the high probability of obtaining EV contents that stand the chance of mutation are a few of such challenges faced by these methods. The intrinsic properties of EVs, however, makes the engineering of these nanoparticles for the purpose of drug delivery to target cells a more favorable approach for cancer management. Engineering parental cells to shed EVs with a particular cargo or loading it directly can achieve encapsulating of therapeutic cargoes into EVs. This has been utilized in breast cancer and leukemia cell studies by Usman et al., [118] in the delivery of RNA drugs by RBC-derived EVs (RBCEVs) which showed an improved miRNA inhibition and CRISPR-Cas9 genome editing with no known cytotoxicity. Other studies on the engineering of EVs include research using mesenchymal stem cells in the overexpression of MiR-379 to obtain MiR-379-rich EVs which functions to subdue metastatic breast cancer development [119].
