*4.1.2. Cancer cell-derived EVs*

Since it is known that EVs released from normal cells trigger positive effects and those released from cells under pathological conditions usually trigger undesirable effects, it might initially seem surprising that cancer cell-derived EVs could play a therapeutic role. Cancer cell-derived MVs carrying tumour antigens could actually help in initiating immune attacks by providing these antigens to antigen-presenting cells. These cells would then activate a T cell-dependent immune response against the tumour; their antigen content theoretically makes them ideal cancer vaccines. This has been reported in a number of studies of animal models of cancer [79, 80].

#### *4.1.3. Normal cell-derived EVs*

Normal cell-derived EVs can be used as drug delivery systems that transfer therapeutic nucleic acids or proteins. Unlike synthetic liposomes and viral vectors, EVs would be immunologically protected as 'self'. In addition to being sufficiently stable with a long tissue half-life, the small size of cell-derived EVs is suitable to allow them to penetrate through the target tissues [81] and cross biological barriers [2] and at the same time be large enough to carry sufficient payload. Moreover, MVs are capable of carrying a wide range of bioactive components, including mRNA, miRNA, DNA and proteins. In this regard, most studies have focused on the delivery of genes to cancerous cells to either replace dysfunctional tumour suppressor genes or to activate immune rejection or trigger cells into apoptotic pathways. Another potential advantage of EVs that makes them competitive in the pool of delivery vehicles is the suggestion that specific peptides could be introduced into EVs to provide them with targeting abilities toward a certain tissue.

### *4.1.4. Immune cell-derived EVs*

poietic cells is by the horizontal transfer of chemokine receptors through EVs, which makes

Blocking specific signalling components of EVs was shown to have therapeutic significance. It was demonstrated that FASL-specific monoclonal antibodies targeting FASL1 displayed on EVs reduced tumour growth in a melanoma model [78]. However, this method may lack specificity and has negative impact on immune function. In the same way, the targeting of MET oncoprotein by RNAi to inhibit its active involvement into EVs was shown to be useful

All the above approaches highlight promising targets to develop small molecule therapeutics. Nevertheless, it is important to note that interfering with EV biogenesis could result in unwanted off-target effects, given that EVs are important for the regulation of normal core cellular processes and of course such approaches will need to be translated into a drug delivery

Since it is known that EVs released from normal cells trigger positive effects and those released from cells under pathological conditions usually trigger undesirable effects, it might initially seem surprising that cancer cell-derived EVs could play a therapeutic role. Cancer cell-derived MVs carrying tumour antigens could actually help in initiating immune attacks by providing these antigens to antigen-presenting cells. These cells would then activate a T cell-dependent immune response against the tumour; their antigen content theoretically makes them ideal cancer vaccines. This has been reported in a number of studies of animal models of cancer [79,

Normal cell-derived EVs can be used as drug delivery systems that transfer therapeutic nucleic acids or proteins. Unlike synthetic liposomes and viral vectors, EVs would be immunologically protected as 'self'. In addition to being sufficiently stable with a long tissue half-life, the small size of cell-derived EVs is suitable to allow them to penetrate through the target tissues [81] and cross biological barriers [2] and at the same time be large enough to carry sufficient payload. Moreover, MVs are capable of carrying a wide range of bioactive components, including mRNA, miRNA, DNA and proteins. In this regard, most studies have focused on the delivery of genes to cancerous cells to either replace dysfunctional tumour suppressor genes or to activate immune rejection or trigger cells into apoptotic pathways. Another potential advantage of EVs that makes them competitive in the pool of delivery vehicles is the suggestion that specific peptides could be introduced into EVs to provide them with targeting

these vesicles valued targets for investigation [34].

in reducing metastasis in late-stage melanoma [31].

system (DDS) that is capable of targeting specific EVs.

IV. Blocking specific EV components.

96 Tumor Metastasis

*4.1.2. Cancer cell-derived EVs*

*4.1.3. Normal cell-derived EVs*

abilities toward a certain tissue.

80].

EVs that are produced by immune cells have been shown to have an important role in the regulation of immunity. They can mediate immune stimulation or suppression and they can drive inflammatory, autoimmune and infectious disease pathology. Therefore, EVs have the potential to be used as therapeutic agents to modulate the immune system. It has been found that EVs released by B cell lines carry MHC class II, co-stimulatory and adhesion molecules indicating that such vesicles could directly stimulate CD4+ T cell clones [82]. This idea was further supported by the observation that the vaccination of mice with exosomes derived from tumour peptide-pulsed dendritic cells (DCs), enhanced tumour-specific cytotoxic T lympho‐ cytes (CTLs) and inhibited tumour growth in a T cell-dependent manner [83]. Numerous studies have shown the direct effects of EVs in T cell activation. It has been demonstrated that immature DC-derived EVs express a low ratio of co-stimulatory molecules to co-regulatory molecules on their surface and therefore act as immunosuppressives [84].
