Fibroblasts in the tumor microenvironment have been proven to actively participate in tumor progression; they can be “educated” by cancer cells acquiring an activated state and, as such, are identified as cancer-associated fibroblasts (CAFs); CAFs, in turn, remodel tumor stroma to be more advantageous for cancer progression by modulating several processes, including angiogenesis, immunosuppression, and drug access, presumably driving the chemoresistance. That is why they are believed to hamper the response to clinical therapeutic options. The communication between cancer cells and fibroblasts can be mediated by extracellular vesicles (EVs), composed of both exosomes (EXOs) and microvesicles (MVs). To verify the role of different subpopulations of EVs in this cross-talk, a nearly pure subpopulation of EXO-like EVs and the second one of mixed EXO- and MV-like EVs were isolated from ovarian cancer cells and administered to fibroblasts. It turned out that EVs can activate fibroblasts to a CAF-like state, supporting their proliferation, motility, invasiveness, and enzyme expression; EXO-like EV subpopulation seems to be more efficient in some of those processes, suggesting different roles for different EV subpopulations. Moreover, the secretome of these “activated” fibroblasts, composed of both soluble and EV-associated molecules, was, in turn, able to modulate the response of bystander cells (fibroblasts, tumor, and endothelial cells), supporting the idea that EVs sustain the mutual cross-talk between tumor cells and CAFs.

Plant-Derived Extracellular Vesicles extracellular vesicles (PDEVs) from organic agriculture (without the use of pesticides and microbicides) contain high levels of antioxidants. Organic PDEVs have shown an increased antioxidant power compared to PDEVs from single plants, suggesting a synergistic effect of the bioactives constitutively expressed in the PDEVs from single fruits. With this study, we wanted to investigate the beneficial effects of a mix of PDEVs on human skin cells. We found detectable levels of citric acid, ascorbic acid, glutathione, catalase, and SOD in a mix of PDEVs deriving from five different fruits (grape, red orange, papaya, pomegranate, and tangerine). We then treated H₂O₂-conditioned fibroblasts with the mix of PDEVs. The results showed that the PDEVs’ mixture reverted the H₂O₂-induced redox imbalance, restoring mitochondrial homeostasis, with a strong reduction of mitochondrial anion superoxide and an increase in sirtuin levels. The antioxidant action was consistent with wound repair on a lesion produced in a fibroblast’s monolayer. This result was consistent with an increased level of vimentin and matrix metalloproteinase-9, whose expression is directly related to the efficiency of the reparative processes. These data support a beneficial role of PDEVs in both preventing and treating skin injuries through their potent antioxidant and reparative activities.

Cancer is a major cause of mortality in humans; often, rather than the primary tumor, it is the presence of metastases that are the cause of death. Extracellular vesicles (EVs) are small structures released by both normal and cancer cells; regarding the latter, they have been demonstrated to modulate almost all cancer-related processes, such as invasion, angiogenesis induction, drug resistance, and immune evasion. In the last years, it has become clear how EVs are widely involved in metastatic dissemination as well as in pre-metastatic niche (PMN) formation. Indeed, in order to achieve a successful metastatic process, i.e., penetration by cancer cells into distant tissues, the shaping of a favorable environment into those distant tissue, i.e., PMN formation, is mandatory. This process consists of an alteration that takes place in a distant organ and paves the way for the engraftment and growth of circulating tumor cells derived from the tumor primary site. This review focuses on the role of EVs in pre-metastatic niche formation and metastatic dissemination, also reporting the last studies suggesting the EVs role as biomarkers of metastatic diseases, possibly in a liquid biopsy approach.

The role of extracellular vesicles (EVs) as mediators of cell-to-cell communication in cancer progression is widely recognized. In vitro studies are routinely performed on 2D culture models, but recent studies suggest that 3D cultures could represent a more valid model. Human ovarian cancer cells CABA I were cultured by the hanging drop method to form tumor spheroids, that were moved to low adhesion supports to observe their morphology by Scanning Electron Microscopy (SEM) and to isolate the EVs. EVs release was verified by SEM and their identity confirmed by morphology (Transmission Electron Microscopy, TEM), size distribution (Nanoparticles Tracking Analysis), and markers (CD63, CD9, TSG-101, Calnexin). CABA I form spheroids with a clinically relevant size, above 400 μm; they release EVs on their external surface and also trap “inner” EVs. They also produce vasculogenic mimicry-like tubules, that bulge from the spheroid and are composed of a hollow lumen delimited by tumor cells. CABA I can be grown as multicellular spheroids to easily isolate EVs. The presence of features typical of in vivo tumors (inner entrapped EVs and vasculogenic mimicry) suggests their use as faithful experimental models to screen therapeutic drugs targeting these pro-tumorigenic processes.

Plant-Derived Extracellular Vesicles (PDEVs) contain high levels of antioxidants, especially when deriving from organic. PDEVs from different vegetal sources has shown an increased antioxidant power, compared to PDEVs from single plants, suggesting a synergistic effect of the bioactives constitutively expressed in the PDEVs from single fruits. With this study we wanted to investigate the beneficial effects of a mix of PDEVs on human skin cells. We found detectable levels of Citric Acid, Ascorbic Acid, Glutathione, Catalase and SOD in a mix of PDEVs deriving from 5 different fruits (Grape, Red Orange, Papaya, Pomegranate and Tangerine). We then treated H2O2-conditioned fibroblasts with the mix of PDEVs. The results showed that the PDEVs ‘mix reverted the H2O2-induced redox imbalance, restoring the mitochondrial homeostasis, with a strong reduction of mitochondrial anion superoxide and increase of sirtuin levels. The antioxidant action was consistent with a wound repair on a lesion produced in a Fibroblasts’ monolayer. This result was consistent with an increased level of Vimentin and Matrix Metalloproteinase-9, whose expression is directly related to the efficiency of the reparative processes. These data support a beneficial role of PDEVs in both preventing and treating skin injuries, through their potent antioxidant and reparative activities.