Ingestion is the preferred way for drug administration. However, many drugs have poor oral bioavailability, warranting the use of injections. Extracellular vesicles (EVs) from cow milk have shown potential utility in improving oral drug bioavailability. However, EVs produced by intestinal epithelial cells have not been investigated for this application. We compared the capacity of cow milk EVs and intestinal epithelial cell-derived counterparts to enhance oral drug bioavailability. EVs were isolated, fluorescently labelled, and loaded with curcumin (CUR) as a model poorly absorbable drug. These were then characterised before testing in an intestinal model (Caco-2). Epithelial cell-derived EVs showed notably higher cell uptake compared to cow milk EVs. Cell uptake was significantly higher in differentiated compared to undifferentiated cells for both types of EVs. While both milk- and cell-derived EVs improved the cell uptake and intestinal permeability of CUR (confirming oral drug bioavailability enhancement potential), epithelial cell EVs demonstrated a superior effect.

The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2^−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy.

Squamous cell carcinomas (SCC) include a number of different types of tumors developing in the skin, in hollow organs, as well as the upper aerodigestive tract (UADT) including the head and neck region and the esophagus which will be dealt with in this review. These tumors are often refractory to current therapeutic approaches with poor patient outcome. The most important prognostic determinant of SCC tumors is the presence of distant metastasis, significantly correlating with low patient survival rates. Rapidly emerging evidence indicate that the extracellular matrix (ECM) composition and remodeling profoundly affect SSC metastatic dissemination. In this review, we will summarize the current knowledge on the role of ECM and its remodeling enzymes in affecting the growth and dissemination of UADT SCC. Taken together, these published evidence suggest that a thorough analysis of the ECM composition in the UADT SCC microenvironment may help disclosing the mechanism of resistance to the treatments and help defining possible targets for clinical intervention.

In recent years, the tumor microenvironment has gained recognition as a key regulator of cancer progression. A central component of the tumor microenvironment, the extracellular matrix, undergoes dynamic remodeling during tumor development and plays a crucial role in disease pathogenesis. This review highlights the EMILIN/Multimerin family as a paradigm of the extracellular matrix's diverse and complex functions in cancer. Owing to their intricate domain architecture, these proteins engage in multifaceted interactions, not only directly modulating tumor cell proliferation and migration but also influencing other elements of the tumor microenvironment such as blood, lymphatic vessels, and immune cells. The functional landscape of these interactions is further complicated by proteolytic processing, which can both disrupt native functions and generate bioactive fragments with novel biological activities. Importantly, some of these fragments are detectable in biological fluids, suggesting their potential as predictive or prognostic biomarkers and contributing to the advancement of personalized therapeutic strategies.