Targeting the endothelium: novel therapeutic approaches using natural extracts, VEGF-mimetic peptides, and tumor angiogenic dynamics

The endothelium, as main topic of my PhD, studies has been analyzed in different physio pathological processes and in conjunction with the effect of chemical and bio-derivates approaches. Firstly, I focused on natural extracts, the molecule erucin and bio-derivate wood distillate, both exerting an anti-inflammatory and antioxidant potential, predictive of the protective effect on endothelium. By using cultured endothelial cells from human umbilical veins (HUVEC) we studied functional and molecular responses following exposure to erucin, a natural isothiocyanate derived from Brassicaceae plants and extracted from the seeds of rocket salad. Erucin promotes endothelial cell migration and tube formation, exerting a potential restoring and/or protective abilities in endothelial dysfunction, mediated by high glucose concentrations. At the same time, sweet chestnut (Castanea sativa) wood distillate (WD), extracted from waste biomass and used as a corroborant and biofertilizer in agriculture, showed both anti-inflammatory and antioxidant activities on the various cell types involved in transcutaneus absorption, skin wellness and wound healing, preserving endothelial functions and barrier integrity. Indeed, endothelial stability and proper functionality are fundamental elements to restore and maintain across a wide range of cardiovascular disorders (CVD), central or peripheral, such as ischemia, myocardial infarction and/or atherosclerosis. On this scenario, the second chapter highlights the therapeutic potential of peptide-based pro-angiogenic therapy in CVD, ischemic disorders and regenerative medicine. Indeed, the second topic aims to investigate the effects of VEGF-mimetic peptides, namely QK and HPLW-2, on endothelial features and functions, unveiling the molecular mechanisms behind their pro-angiogenic effects. Finally, the third topic collects a big part of my previous studies and interest dedicated to the preclinical and clinical cancer biology. During my PhD I was involved in a clinical observational study, trough the project CORELAB, aimed to the investigation of novel predictive biomarkers of immune checkpoint inhibitors (ICI) therapy in non-small cell lung cancer (NSCLC) patients. Approximately 100 patients were enrolled and profiled by the analysis of platelet-released angiogenic mediators. Indeed, their interactions and crosstalk with the tumor, made them became “Tumor educated platelets” that could represent a floating picture of tumor microenvironment. Therefore, analyzing them we tried to unveil the features of tumor mass and the surrounding microenvironment, affecting the different efficacy and clinical outcomes in ICI administration. On the whole, these data will be located in a bigger puzzle made by clinical, experimental and follow up data about the patients. In this context, it is also important to consider the imprinting effect that the TME exerts on tumor progression. The TME supports malignancy through a close crosstalk, mediated by various factors, particularly inflammatory cytokines. Indeed, the connection between inflammation and cancer has become an established paradigm in carcinogenesis. In collaboration with the University of Florence, we demonstrated a strong association between PGE2 and ERK5 in NSCLC. Our findings highlight the role of the PGE2/EP1/ERK5 axis in driving the malignancy of NSCLC cells in vitro.