Ricerc@Sapienza

Glioblastoma multiforme (GBM) is the most frequent and malignant type of brain tumor. GBM is one of the abundant vasculature tumors and microvessel density correlates to high invasiveness and treatment resistance. Malignant gliomas are characterized by cellular heterogeneity. In particular, the presence of an undifferentiated cell population defined Glioblastoma Stem Cells (GSCs) has been reported. GSCs are considered the main cell population responsible for the beginning of the development of neoplastic process and recurrence formation. Several studies indicate that GSCs are able to differentiate into endothelial-like cells. These glioblastoma-derived endothelial cells are usually abnormal cells, generated by a process termed Vasculogenic Mimicry. This ability of GSCs correlates with increasing malignancy and aggressiveness of tumor. Previous studies performed in our laboratory have focused on the effects mediated by muscarinic receptors activation in GBM. In particular, we have analyzed the effects mediated by M2 receptor activation both in glioblastoma cell lines and in GSCs, obtained from human glioblastoma biopsies. The activation of muscarinic M2 receptor by orthosteric agonist Arecaidine Propargyl Ester (APE) caused a significant decrease of cell proliferation and survival (Ferretti et al, 2013; Di Bari et al, 2018). Recently we have tested a new dualsteric agonist for M2 receptor, N8-Iperoxo, that showed high selectivity and more efficiency than APE and that is able to activate M2 receptor at very low concentration (Cristofaro et al, 2018). Preliminary data also showed that M2 receptor was able to impair the in vitro vasculogenesis in Huvec. Starting from this evidence, in this project we will evaluate the ability of the N8-Iperoxo to negatively modulate neo-angiogenesis-GSCs derived. The impairment of GSCs differentiation into endothelial-like cells could represent an additional therapeutic strategy to counteract glioblastoma growth and invasiveness.