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Phosphoinositide-specific phospholipases C (PLCs) are a class of enzymes involved in several cell activities, such as cell cycle regulation, proliferation, differentiation and cytoskeletal dynamics. Among these enzymes, PLCγ1 is one of the most expressed PLCs in the brain, contributing to a complex network in the developing nervous system. Several studies have shown that PLCγ1 signaling imbalance is linked to several brain disorders, including glioblastoma, the most aggressive brain tumor in adults. Indeed, it has been demonstrated a link between PLCγ1 inhibition and the arrest of glioma cell motility of fetal rat brain aggregates and the impairment of cell invasion abilities following its down-regulation. This study aims to determine the pathological influence of PLCγ1 in glioblastoma, through a translational study which combines in silico data, data from glioblastoma patients' samples and data on engineered cell lines. We found out that PLCγ1 gene expression correlates with the pathological grade of gliomas, and it is higher in fifty patients' glioblastoma tissue samples compared to twenty healthy controls. Moreover, it was demonstrated that PLCγ1 silencing in U87-MG leads to a reduction in cell migration and invasion abilities. The opposite trend was observed following PLCγ1 overexpression, suggesting an interesting possible involvement of PLCγ1 in gliomas' aggressiveness.

The immune system is a complex network that acts to protect vertebrates from foreign microorganisms and carries out immunosurveillance to combat cancer. In order to avoid hyper-activation of the immune system leading to collateral damage tissues and organs and to prevent self-attack, the network has the intrinsic control mechanisms that negatively regulate immune responses. Central to this negative regulation are regulatory T (T-Reg) cells, which through cytokine secretion and cell interaction limit uncontrolled clonal expansion and functions of activated immune cells. Given that positive or negative manipulation of T-Regs activity could be utilised to therapeutically treat host versus graft rejection or cancer respectively, understanding how signaling pathways impact on T-Regs function should reveal potential targets with which to intervene. The phosphatidylinositol-3-kinase (PI3K) pathway controls a vast array of cellular processes and is critical in T cell activation. Here we focus on phosphoinositide 3-kinases (PI3Ks) and their ability to regulate T-Regs cell differentiation and function.

The activation of inositide signalling pathways, such as Akt/mTOR, has been demonstrated in high-risk MDS (1). Lenalidomide is currently used in the treatment of del(5q) low-risk MDS patients, where it may suppress the del(5q) clone and restore a normal erythropoiesis, via inhibition of Akt phosphorylation (2). Here, we studied the expression of inositide signalling molecules in 6 low-risk MDS patients who were given Lenalidomide by immunocytochemistry and Real-Time PCR. In our case series, 4 out of 6 del(5q) low-risk MDS patients responded to Lenalidomide and showed an activation of erythropoiesis, in that Beta-Globin levels increased, as compared with baseline. Moreover, these subjects also displayed an activation of PI-PLCgamma1 and Akt. Interestingly, Akt resulted to be specifically phosphorylated in cells not showing the 5q deletion, hinting at a clonal activation of this pathway. The 2 non responder patients early discontinued Lenalidomide for adverse events, and for these patients neither a clinical assessment of Lenalidomide effect, nor a molecular analysis, were possible. Our data show Akt/PI-PLCgamma1 activation during Lenalidomide treatment, and confirm the activation of erythropoiesis in responder patients. In addition, our results indicate that Akt is specifically phosphorylated in the 5q+ clone. Therefore, it is conceivable that Lenalidomide strengthens the proliferation of the 5q+ clone, whilst the del(5q) clone undergoes an apoptotic process, allowing the restoration of the normal erythropoiesis. This is extremely important, not only for MDS pathogenesis, but also for the development of innovative targeted therapies.