Cross-talk between sphingosine-1-phosphate and EGF receptor mediated signaling pathways as a novel mechanism that promotes the invasiveness of human glioblastoma cells
Figure. In glioblastoma cells expressing EGFRvIII, ERK is phosphorylated (pERK), and therefore active, constitutively. In turn, pERK phosphorylates SK1 (pSK1) determining its activation with the consequent formation of S1P. S1P is released into the extracellular environment and binds to its S1P1R receptor which, once activated, phosphorylates AKT (pAKT) promoting the invasiveness of glioblastoma cells.
Glioblastoma multiforme is the most widespread and most aggressive human brain tumor. In fact, despite the progress of neurosurgery and neuro-oncology, the survival of patients with glioblastoma is only 15 months from diagnosis. It is therefore important to continue to study the biological characteristics of this tumor in order to understand the mechanisms responsible for its aggressiveness and resistance to therapies.The strong ability of glioblastoma cells to move and infiltrate brain tissue is certainly one of the main causes of the high malignancy of this tumor, and several protagonists participate in the implementation of these invasive strategies. Among these molecules are the sphingolipids, a class of lipids mediators active in the regulation of multiple physiological and pathophysiological processes, and, in particular, sphingosine-1-phosphate (S1P) an oncopromoter able to stimulate growth, invasiveness and angiogenesis of tumor cells. On the other hand, growth factor receptors are very often mutated and/or over-expressed in tumors.In the present study, EGF receptor expression EGFRvIII - the most commonly observed mutated form in human glioblastoma - has been observed to be associated with increased S1P formation and release. In turn, S1P, by binding to its specific receptors expressed in glioblastoma cells, stimulates their invasiveness. This research also evaluated the molecular mechanisms underlying this correlation, identifying ERK and AKT as key molecules responsible respectively for the increased production of S1P and the increased invasiveness of EGFRvIII expressing cells.The results of this study have therefore elucidated part of the biological and molecular mechanisms that contribute to the acquisition of an invasive phenotype by glioblastomas expressing EGFRvIII. These observations may suggest new targets and therapeutic strategies for a tumor