CB-23. FIBULIN-3 REGULATES NOTCH SIGNALING, TUMOR INVASION, AND CELL SURVIVAL IN MALIGNANT GLIOMAS

摘要: Glioblastomas are the most common primary brain tumors and have extremely poor prognosis owing to their highly invasive nature. Glioma cells secrete a variety of ECM proteins that are absent in their glial counterparts and are critical molecules that favor invasion. We recently identified fibulin-3 as an ECM protein highly expressed in gliomas but absent in normal brain and rarely expressed in other solid tumors. We demonstrated that fibulin-3 regulates the expression of metalloproteases and is sufficient to promote tumor cell invasion through brain parenchyma. In the present work, we describe a novel role of fibulin-3 regulating the sensitivity of glioma cells to apoptotic treatments. Using gain-and loss-of-function approaches, we observed that fibulin-3 overexpression reduced glioma cell apoptosis in vitro and in vivo, while knockdown caused the opposite effect. Because Notch signaling is a predominant prosurvival pathway in gliomas and fibulin-3 bears homology with the Notch ligands of the Delta family, we investigated a possible interaction of fibulin-3 with this pathway. We observed that fibulin-3 induced Notch cleavage and activated a Notch-dependent reporter in cultured glioma cells. Moreover, overexpression or knockdown of this protein regulated the expression of downstream Notch effectors, such as Hes-1 and Hes-5, both in vitro and in vivo.Furthermore, analysis of fibulin-3 and Hes-1 in clinical samples showed a strong correlation between expression of both proteins and tumor grade. Finally, we demonstrated that the pro-invasive effect of fibulin-3 can be abolished by blockade of Notch signaling using pharmacological inhibitors or …