The role of Pigment Epithelium-Derived Factor in self-renewal and tumor growth of glioma stem cells

Abstract

Glioma stem cells (GSCs) require a niche that provides soluble factors to promote GSCs maintenance and self-renewal ability. However, the mechanisms maintaining the stemness of GSCs out of niche microenvironment was not elucidated yet. Here, I identified that an autocrine pigment epithelium-derived factor (PEDF) signaling plays an essential role in regulating self-renewal capability in GSCs out of niche environment. PEDF sustains self-renewal activity of GSCs by Notch1 cleavage, and cleaved Notch1 (NICD) induced expression of Sox2 through the direct interaction with its promoter region. EGFRvIII has been associated with glioma stemness, but the direct molecular mechanism is largely unknown. Here, I showed that EGFRvIII induces the expression and secretion of PEDF via activation of STAT3, thereby promoting self-renewal in GSCs. Silencing of PEDF expression in GSCs reduced self-renewal, tumorigenic potential in orthotopic implantation of GSCs. Furthermore, loss of PEDF expression increased survival period of GSCs-bearing mice. Importantly, the fact that PEDF expression correlated with poor prognosis of glioblasoma patients implicates PEDF as a new therapeutic target for the treatment of GSCs.