Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells

Prion protein (PrP(C)) is a cell surface glycoprotein whose misfolding is responsible for prion diseases. Although its physiological role is not completely defined, several lines of evidence propose that PrP(C) is involved in self-renewal, pluripotency gene expression, proliferation and differentiation of neural stem cells. Moreover, PrP(C) regulates different biological functions in human tumors, including glioblastoma (GBM). We analyzed the role of PrP(C) in GBM cell pathogenicity focusing on tumor-initiating cells (TICs, or cancer stem cells, CSCs), the subpopulation responsible for development, progression and recurrence of most malignancies. Analyzing four GBM CSC-enriched cultures, we show that PrP(C) expression is directly correlated with the proliferation rate of the cells. To better define its role in CSC biology, we knocked-down PrP(C) expression in two of these GBM-derived CSC cultures by specific lentiviral-delivered shRNAs. We provide evidence that CSC proliferation rate, spherogenesis and in vivo tumorigenicity are significantly inhibited in PrP(C) down-regulated cells. Moreover, PrP(C) down-regulation caused loss of expression of the stemness and self-renewal markers (NANOG, Sox2) and the activation of differentiation pathways (i.e. increased GFAP expression). Our results suggest that PrP(C) controls the stemness properties of human GBM CSCs and that its down-regulation induces the acquisition of a more differentiated and less oncogenic phenotype.