Abstract
Cellular prion protein (PrPC) is a membrane-anchored glycoprotein representing the physiological counterpart of PrP scrapie (PrPSc), which plays a pathogenetic role in prion diseases. Relatively little information is however available about physiological role of PrPC. Although PrPC ablation in mice does not induce lethal phenotypes, impairment of neuronal and bone marrow plasticity was reported in embryos and adult animals. In neurons, PrPC stimulates neurite growth, prevents oxidative stress-dependent cell death, and favors antiapoptotic signaling. However, PrPC activity is not restricted to post-mitotic neurons, but promotes cell proliferation and migration during embryogenesis and tissue regeneration in adult. PrPC acts as scaffold to stabilize the binding between different membrane receptors, growth factors, and basement proteins, contributing to tumorigenesis. Indeed, ablation of PrPC expression reduces cancer cell proliferation and migration and restores cell sensitivity to chemotherapy. Conversely, PrPC overexpression in cancer stem cells (CSCs) from different tumors, including gliomas—the most malignant brain tumors—is predictive for poor prognosis, and correlates with relapses. The mechanisms of the PrPC role in tumorigenesis and its molecular partners in this activity are the topic of the present review, with a particular focus on PrPC contribution to glioma CSCs multipotency, invasiveness, and tumorigenicity.
Highlights
The discovery of molecules with pleiotropic functions in heterogeneous pathophysiologic conditions, is a common event in cell biology
This review aims to collect and critically analyze the most recent discoveries about the role of PrPC in cancer development and progression, focusing on gliomas and glioblastoma stem cells (GSCs), and to analyze the possible role of PrPC as a target candidate for novel therapeutic approaches
It has been demonstrated that PrPC depletion in neuroectodermal cells, neuronal stem cells, and in mice embryos produced a down-regulation of Notch 1 receptor and its cognate ligands, Jagged 1 and 2, and of the expression of target genes including nestin, OLIG2 and N-cadherin, depicting a molecular scenario in which PrPC plays a pivotal role in stemness and self-renewal of neural stem cells (NSCs) [112]
Summary
The discovery of molecules with pleiotropic functions in heterogeneous pathophysiologic conditions, is a common event in cell biology. As observed in many other solid tumors, a major cause of GBM development, aggressiveness and relapse is the presence, within the tumor mass, of multipotent cells from which more differentiated cells origin to form the bulk of tumor mass These poorly differentiated cells grow into specific stem cell microenvironments called tumor niches, which contain heterogeneous cell populations including, beside tumor-promoting stem-like cells, ependymal and endothelial cells, astrocytes, and immune system cells. These tumorigenic cell subpopulations have been named glioblastoma stem cells (GSCs), because somehow represent the pathogenic counterpart of normal neural stem cells (NSCs) [40,41]. This review aims to collect and critically analyze the most recent discoveries about the role of PrPC in cancer development and progression, focusing on gliomas and GSCs, and to analyze the possible role of PrPC as a target candidate for novel therapeutic approaches
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