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Ephrina2 receptor in human glioblastoma cancer stem cells and identification of new, putative therapeutic targets.

Authors :
Vescovi, A
Binda, E
Mazza, T
Dimeco, F
Vescovi, AL
Vescovi, A
Binda, E
Mazza, T
Dimeco, F
Vescovi, AL
Publication Year :
2014

Abstract

Human glioblastomas (hGBMs) have been shown to embody a relatively small subset of cells which bear the defining features of somatic stem cells and the ability to establish, expand and perpetuate these tumors. They are defined cancer stem cell or tumor propagating cells (TPCs). This has caused a paradigmatic shift in the way we interpret hGBM physiology, for it identifies TPCs as a major culprit to be tackled for the development of novel therapeutics. Hence, we inferred that the study of regulatory mechanisms of normal neurogenesis may lead us to identify specific inhibitors of TPCs. METHODS: TPCs from human GBMs were used to determine the role of a neural stem cell regulator, the EphA2 receptor, in modulating self-renewal and tumorigenicity. We used a combined series of in vitro experiments which include primary tissue cultures, FACS analysis, next generation sequencing screening and in vivo, orthotopic xenografting experiments entailing the intracerebral delivery of putative therapeutic agents. RESULTS: We determined the over-expression of the Ephrin receptor type A2 (EphA2) in hGBM TPCs. EphA2 upregulation causally underlies self-renewal and expansion of the TPCs pool. Most important, both the EphA2 cognate ligand ephrinA1-Fc causes EphA2 downregulation in TPCs and suppress TPC self-renewal and intracranial tumorigenicity. This points to EphA2 as a key effector in TPCs self-renewal and tumorigenicity. Notably, intracranial administration of ephrinA1-Fc causes both down-regulation of EphA2 in hGBMs orthotopic xenografts pre-established in mice, whose growth and expansion throughout the brain parenchyma is significantly hindered in the absence of cytotoxic effects. CONCLUSIONS: We identify TPCs as a major target of EphA2 overexpression in hGBM, that drives their self-renewal and tumorigenicity. We propose TPCs as a specific cellular target in which enforced down-regulation of a molecular target such as EphA2 may be exploited for therapeutic purposes, under therapy

Details

Database :
OAIster
Notes :
STAMPA, English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1308924611
Document Type :
Electronic Resource