Abstract
Author SummaryGlioblastomas are the most common and aggressive primary brain tumors in adults, with a median survival of only 12–15 months. Glioblastomas display a cellular hierarchy with a subset of cells having stem cell–like properties, including the capacity to self-renew and propagate tumors. Specific ablation of cancer stem cells is widely thought to be critical for effective and long-lasting treatment of cancers. We report the identification of the antiapoptotic protein A20 (which is also known as TNFAIP3) as a novel regulator of glioma stem cell survival. Glioma stem cells overexpress A20 relative to non-stem glioma cells, and this protects them from cell death, whereas depletion of A20 attenuates glioma stem cell survival and tumor growth. Interrogation of a molecular glioma database reveals that A20 levels correlate with decreased survival in patients. These data indicate that A20 is a tumor enhancer in the context of glioma, which importantly contrasts with its known function as a tumor suppressor in the context of lymphoma. Therefore, A20 may be a context-specific regulator of cancer stem cell survival and growth.
Highlights
Tumors are aberrant organ systems that display a complex interplay between neoplastic cells and recruited vascular, inflammatory, and stromal elements [1]
We report the identification of the antiapoptotic protein A20 as a novel regulator of glioma stem cell survival
A20 Is Highly Expressed in Glioma Stem Cells To determine whether A20 could differentially contribute to glioma biology through the recently identified glioma subfractions, we utilized several complementary methods to evaluate A20 expression in freshly isolated glioblastoma stem cell (GSC)-enriched and -depleted cultures derived using our previously published methodology [11,12,15,21,23,25]
Summary
Tumors are aberrant organ systems that display a complex interplay between neoplastic cells and recruited vascular, inflammatory, and stromal elements [1]. Cancer stem cells have been derived from several primary brain tumors, but both their derivation and characterization are incomplete and rapidly expanding [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35]. Glioblastoma (World Heath Organization grade IV astrocytoma) is the most common primary brain tumor in adults and one of the most aggressive and deadly cancers [36,37]. Significant effort has been undertaken to identify potential targets in cancer stem cells that promote tumor maintenance and that might be amenable to disruption [35]
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