Neural stem cells adopt tumorigenic properties by constitutively activated NF-kappaB and subsequent VEGF up-regulation

One of the challenges in stem cell research is to avoid transformation during cultivation. We studied high passage subventricular zone derived neural stem cells (NSCs) cultures of adult rats in the absence of growth factors epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). We...

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Veröffentlicht in:Stem cells and development 2010-07, Vol.19 (7), p.999-1015
Hauptverfasser: Kaus, Aljoscha, Widera, Darius, Kassmer, Susannah, Peter, Jan, Zaenker, Kurt, Kaltschmidt, Christian, Kaltschmidt, Barbara
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container_end_page 1015
container_issue 7
container_start_page 999
container_title Stem cells and development
container_volume 19
creator Kaus, Aljoscha
Widera, Darius
Kassmer, Susannah
Peter, Jan
Zaenker, Kurt
Kaltschmidt, Christian
Kaltschmidt, Barbara
description One of the challenges in stem cell research is to avoid transformation during cultivation. We studied high passage subventricular zone derived neural stem cells (NSCs) cultures of adult rats in the absence of growth factors epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). We termed this culture exogenous growth factor independent neural stem cells (GiNSCs). GiNSCs expressed stemness markers, displayed a high constitutive NF-kappaB activity and an increased, aberrant, polyploid DNA content. GiNSCs showed a tumorigenic phenotype and formed colonies in a soft agar assay. Microarray analysis showed the up-regulation of the NF-kappaB target gene vascular endothelial growth factor (VEGF). In contrast, proneuronal genes were down-regulated. Under neuronal differentiation conditions GiNSCs adopted a glioma-like phenotype, with nuclear p53, preserving high amounts of Nestin positive cells and prolonged proliferation. Neutralization of VEGF strongly inhibited proliferation and induced differentiation. In a gain of function approach, the transfection of NSCs with constitutively active upstream kinase IKK-2 led to constitutively activated NF-kappaB, proliferation in absence of growth factors and augmented VEGF secretion. In a rescue experiment a reduction of NF-kappaB activity by overexpression of IkappaB-AA1 was able to shift the morphology toward an elongated cell form, increased cell death, and decreased proliferation. Thus GiNSCs may provide a potent tool in cancer research, as their exogenous cytokine independent proliferation and their constitutively high NF-kappaB expression presumes cancerous properties observed in gliomas. In addition, this study might add a novel mechanism for detecting oncogenic transformation in therapeutic stem cell cultures.
doi_str_mv 10.1089/scd.2009.0416
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subjects Animals
Biomarkers - metabolism
Cell Culture Techniques
Cell Differentiation
Cell Proliferation
Cells, Cultured
Humans
Microarray Analysis
Neurons - cytology
Neurons - physiology
NF-kappa B - metabolism
Phenotype
Rats
Rats, Wistar
Stem Cells - cytology
Stem Cells - physiology
Tumor Suppressor Protein p53 - metabolism
Up-Regulation
Vascular Endothelial Growth Factor A - metabolism
title Neural stem cells adopt tumorigenic properties by constitutively activated NF-kappaB and subsequent VEGF up-regulation
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