Perivascular Nitric Oxide Activates Notch Signaling and Promotes Stem-like Character in PDGF-Induced Glioma Cells

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
Cell stem cell (Impact Factor: 22.27). 02/2010; 6(2):141-52. DOI: 10.1016/j.stem.2010.01.001
Source: PubMed


eNOS expression is elevated in human glioblastomas and correlated with increased tumor growth and aggressive character. We investigated the potential role of nitric oxide (NO) activity in the perivascular niche (PVN) using a genetic engineered mouse model of PDGF-induced gliomas. eNOS expression is highly elevated in tumor vascular endothelium adjacent to perivascular glioma cells expressing Nestin, Notch, and the NO receptor, sGC. In addition, the NO/cGMP/PKG pathway drives Notch signaling in PDGF-induced gliomas in vitro, and induces the side population phenotype in primary glioma cell cultures. NO also increases neurosphere forming capacity of PDGF-driven glioma primary cultures, and enhances their tumorigenic capacity in vivo. Loss of NO activity in these tumors suppresses Notch signaling in vivo and prolongs survival of mice. This mechanism is conserved in human PDGFR amplified gliomas. The NO/cGMP/PKG pathway's promotion of stem cell-like character in the tumor PVN may identify therapeutic targets for this subset of gliomas.

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    • "Thus targeting NO production constitutes a potential way to diminish BTSC maintenance and might increase patient survival [103]. The cellular response of NO in BTSCs was shown to be mainly regulated by the Notch self-renewal pathway [103]. In addition, endothelial cells are known to produce Notch ligands [105]. "
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    • "The cancer stem cell hypothesis predicts that the conversion of highly tumorigenic cancer stem cell to non-stem cell progeny is irreversible. However, there is mounting evidence in several cancers such as colon cancer, glioblastoma, and melanoma that the conversion of cancer stem cells to differentiated progeny is reversible (Charles et al, 2010; Roesch et al, 2010; Schwitalla et al, 2013; Suva et al, 2014). This has been demonstrated in melanoma with JARID1B as a cancer stem cell marker, in the perivascular niche of gliomas with nitric oxide promoting stem cell character, and in colon cancer where inflammation triggers dedifferentiation of non-stem cells to stem cells. "
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    • "Strong activation of the wnt pathway, which is also very important for the normal intestinal stem cells, results in the conversion of the differentiated cells into a more stem cell-like state [58] [59]. Similarly, in glioblastoma, nitric oxide that is produced by the tumor vasculature activates Notch signaling and induces the expression of the stem cell marker nestin in the cells located in the perivascular niche [60]. Induction of dedifferentiation by inflammation or other environmental stimuli has also major "
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