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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    • "Aberrant Notch signaling is linked to many types of cancer, and Notch pathway components are expressed by brain tumor cells (El Hindy et al., 2013; Fan et al., 2004; Hallahan et al., 2004; Leong and Karsan, 2006; Phillips et al., 2006; Purow et al., 2005; Shih and Holland, 2006). Subpopulations of glioma cells display Notch signaling, which may promote their stem cell character (Charles et al., 2010; Shih and Holland, 2006; Zhu et al., 2011). In vitro and xenotransplantation studies with glioma cell lines revealed that blocking Notch can inhibit growth, survival, and radio-resistance of glioma cells supporting an oncogenic function in brain tumors (Fan et al., 2010; Purow et al., 2005; Wang et al., 2010; Xu et al., 2010). "
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    ABSTRACT: In the brain, Notch signaling maintains normal neural stem cells, but also brain cancer stem cells, indicating an oncogenic role. Here, we identify an unexpected tumor suppressor function for Notch in forebrain tumor subtypes. Genetic inactivation of RBP-Jκ, a key Notch mediator, or Notch1 and Notch2 receptors accelerates PDGF-driven glioma growth in mice. Conversely, genetic activation of the Notch pathway reduces glioma growth and increases survival. In humans, high Notch activity strongly correlates with distinct glioma subtypes, increased patient survival, and lower tumor grade. Additionally, simultaneous inactivation of RBP-Jκ and p53 induces primitive neuroectodermal-like tumors in mice. Hence, Notch signaling cooperates with p53 to restrict cell proliferation and tumor growth in mouse models of human brain tumors.
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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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    ABSTRACT: There is a lot of experimental evidence that brain tumors might be sustained by a subpopulation of immature cells, so-called brain tumor stem cells (BTSCs), which do not only drive tumor formation but are highly resistant to conventional therapies. Recent findings suggest a critical role of the molecular and cellular tumor microenvironment in which these cells reside for the maintenance of stem cell properties and therapy resistance. However, detection of different BTSC phenotypes even in the same patient tumor and the observation of a marked plasticity due to instability of the BTSC phenotype caused by the environmental niche have led to a controversial discussion on the validity of the cancer stem cell concept. What complicates the situation even more is that there are different types of niches and little is known about the interplay of the niche components with one another and with different types of BTSCs in the context of stem cell maintenance. In this article we review our current knowledge on different BTSC phenotypes and the cellular components and physiology of the niche in which these cells reside. In addition, we will summarize the molecular and functional interaction of niche cells and niche conditions and how this impacts on BTSC maintenance.
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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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