Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
Cell Stem Cell. 2010 Feb 5;6(2):141-52. doi: 10.1016/j.stem.2010.01.001.
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.
内皮型一氧化氮合酶（eNOS）在人类脑胶质瘤中表达升高，并与肿瘤生长和侵袭性特征增加相关。我们使用 PDGF 诱导的胶质细胞瘤的基因工程小鼠模型，研究了一氧化氮（NO）活性在血管周腔隙（PVN）中的潜在作用。在与表达巢蛋白、Notch 和 NO 受体可溶性鸟苷酸环化酶（sGC）的血管周胶质细胞相邻的肿瘤血管内皮中，eNOS 表达高度升高。此外，NO/cGMP/PKG 通路在 PDGF 诱导的体外胶质细胞瘤中驱动 Notch 信号，诱导原代胶质瘤细胞培养物中的侧群表型。NO 还增加了 PDGF 驱动的神经胶质瘤原代培养物的神经球形成能力，并增强了它们在体内的致瘤能力。这些肿瘤中 NO 活性的丧失抑制了体内的 Notch 信号，并延长了小鼠的存活时间。这种机制在人类 PDGFR 扩增的脑胶质瘤中是保守的。NO/cGMP/PKG 通路在肿瘤 PVN 中促进干细胞样特征，可能为这部分脑胶质瘤确定治疗靶点。
