Perivascular Nitric Oxide Activates Notch Signaling and Promotes Stem-like Character in PDGF-Induced Glioma Cells
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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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In a genetically engineered mouse model of PDGF-induced gliomas, the interaction between glioma-initiating cells and the perivascular microenvironment is mediated through perivascular nitric oxide, which activates notch signaling to promote stem-like character.
“Using a genetically engineered mouse model of PDGF-induced gliomas, it has been shown that this interaction was mediated through perivascular nitric oxide, which activates notch signaling to promotes stem-like character [48].”
From Tumor microenvironment complexity and therapeutic implications at a glance (2020) · cites this paper as [48]
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- Authors
- Charles, N., Ozawa, T., Squatrito, M., Bleau, A.-M., Brennan, C. W., Hambardzumyan, D., & Holland, E. C.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Holland, Eric C.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 6
- Issue
- 2
- Pages
- 141-152
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC3818090
- OpenAlex
- W2000078674
- Cited by
- 550
- References
- 46
- Citations by year
- 2026: 6 · 2025: 19 · 2024: 18 · 2023: 29 · 2022: 49 · 2021: 41 · 2020: 34 · 2019: 30 · 2018: 46 · 2017: 38 · 2016: 32 · 2015: 44 · 2014: 35 · 2013: 37 · 2012: 43
- FWCI
- 18.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (U54CA126518, U54CA143798, R01CA100688)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- nitric oxide, Notch signaling, glioma, perivascular niche, endothelial nitric oxide synthase, side population cells, glioma stem cells, neurospheres, cGMP-PKG signaling, tumor vascular endothelium, tumor microenvironment
- MeSH terms
- Animals, Cell Line, Chickens, Glioma, Cyclic GMP, Humans, Nitric Oxide, Platelet-Derived Growth Factor, Tumor Cells, Cultured, Neoplastic Stem Cells, Signal Transduction, Mice, SCID, Mice, Inbred NOD, Receptors, Platelet-Derived Growth Factor, Cyclic GMP-Dependent Protein Kinases, Mice, Receptors, Notch, Nitric Oxide Synthase Type III
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