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PMID: 20144787 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells.

Cell stem cell ·Vol. 6 ·No. 2 ·2010-02-05 ·Pages 141-52

Charles N, Ozawa T, Squatrito M, Bleau AM, Brennan CW, Hambardzumyan D, Holland EC

Abstract

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.

MeSH Terms
Animals Cell Line Chickens Cyclic GMP/metabolism Cyclic GMP-Dependent Protein Kinases/metabolism Glioma/blood supply,metabolism,pathology Humans Mice Mice, Inbred NOD Mice, SCID Neoplastic Stem Cells/metabolism,pathology Nitric Oxide/metabolism Nitric Oxide Synthase Type III/metabolism Platelet-Derived Growth Factor/metabolism Receptors, Notch/metabolism Receptors, Platelet-Derived Growth Factor/metabolism Signal Transduction Tumor Cells, Cultured
Chemicals
Platelet-Derived Growth Factor Receptors, Notch Nitric Oxide Nitric Oxide Synthase Type III Nos3 protein, mouse Receptors, Platelet-Derived Growth Factor Cyclic GMP-Dependent Protein Kinases Cyclic GMP
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Charles Nikki
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
Ozawa Tatsuya
Squatrito Massimo
Bleau Anne-Marie
Brennan Cameron W
Hambardzumyan Dolores
Holland Eric C
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Article Info
Journal
Cell stem cell
Abbr.
Cell Stem Cell
ISSN
1875-9777
DOI
10.1016/j.stem.2010.01.001
Published
2010-02-05
Pages
141-52
Language
English
Region
United States
NLM ID
101311472
PMCID
PMC3818090
Subset
IM
Grants
NCI NIH HHS · R01 CA100688 · United States
NCI NIH HHS · U54 CA126518 · United States
NCI NIH HHS · U54 CA143798 · United States
Corrections
CommentIn
PMID: 20144782
External Links
PubMed source DOI: 10.1016/j.stem.2010.01.001 PMC Full Text View journal details
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