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

Abstract

SUMMARY 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.

The ecology of brain tumors: lessons learned from neurofibromatosis-1

“…Microglia are known in other pathological conditions to increase endothelial cell migration and proliferation as well as to stimulate reactive gliosis. In this manner, microgliainduced neoangiogenesis might create a supportive niche for cancer stem cells, as has been reported for highgrade gliomas (Ludwig et al, 2000;Ren et al, 2004;Calabrese et al, 2007;Charles et al, 2010), and account for the highly vascular nature of these otherwise relatively benign tumors. Although it is not known what impact Nf1 heterozygosity has on brain endothelial cell function, Nf1 þ /À aortic endothelial cells exhibit increased motility and proliferation and likely participate in establishing a permissive environment for peripheral nerve sheath tumors .…”

c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

“…Recently, Eyler et al 54 found that proliferation of glioma stem-like cells is facilitated by nitrogen oxide (NO), whereas the increase of NO had no effect on cell growth of normal neural stem cells. The role of NO in facilitating glioma cell growth was further supported by Charles et al, 55 in which they found that NO activates Notch signaling and promotes glioma stem-like cell population in vivo. In our study, we found that Notch signaling is activated by JNK signaling.…”

The brain tumor microenvironment

“…Tumor endothelial cells, which highly express eNOS, the enzyme required for nitric oxide synthesis in the endothelium, lies adjacent to nestin-expressing BTSCs associated with the PVN. Activated Notch signaling by nitric oxide in BTSCs was shown to accelerate tumor progression (Charles et al, 2010). This finding identifies potentially new targets for the rational design of drugs against the PVN.…”

“…NO activates notch signaling in a population of BTSCs, to enhance their self-renewal characteristics in vitro and their tumorigenic capacities in vivo. Further, eNOS, an enzyme that synthesizes NO from the vascular endothelium, is elevated in the platelet-derived growth factor (PDGF)-subset of gliomas and suppression of eNOS activity, which corresponded to a decrease in notch signaling in these tumors, prolonged survival of tumor bearing mice (Charles et al, 2010). It remains to be determined whether maintenance of cancer stem cell populations by NO signaling from the tumor endothelium is conserved across other brain tumor subtypes and other types of cancers.…”