Perivascular nitric oxide activates Notch signaling and promotes stem-like character in PDGF-induced gliomas.

摘要

Nitric oxide (NO) is a free radicle gaseous molecule synthesized from a family of nitric oxide synthases (NOSs). Endothelial nitric oxide synthase (eNOS) is the major NO producing enzyme in the endothelium. The expression of eNOS is elevated in human glioblastomas and is correlated with increased tumor growth and aggressive character In this study, I investigated a potential role for nitric oxide (NO) in the perivascular niche (PVN) using a genetic engineered mouse model of PDGF-induced gliomas. I show that eNOS expression is highly elevated in the tumor vascular endothelium and is closely aligned with perivascular glioma stem-like cells that express both nestin and notch, as well as the receptor for NO, soluble guanylate cyclase (sGC). I further show that the NO/cGMP pathway drives notch signaling in vitro, and induces ABCG2 protein expression as well as the side population (SP) phenotype in PDGF-induced glioma primary cultures. Notch signaling is demonstrated to be required for the SP phenotype in these PDGF-induced glioma primary cultures. Activation of the NO/cGMP pathway enhances the neurosphere forming capacity of these PDGF-driven glioma primary cultures, and enhances their tumorigenic capacity in vivo. In addition, genetic ablation of eNOS suppresses Notch pathway components in vivo and prolongs survival of tumor bearing animals. Suppression of NOS activity in vivo diminishes notch signaling and the SP phenotype. Furthermore, I show that activation of the NO-cGMP-Notch signaling axis is conserved in a subset of human PDGFR-gene amplified gliomas. This novel role of NO signaling in the glioma PVN presents attractive novel therapeutic targets for the treatment of gliomas.