NOS Expression and NO Function in Glioma and Implications for Patient Therapies

Abstract

Significance: Gliomas are central nervous system tumors that primarily occur in the brain and arise from glial cells. Gliomas include the most common malignant brain tumor in adults known as grade IV astrocytoma, or glioblastoma (GBM). GBM is a deadly disease for which the most significant advances in treatment offer an improvement in survival of only ∼2 months.

Critical issues: To develop novel treatments and improve patient outcomes, we and others have sought to determine the role of molecular signals in gliomas. Recent Advances: One signaling molecule that mediates important biologies in glioma is the free radical nitric oxide (NO). In glioma cells and the tumor microenvironment, NO is produced by three isoforms of nitric oxide synthase (NOS), NOS1, NOS2, and NOS3. NO and NOS affect glioma growth, invasion, angiogenesis, immunosuppression, differentiation state, and therapeutic resistance.

Future directions: These multifaceted effects of NO and NOS on gliomas both in vitro and in vivo suggest the potential of modulating the pathway for antiglioma patient therapies. Antioxid. Redox Signal. 26, 986-999.

Keywords: cancer stem cell; glioma; nitric oxide synthase/NOS; nitric oxide/NO; therapy.

FIG. 1.

Nitric oxide and nitric oxide synthases regulate glioma angiogenesis. NOS in the tumor vasculature and glioma cells produces NO to promote tumor angiogenesis, blood vessel permeability, and endothelial progenitor cell recruitment. The NOS/NO pathway in gliomas can lead to upregulation of VEGF to promote angiogenesis or mediate VEGF-independent effects downstream of osteopontin. NO, nitric oxide; NOS, nitric oxide synthase; VEGF, vascular endothelial growth factor. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Nitric oxide and nitric oxide synthases can mediate therapeutic resistance in gliomas. NOS and NO promote a BTIC/glioma stem cell phenotype, which is associated with therapeutic resistance. NO is elevated by irradiation of glioma cells, and the NO can then have bystander effects on adjacent cancer and stromal cells. BTIC, brain tumor initiating cell. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

The concentration of nitric oxide produce during therapeutic approaches will be critical for biological response. Elevation of NO and targeting of NOS can produce antitumorigenic effects as long as NO levels are in a therapeutic range. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars