Cyclooxygenase-2 and inducible nitric oxide synthase expression in human astrocytic gliomas: correlation with angiogenesis and prognostic significance

Angiogenesis, which plays a key role in the development of astrocytic gliomas, depends on the local balance between various molecules that induce and inhibit neovascularization. Whereas recent experimental studies have indicated that cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) regulate angiogenesis by modulating vascular endothelial growth factor (VEGF) production, little is known about the relationships among expression of these markers, angiogenesis, and clinical outcome in astrocytic glioma cases. We therefore examined immunohistochemical expression of COX-2, iNOS, and VEGF in 51 high-grade astrocytomas including 31 glioblastomas (grade IV) and 20 anaplastic astrocytomas (grade III), 49 low-grade astrocytomas (grade II), and 43 reactive astrogliosis specimens, and determined the relationship with microvessel density (MVD) and prognostic significance. Stepwise increase of immunoreactive scores for COX-2, iNOS, and VEGF was found from astrogliosis, through low-grade to high-grade astrocytoma. The COX-2 expression strongly correlated with iNOS, VEGF, and high MVD, both overall and in all tumors, whereas iNOS expression was weakly associated with VEGF and high MVD. Univariate analysis revealed a significant association between COX-2 overexpression and a poor outcome. The findings for COX-2 and VEGF-related angiogenesis raise the possibility that the COX-2 pathway may contribute to astrocytic tumorigenesis by promoting new vessel formation with prognostic implications.