Cyclooxygenase-2 expression in astrocytes and microglia in human oligodendroglioma and astrocytoma

Abstract

Cyclooxygenases (cox) are potent mediators of inflammation and two cox-isoenzymes, cox-1, cox-2, are described to date. Cox-2 is cytokine-inducible in inflammatory cells and enhanced cox-2 expression has been attributed a key role in the development of edema and immunomodulation in pathologically altered brain tissues. In normal cerebral cortex cox-2 is present only in neurons, but not in the glial or vascular endothelial cells. The function of microglia in glioma biology is unclear. Microglia have both neurotrophic and neurotoxic functions and have been shown to release a variety of cytokines. Our preliminary results showed that the expression pattern of cox-2 is predominantly neuronal although glial expression was observed with the correlation of high malignancy. In this study we aimed to assess the phenotypes (astrocyte, microglia) of the cox-2-expressing glial cells in various types of human gliomas and to compare their expression patterns. For this purpose we employed dual immunohistochemistry for cox-2 and GFAP (astrocyte) or LCA-MAC (microglia-macrophage) in archival formalin-fixed, paraffin embedded human tissue diagnosed as oligodendroglioma and/or astrocytoma. The results showed that cox-2 immunoreactivity is up-regulated in the neurons according to the tumor grade. Most of the cox-2 immunoreactive glia were GFAP-positive in anaplastic oligodendrogliomas and at lesser extend in glioblastomas. Cox-2 and LCA co-localization was detected in more glial cells in glioblastomas. It may be speculated that the induction of cox-2 in microglia may contribute to the deleterious effects of prostanoids in cerebral edema formation during the progression of oligodendrogliomas. The detection of cox-2 in astrocytes surrounding the necrotic areas might be important to develop new strategies, such as the usage of cox-2 inhibitors combine with chemotherapy and radiotherapy in the treatment of glioma patients.

Combination of a Ptgs2 Inhibitor and an Epidermal Growth Factor Receptor-Signaling Inhibitor Prevents Tumorigenesis of Oligodendrocyte Lineage-Derived Glioma-Initiating Cells

“…First, EGFR signaling is known to be involved in OPC proliferation and tumorigenesis [43,44]. Second, the accumulation of Cox2-expressing astrocytes is more often observed in high-grade oligodendroglioma than in GBM [45,46]. Third, hGIC1 and Hs683 strongly expressed egfrvIII, which was shown by Mellinghoff et al to cause ''pathway addiction'' of the tumor cells [47].…”

Tumor-associated edema in brain cancer patients: pathogenesis and management

“…Microglial cells infiltrating brain tumors are characterized by high expression levels of cyclooxygenase-2 (COX-2) which generates prostaglandin E2 (PGE2). COX-2 is also expressed by glioma cells [18,19]. COX-2-derived PGE2, in turn, may promote the growth of experimental gliomas and contribute to edema development [20,21].…”

Recent developments in the inhibitors of neuroinflammation and neurodegeneration: inflammatory oxidative enzymes as a drug target

“…As the development of selective COX-2 inhibitors, their adverse effects and computer-aided drug design approaches to design effective anti-inflammatory agents with reduced side effects have been recently reviewed [71][72][73][74][75], this article focuses on the neuroinflammation aspect of COX-2 inhibitors. COX-2 is the key enzyme in the formation of prostaglandins and is expressed in activated microglial cells astrocytes [76][77][78], which appear to be an important source of prostaglandins during inflammatory conditions. COX-1 is constitutively expressed in many cell types [79].…”

“…It was also reported that inhibition of pro-inflammatory leukotriene production could significantly enhance the inhibitory effects of NSAIDs on the neurotoxicity of microglial cells. The authors suggested using 5-LOX inhibitors in combination with NSAIDs for their synergistic beneficial effects in AD and possibly in normal aging [77]. Meanwhile, the 5-LOX inhibitor, nordihydroguaiaretic acid, inhibited TNF-a production by microglia in a mouse model of ALS [109].…”