Elsevier

Brain Research

Volume 885, Issue 1, 1 December 2000, Pages 111-116
Brain Research

Short communication
Cyclooxygenase (COX)-1 expressing macrophages/microglial cells and COX-2 expressing astrocytes accumulate during oligodendroglioma progression

https://doi.org/10.1016/S0006-8993(00)02978-4Get rights and content

Abstract

Cyclooxygenases (COX, prostaglandin endoperoxide synthases, PGG/H synthases) are potent mediators of edema, impeding blood flow and immunomodulation in the pathologically altered brain. Two COX iso-enzymes have been associated with brain disease, the constitutively expressed COX-1 and the cytokine-inducible COX-2. We have used single and double labeling immunohistochemistry to analyse COX-1 and COX-2 expression in twenty-six primary WHO grade II oligodendrogliomas, sixteen primary WHO grade III anaplastic oligodendrogliomas, twenty-seven matched recurrences and ten neuropathologically unaltered brains. COX-1 immunoreactivity was predominantly observed in macrophages/microglial cells. The number of COX-1 expressing macrophages/microglial cells was significantly lower in primary oligodendrogliomas than in primary anaplastic oligodendrogliomas (P<0.0001) and in anaplastic oligodendroglioma relapses (P=0.011). Patients with low COX-1 labeling scores in the primary tumors had significantly longer time to progression and overall survival (P=0.0285) than those with high COX-1 labeling scores. COX-2 immunoreactivity was predominantly observed in disseminated neurons and astrocytes. In glioblastoma multiforme relapses, accumulation of COX-2 expressing astrocytes was observed surrounding areas of focal necrosis. The number of COX-2 expressing astrocytes was significantly (P=0.0471) lower in primary oligodendrogliomas than in high grade oligodendroglioma relapses. These data provide convincing evidence for the differential accumulation of cyclooxygenase isoforms during oligodendroglioma progression in vivo.

Introduction

Cyclooxygenases (COX, prostaglandin endoperoxide synthases, PGG/H synthases) catalyse the synthesis of the eicosanoid prostaglandin metabolites PGG2 and PGH2 which are metabolised to PGE2, PGD2 and PGF, the thromboxane TXA2, or the functional antagonist of TXA2, PGI2 (prostacyclin) [7], [15]. Eicosanoids are potential modulators of the immune system, blood perfusion, and tumor growth. Two cyclooxygenase isoforms, COX-1 and COX-2, have been described that both catalyse identical reaction products [8], [16]. COX-1 is an enzyme of a molecular mass of 66 kd. COX-2 is a 70 kd homologue that shares 61% sequence identity with COX-1. While constitutive COX-1 expression is associated with physiological eicosanoid production, COX-2 is cytokine-inducible following proinflammatory stimuli.

In a wide variety of diseases of the brain, induction of COX-2 expression is associated with complex pathophysiological derangements like ischemia [14], trauma [6], HIV-induced encephalitis [1], inflammation [11], Alzheimer’s disease [13] and fever [2]. More importantly, COX-2 expression modulates tumor growth. Recent reports have revealed distinct interactions of cyclooxygenases in tumor development. In human colorectal cancer cells, COX-2 regulates angiogenesis [19], apoptosis [17] and cell adhesion [18]. Inhibition of cyclooxygenase has therefore become a promising therapeutic strategy in colorectal cancer [5]. In this context, it is of note that in brain neoplasia, inhibitors of eicosanoid biosynthesis suppress proliferation of glioblastoma cells [20].

In order to provide a pathological basis for the involvement of cyclooxygenases in oligodendrogliomas, we have analysed the expression of COX-1 and COX-2 in 69 oligodendroglioma tissue samples by immunohistochemistry. Twenty-six primary WHO grade II oligodendrogliomas and sixteen primary WHO grade III anaplastic oligodendrogliomas were included. Nineteen grade II tumors progressed, ten were again grade II oligodendrogliomas, and nine had progressed to higher grade lesions. Eight anaplastic oligodendrogliomas progressed, five were again WHO grade III tumors, and three had progressed to glioblastoma multiforme. Double labeling experiments confirmed the nature of COX-1 and COX-2 expressing cells.

Section snippets

Oligodendroglioma patients

All oligodendrogliomas were resected at the Department of Neurosurgery in Tübingen or at the Department of Neurosurgery of the Asklepios Klinik Schildautal in Seesen and have been described in detail before. Resection was documented by the surgeons as incomplete or macroscopically complete (Table 1). Diagnosis was performed according to the WHO classification system [10].

Immunohistochemistry

Brain samples were removed immediately after death, fixed in buffered formalin and embedded in paraffin. Five μm sections

Results

In control brains without neuropathological alterations, COX-1 immunoreactivity was detected in few (5-10% of all cells) macrophages/microglial cells (Table 1). COX-2 immunoreactivity was observed in singular neurons located in the neocortex and allocortex. No endothelial or glial cells expressed COX-2.

In oligodendrogliomas, COX-1 immunoreactivity was predominantly detected in grouped accumulations of macrophages/microglial cells throughout areas of solid tumor growth with frequent

Discussion

The pathophysiological role of COX-1 expression has been obscured due to its constitutive expression in a wide range of organs including the brain. COX-1 expression in macrophages/microglial cells has been described before but its expression was again constitutive and unrelated to pyogenic stimuli [11]. In this context it is of note that both COX-1 and COX-2 catalyse identical reaction products [16]. The numerical increase of COX-1 expressing macrophages/microglial cells in high grade or

Acknowledgements

Supported by a grant from the fortüne program (#638-0-0) of the University of Tuebingen. We thank Thai Dung Nguyen for expert technical assistance.

References (20)

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