Short communicationCyclooxygenase (COX)-1 expressing macrophages/microglial cells and COX-2 expressing astrocytes accumulate during oligodendroglioma progression
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 PGF2α, 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)
- et al.
HIV-1 gp120-induced apoptosis in the rat neocortex involves enhanced expression of cyclo-oxygenase type 2 (COX-2)
Biochem. Biophys. Res. Commun.
(1998) - et al.
Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain; its possible role in febrile response
Brain Res.
(1995) - et al.
Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2
J. Biol. Chem.
(1996) - et al.
Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase-2
Cell
(1995) - et al.
Cyclooxygenase regulates angiogenesis induced by colon cancer cells
Cell
(1998) - et al.
Multiple epitope labeling by the exclusive use of alkaline phosphatase conjugates in immunohistochemistry
Histochem. Cell Biol.
(1998) - et al.
Patterns of Cyclooxygenase-1 and -2 expression in human gliomas in vivo
Acta Neuropathologica
(1999) - et al.
COX-2 inhibitors for colorectal cancer
Nat. Med.
(1998) - et al.
Brain kininogen following experimental brain injury: evidence for a secondary event
J. Neurosurg.
(1989) - et al.
Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment
FASEB J.
(1991)
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