Abstract
Cyclooxygenases (cox) are potent mediators of inflamation and two cox-izoenzymes, 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.
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References
Anderson WF, Umar A, Hawk ET (2004) Cyclooxygenase inhibition in cancer prevention and treatment. Expert Opin Pharmacother. 4(12):2193–2204
Badie B, Schartner JM (2000) Flow cytometric characteriztion of tumor-associated macrophages in expperimental gliomas. Neurosurgery 46:957–961
Badie B, Schartner J, Prabakaran S, Paul J, Vorpahl J (2001) Expression of Fas ligand by microglia: possible role in glioma immune evasion. J Neuroimmunol 120(1–2):19–24
Badie B, Schartner JM, Hagar AE et al (2003) Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation. Clin Cancer Res 9:872–877
Breder CD, Saper CB (1996) Expression of inducible cyclooxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolysaccharide. Brain Res 713(1–2):64–69
Breder CD, Dewitt D, Beasley T, Bari F (1995) Characterization of inducible cyclooxygenase in rat brain. J Comp Neurol 355:296–315
Brunda MJ, Herberman RB AND, Holden HT (1980) Inhibition of murine natural killer cell activity by prostaglandins. J Immunol 124:2682–2687
Deininger HM, Weller M, Streffer J et al (1999) Patterns of cyclooxygenase-1 and -2 expression in human gliomas in vivo. Acta Neuropathol 98:240–244
Deininger HM, Meyermann R, Trautmann K et al (2000) Cyclooxygenase (cox)-1 expressing macrophages/microglial cells and cox-2 expressing astrocytes accumulate during oligodendroglioma progression. Brain Re s 885:111–116
Dempke W, RieE C, Grothey A, Schmoll JH (2001) Cyclooxygenase-2: a novel target for cancer chemotherapy? J Cancer Res Clin Oncol 127:411–417
Elmquist JK, Breder CD, Sherin JE, Scammell TE, Hickey WF, Dewitt D, Saper CB (1997) Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages. J Comp Neurol 381(2):119–129
Evans JF, Kargman SL (2004) Cancer and Cyclooxygennase-2 inhibition. Curr Pharm Des 10:627–634
Holland EC (2000) Glioblastoma multiforme: the terminator. Proc Natl Acad Sci U S A. 97:6242–6244
Hoozemans JJM, Veerhuis R, Janssen I et al. (2002) The role of cyclooxygenase 1 and 2 activity in prostaglandin E2 secretion by cultured human adult microglia. Implications for Alzheimer’s disease. Brain Res 951(2):218–226
Joki T, Heese O, Nikas DC, Bello L, Zhang J, Kraeft SK, Seyfried NT, Abe T, Chen LB, Carroll RS, Black PM (2000) Expression of cyclooxygenase 2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitor, NS.398. Cancer Res 60:4926–4931
Jaworowicz DJ Jr, Korytko PJ, Singh Langman S, Boje KM (1998) Nitric oxide and prostaglandin E2 formation parallels blood-brain barrier disruption in an experimental rat model of bacterial meningitis. Brain Res Bull 46:541–546
Kamei D, Murakami M, Nakatani Y, Ishikawa Y, Ishii T, Kudo I (2003) Potential role of microsomal prostaglandin E synthase-1 in tumorigenesiis. J Biol Chem. 278(21):19396–19405
Kleihues PB, Burger PC, Schethauer BW (1996) Histological typing of the tumours of the Central Nervous System. Springer, Stuttgart
Mark KS, Trickler WJ, Miller DW (2001) Tumor necrosis factor-alpha induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells. J Pharmacol Exp Ther 297:1051–1058
Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, Edwards DA, Flickinger AG, Moore RJ, Seibert K (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60:1306–1311
Merril JE, Zimmerman AP (1991) Natural and induced cytotoxicity of oligodendrocytes by microglia is inhibitable by TGF beta. Glia 4(3):327–331
Pasinetti GM, Aisen PS (1998) Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer’s disease. Neuroscience 87:319–324
Pannullo SC, Burton J, Serventi J et al (2006) Phase I/II trial of twice-daily temozolomide and celecoxib for treatment of relapsed malignant glioma: final data. J Clin Oncol (Meeting Abstracts) 18:1519
Parney IF, Farr-Jones MA, Chang LJ, Petruk KC (2000) Human glioma immunobiology in vitro: implications for immunogene therapy. Neurosurgery. 46(5):1169–1177 discussion 1177-8
Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8:138–140
Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C et al (2002) Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62:632–635
Roggendorf W, Strupp S, Paulus W (1996) Distrution and characterization of microglia/macrohages in human brain tumors. Acta Neuropathol 92:288–293
Sairanen T, Ristimaki A, Karjalainen Linsberg ML, Paetau A, Kaste M, Lindsberg PJ (1998) Cyclooxygenae-2 is induced globally in infracted human brain. Ann Neurol 43:738–747
Sano H, Kawahito Y, Wilder RL, Hashiramoto A, Mukai S, Asai K, Kimura S, Kato H, Kondo M, Hla T (1995) Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 55(17):3785–3789
Shinonaga M, Chang CC, Suzuki N, Sato M, Kuwabara T (1988) Immunohistological evaluation of macrophage infiltrates in brain tumors. Correlation with peritumoral edema. J Neurosurg 68(2):259–265
Smith WL, Garavito RM, Dewit DL (1996) Prostaglandin endoperoxidase H synthases (cyclooxygenase)-1 and 2. J Biol Chem. 271(52):33157–33160
Steinbach G, Lynch PM, Philiips RKS, Wallace MH, Hawk E, Gordon GB et al (2000) The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342:1946–1952
Streit WJ (1994) Cellular immune response in brain tumors. Neuropathol Appl Neurobiol 20(2):205–206
Subbaramaiah K, Dannenberg AJ (2003) Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci 24(2):96–102
Taketo MM (1996) Cyclooxygenase-2 inhibitors in tumorigenesis (Part II). J Natl Cancer Inst (Bethesda). 90:1609–1620
Temel SG, Minbay FZ, Kahveci Z, Jennes L (2006) Microwave assisted antigen retrieval and incubation with cox-2 antibody of archival paraffin-embedded human oligodendroglioma and astrocytomas. J Neurosci Methods 156(1–2):154–160
Tsujii M, Kuwano S, DuBios RN (1997) Cyclooxygenase-2 (COX-2) expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 94(7):3336–3340
Tsujii M, Kuwano S, Tsujii S et al (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716
Tucker ON, Dannenberg AJ, Yang EK, Zhan F, Teng L, Daly JM et al (1999) Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res 59:987–990
Van Rees BP, Saukkonen K, Ristimaki A, Pollowski W, Tytgat GN, Drillenberg P et al (2002) Cyclooxygenase-2 expression during carcinogenesis in the human stomach. J Pathol 196:171–179
Vijitruth R, Liu M, Choi D-Y, Ngyen XV, Hunter RL, Bing G (2006) Cyclooxygenase-2 mediates microglial activation and secondary dopaminergic cell death in the mouse MPTP model of Parkinson’s disease. J Neuroinflamm 3(6)
Wagner S, Czub S, Greif M, Vince GH, Süss N, Kerkau S, Rieckmann P, Roggendorf W, Roosen K, Tonn JC (1999) Microglial/macrophage expression of interleukin 10 in human glioblastomas. Int J Cancer 82(1):12–16
Walsh DT, Minghetti L, Perry VH (2000) Cyclooxygenase-2 is highly expressed in microglial-like cells in Murine Model of Prion Disease. Glia 29:392–396
Yamagata K, Andreasson KI, Kaufmann WE, Barnes CE, Worley PF (1993) Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11:371–386
Yunk WK, Albrigh RE, Olson J et al (2000) A pahse II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83:588–593
Zimmerman KC, Sarbia M, Weber AA, Borchard F, Gabbert HE, Schror K (1999) Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res 59:198–204
Acknowledgment
Figures 1 and 2 was used in our previous manuscript titled as “Microwave-assisted antigen retrieval and incubation with cox-2 antibody of archival paraffin-embedded human oligodendroglioma and astrocytomas”, in Journal of Neuroscience Methods 156: 154–160 (2006). This study was done in the Histology & Embryology department.
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Temel, S.G., Kahveci, Z. Cyclooxygenase-2 expression in astrocytes and microglia in human oligodendroglioma and astrocytoma. J Mol Hist 40, 369–377 (2009). https://doi.org/10.1007/s10735-009-9250-1
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DOI: https://doi.org/10.1007/s10735-009-9250-1