Abstract
The peripheral benzodiazepine receptor (PBR) is a 18 kDa molecule mainly involved in cholesterol transport through the mitochondrial membrane. In microglia, PBR is expressed from the earliest stages of activation and appears to exert a pro-inflammatory function. This molecule is commonly up-regulated in inflammatory, degenerative, infective and ischaemic lesions of the central nervous system but it has never been reported in glioma-infiltrating microglia. We examined two anaplastic astrocytomas showing minimal contrast-enhancement and therefore little damage of the blood brain barrier to minimise the presence of blood borne macrophages within tumour tissue. The two lesions were studied in vivo using positron emission tomography (PET) with the specific PBR ligand [11C](R)-PK11195 and the corresponding tumour tissue was investigated with an anti-PBR antibody. Glioma-infiltrating microglia were characterised for molecules involved in antigen presentation and cytotoxic activity. As comparison, PBR was investigated in three brains with multiple sclerosis (MS) and three with Parkinson’s disease (PD). The expression profile of four anaplastic astrocytomas was also exploited and results were compared to the profile of eleven samples of normal temporal lobe and nine cases of PD. PET studies showed that [11C](R)-PK11195 binding was markedly lower in tumours than in the contralateral grey matter. Pathological investigation revealed that glioma-infiltrating microglia failed to express PBR and cytotoxic molecules although some cells still expressed antigen presenting molecules. PBR and cytotoxic molecules were highly represented in MS and PD. Evaluation of microarray datasets confirmed these differences. Our results demonstrated PBR suppression in glioma-infiltrating microglia and suggested that PBR may have a relevant role in modulating the anti-tumour inflammatory response in astrocytic tumours.
Similar content being viewed by others
References
Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318
Schwartz M, Butovsky O, Bruck W et al (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29:68–74
Gebicke-Haerter PJ (2005) Microarrays and expression profiling in microglia research and in inflammatory brain disorders. J Neurosci Res 81:327–341
Hussain SF, Yang D, Suki D et al (2006) The role of human glioma-infiltrating microglia/macrophages in mediating antitumour immune responses. Neurooncology 8:261–279
Roggendorf W, Strupp S, Paulus W (1996) Distribution and characterization of microglia/macrophages in human brain tumours. Acta Neuropathol (Berl) 92:288–293
Tran CT, Wolz P, Egensperger R et al (1998) Differential expression of MHC class II molecules by microglia and neoplastic astroglia: relevance for the escape of astrocytoma cells from immune surveillance. Neuropathol Appl Neurobiol 24:293–301
Schartner JM, Hagar AR, Van HM et al (2005) Impaired capacity for upregulation of MHC class II in tumour-associated microglia. Glia 51:279–285
Town T, Nikolic V, Tan J (2005) The microglial “activation” continuum: from innate to adaptive responses. J Neuroinflammation 2:24
Watters JJ, Schartner JM, Badie B (2005) Microglia function in brain tumours. J Neurosci Res 81:447–455
Banati RB (2002) Visualising microglial activation in vivo. Glia 40:206–217
Papadopoulos V, Baraldi M, Guilarte TR et al (2006) Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 27:402–409
Veenman L, Gavish M (2006) The peripheral benzodiazepine receptor and the cardiovascular system. Implications for drug development. Pharmacol Ther 110:502–524
Gavish M, Bachman I, Shoukrun R et al (1999) Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev 51:629–650
Bribes E, Carriere D, Goubet C et al (2004) Immunohistochemical assessment of the peripheral benzodiazepine receptor in human tissues. J Histochem Cytochem 52:19–28
Choi HB, Khoo C, Ryu JK et al (2002) Inhibition of lipopolysaccharide-induced cyclooxygenase-2, tumour necrosis factor-alpha and [Ca2+]i responses in human microglia by the peripheral benzodiazepine receptor ligand PK11195. J Neurochem 83:546–555
Farges RC, Torres SR, Ferrara P et al (2004) Involvement of steroids in anti-inflammatory effects of peripheral benzodiazepine receptor ligands. Life Sci 74(11):1387–1395
Han Z, Slack RS, Li W et al (2003) Expression of peripheral benzodiazepine receptor (PBR) in human tumours: relationship to breast, colorectal, and prostate tumour progression. J Recept Signal Transduct Res 23:225–238
Turkheimer FE, Aston JA, Banati RB et al (2003) A linear wavelet filter for parametric imaging with dynamic PET. IEEE Trans Med Imaging 22(3):289–301
Logan J, Fowler JS, Volkow ND et al (1996) Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 16:834–840
Dussossoy D, Carayon P, Feraut D et al (1996) Development of a monoclonal antibody to immuno-cytochemical analysis of the cellular localization of the peripheral benzodiazepine receptor. Cytometry 24:39–48
Banati RB, Newcombe J, Gunn RN et al (2000) The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 123:2321–2337
Cahard D, Canat X, Carayon P et al (1994) Subcellular localization of peripheral benzodiazepine receptors on human leukocytes. Lab Invest 70:23–28
Turkheimer FE, Roncaroli F, Hennuy B et al (2006) Chromosomal patterns of gene expression from microarray data: methodology, validation and clinical relevance in gliomas. BMC Bioinformatics 7:526–544
Duke DC, Moran LB, Turkheimer FE et al (2004) Microglia in culture: what genes do they express? Dev Neurosci 26:30–37
Kleihues P, Louis DN, Scheithauer BW et al (2002) The WHO classification of tumours of the nervous system. J Neuropathol Exp Neurol 61:215–225
Wilms H, Claasen J, Rohl C et al (2003) Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro. Neurobiol Dis 14:417–424
Moran LB, Duke DC, Turkheimer FE et al (2004) Towards a transcriptome definition of microglial cells. Neurogenetics 5:95–108
Kuhlmann AC, Guilarte TR (2000) Cellular and subcellular localization of peripheral benzodiazepine receptors after trimethyltin neurotoxicity. J Neurochem 74:1694–1704
Chen MK, Baidoo K, Verina T et al (2004) Peripheral benzodiazepine receptor imaging in CNS demyelination: functional implications of anatomical and cellular localization. Brain 127:1379–1392
Olson JM, Junck L, Young AB et al (1988) Isoquinoline and peripheral-type benzodiazepine binding in gliomas: implications for diagnostic imaging. Cancer Res 48:5837–5841
Benavides J, Cornu P, Dennis T et al (1988) Imaging of human brain lesions with an omega 3 site radioligand. Ann Neurol 24:708–712
Ferrarese C, Appollonio I, Frigo M et al (1989) Benzodiazepine receptors and diazepam-binding inhibitor in human cerebral tumours. Ann Neurol 26:564–568
Black KL, Ikezaki K, Santori E et al (1990) Specific high-affinity binding of peripheral benzodiazepine receptor ligands to brain tumours in rat and man. Cancer 65:93–97
Broaddus WC, Bennett JP Jr (1990) Peripheral-type benzodiazepine receptors in human glioblastomas: pharmacologic characterization and photoaffinity labeling of ligand recognition site. Brain Res 518:199–208
Cornu P, Benavides J, Scatton B et al (1992) Increase in omega 3 (peripheral-type benzodiazepine) binding site densities in different types of human brain tumours. A quantitative autoradiography study. Acta Neurochir (Wien) 119:146–152
Takada A, Mitsuka S, Diksic M et al (1992) Autoradiographic study of peripheral benzodiazepine receptors in animal brain tumour models and human gliomas. Eur J Pharmacol 228:131–139
Miyazawa N, Hamel E, Diksic M (1998) Assessment of the peripheral benzodiazepine receptors in human gliomas by two methods. J Neurooncol 38:19–26
Miettinen H, Kononen J, Haapasalo H et al (1995) Expression of peripheral-type benzodiazepine receptor and diazepam binding inhibitor in human astrocytomas: relationship to cell proliferation. Cancer Res 55:2691–2695
Brown RC, Degenhardt B, Kotoula M et al (2000) Location-dependent role of the human glioma cell peripheral-type benzodiazepine receptor in proliferation and steroid biosynthesis. Cancer Lett 156:125–132
Vlodavsky E, Soustiel JF (2007) Immunohistochemical expression of peripheral benzodiazepine receptors in human astrocytomas and its correlation with grade of malignancy, proliferation, apoptosis and survival. J Neurooncol 81(1):1–7
Banati RB, Myers R, Kreutzberg GW (1997) PK (‘peripheral benzodiazepine’)–binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK11195 binding to activated microglia. J Neurocytol 26:77–82
Hong SH, Choi HB et al (2006) Mitochondrial ligand inhibits store-operated calcium influx and COX-2 production in human microglia. J Neurosci Res 83:1293–1298
Shono T, Tofilon PJ, Bruner JM et al (2001) Cyclooxygenase-2 expression in human gliomas: Prognostic significance and molecular correlations. Cancer Res 61:4375–4381
Hara A, Okayasu I (2004) Cyclooxigenase 2 and inducible nitric oxide synthase in human astrocytic gliomas: correlation with angiogenesis and prognostic significance. Acta Neuropathol 108:43–48
He BP, Wang JJ et al (2006) Differential reactions of microglia to brain metastases of lung cancer. Mol Med 12:161–170
Turkheimer FE, Edison P et al (2007) Reference and target region modelling of [11C]-(R)-PK11195 brain studies. J Nucl Med 48:158–167
Junck L, Olson JM et al (1989) PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site. Ann Neurol 26:752–758
Pappata S, Cornu P et al (1991) PET study of carbon-11-PK 11195 binding to peripheral type benzodiazepine sites in glioblastoma: a case report. J Nucl Med 32:1608–1610
Acknowledgements
This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas (17022023) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Dr. Roncaroli’s research is partly supported by the Charity BRTC. We thank Dr. Nobuhiro Mikuni from the Department of Neurosurgery at the Kyoto University Graduate School of Medicine for recruiting the patients, Ms. Lynne Christian from the Department of Neuropathology at the Imperial College in London for critically reviewing the manuscript, Professor Graeber and Dr. Moran, Department of Neuropathology, Imperial College for kindly making available their dataset generated with cases of Parkinson’s Disease.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Takaya, S., Hashikawa, K., Turkheimer, F.E. et al. The lack of expression of the peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas. J Neurooncol 85, 95–103 (2007). https://doi.org/10.1007/s11060-007-9396-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-007-9396-1