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Journal of Neuro-Oncology
Published in: Journal of Neuro-Oncology 1/2010

01-03-2010 | Laboratory Investigation - Human/Animal Tissue

In vivo assessment of high-grade glioma biochemistry using microdialysis: a study of energy-related molecules, growth factors and cytokines

Authors: Hani J. Marcus, Keri L. H. Carpenter, Stephen J. Price, Peter J. Hutchinson

Published in: Journal of Neuro-Oncology | Issue 1/2010

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Abstract

Microdialysis enables measurement of the chemistry of the cerebral extracellular fluid. This study’s objective was to utilise microdialysis to monitor levels of glucose, lactate, pyruvate, glutamate and glycerol in patients following surgery for intrinsic brain tumours, and to assess the concentration of growth factors, cytokines and other proteins involved in the pathogenesis of high-grade gliomas in vivo. Eight patients with suspected high-grade gliomas were studied. Seven of these underwent resection with one microdialysis catheter placed at the tumour resection margin and, in six of these seven cases, a second microdialysis catheter in macroscopically normal peritumour tissue. The remaining glioma patient had an image-guided biopsy with a single catheter inserted stereotactically at the tumour margin. Histology demonstrated WHO IV glioblastoma in five cases, WHO III anaplastic astrocytoma in two cases, and one cerebral lymphoma. In the high-grade gliomas (WHO IV and III), tumour margin microdialysates consistently showed significantly lower glucose, higher lactate/pyruvate (L/P) ratio, higher glutamate and higher glycerol, relative to peritumour microdialysates (P < 0.05). These results indicate that malignant glioma margin tissue is metabolically extremely active. There was great variability in the microdialysate concentrations of growth factors (TGFα, EGF, VEGF), cytokines (IL-1α, IL-1β, IL-1ra, IL-6, IL-8), matrix metalloproteinases (MMP-2, MMP-9) and their endogenous inhibitors (TIMP-1, TIMP-2). Notably, microdialysates from the glioma resection margin demonstrated significantly higher IL-8 concentration and higher MMP-2/TIMP-1 ratio when compared to peritumour microdialysates (P < 0.05), suggesting an environment favouring invasion and angiogenesis at the tumour margin. Microdialysis is a promising technique to study in vivo glioma metabolism, and may assist in the development of new therapies.
Literature
1.
Ungerstedt U, Pycock C (1974) Functional correlates of dopamine neurotransmission. Bull Schweiz Akad Med Wiss 30:44–55PubMed
2.
Persson L, Hillered L (1992) Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis. J Neurosurg 76:72–80CrossRefPubMed
3.
Landolt H, Langemann H (1996) Cerebral microdialysis as a diagnostic tool in acute brain injury. Eur J Anaesthesiol 13:269–278CrossRefPubMed
4.
Persson L, Valtysson J, Enblad P, Warme PE, Cesarini K, Lewen A, Hillered L (1996) Neurochemical monitoring using intracerebral microdialysis in patients with subarachnoid hemorrhage. J Neurosurg 84:606–616CrossRefPubMed
5.
During MJ, Spencer DD (1993) Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341:1607–1610CrossRefPubMed
6.
Roslin M, Henriksson R, Bergstrom P, Ungerstedt U, Bergenheim AT (2003) Baseline levels of glucose metabolites, glutamate and glycerol in malignant glioma assessed by stereotactic microdialysis. J Neurooncol 61:151–160CrossRefPubMed
7.
Klegeris A, Walker DG, McGeer PL (1997) Regulation of glutamate in cultures of human monocytic THP-1 and astrocytoma U-373 MG cells. J Neuroimmunol 78:152–161CrossRefPubMed
8.
Behrens PF, Langemann H, Strohschein R, Draeger J, Hennig J (2000) Extracellular glutamate and other metabolites in and around RG2 rat glioma: an intracerebral microdialysis study. J Neurooncol 47:11–22CrossRefPubMed
9.
Hillman J, Aneman O, Persson M, Andersson C, Dabrosin C, Mellergard P (2007) Variations in the response of interleukins in neurosurgical intensive care patients monitored using intracerebral microdialysis. J Neurosurg 106:820–825CrossRefPubMed
10.
Hutchinson PJ, O’Connell MT, Rothwell NJ, Hopkins SJ, Nortje J, Carpenter KLH, Timofeev I, Al-Rawi PG, Menon DK, Pickard JD (2007) Inflammation in human brain injury: intracerebral concentrations of IL 1alpha, IL-1beta and their endogenous inhibitor IL-1ra. J Neurotrauma 24:1545–1557CrossRefPubMed
11.
Hillman J, Aneman O, Anderson C, Sjogren F, Saberg C, Mellergard P (2005) A microdialysis technique for routine measurement of macromolecules in the injured human brain. Neurosurgery 56:1264–1268 discussion 1268-1270CrossRefPubMed
12.
Flannery T, McConnell RS, McQuaid S, McGregor G, Mirakhur M, Martin L, Scott C, Burden R, Walker B, McGoohan C, Johnston PG (2007) Detection of cathepsin S cysteine protease in human brain tumour microdialysates in vivo. Br J Neurosurg 21:204–209CrossRefPubMed
13.
Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313:144–147CrossRefPubMed
14.
Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B (1987) Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 84:6899–6903CrossRefPubMed
15.
Bigner SH, Vogelstein B (1990) Cytogenetics and molecular genetics of malignant gliomas and medulloblastoma. Brain Pathol 1:12–18CrossRefPubMed
16.
Ekstrand AJ, James CD, Cavenee WK, Seliger B, Pettersson RF, Collins VP (1991) Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res 51:2164–2172PubMed
17.
Gauthier T, Hamou MF, Monod L, Gallay P, Carrel S, de Tribolet N (1993) Expression and release of interleukin-1 by human glioblastoma cells in vitro and in vivo. Acta Neurochir (Wien) 121:199–205CrossRef
18.
Tada M, Diserens AC, Desbaillets I, Jaufeerally R, Hamou MF, de Tribolet N (1994) Production of interleukin-1 receptor antagonist by human glioblastoma cells in vitro and in vivo. J Neuroimmunol 50:187–194CrossRefPubMed
19.
Ilyin SE, Gonzalez-Gomez I, Romanovicht A, Gayle D, Gilles FH, Plata-Salaman CR (2000) Autoregulation of the interleukin-1 system and cytokine-cytokine interactions in primary human astrocytoma cells. Brain Res Bull 51:29–34CrossRefPubMed
20.
Oelmann E, Kraemer A, Serve H, Reufi B, Oberberg D, Patt S, Herbst H, Stein H, Thiel E, Berdel WE (1997) Autocrine interleukin-1 receptor antagonist can support malignant growth of glioblastoma by blocking growth-inhibiting autocrine loop of interleukin-1. Int J Cancer 71:1066–1076CrossRefPubMed
21.
Chang C, Werb Z (2001) The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol 11:S37–S43PubMed
22.
Deryugina EI, Bourdon MA, Luo GX, Reisfeld RA, Strongin A (1997) Matrix metalloproteinase-2 activation modulates glioma cell migration. J Cell Sci 110:2473–2482PubMed
23.
Komatsu K, Nakanishi Y, Nemoto N, Hori T, Sawada T, Kobayashi M (2004) Expression and quantitative analysis of matrix metalloproteinase-2 and -9 in human gliomas. Brain Tumor Pathol 21:105–112CrossRefPubMed
24.
Lampert K, Machein U, Machein MR, Conca W, Peter HH, Volk B (1998) Expression of matrix metalloproteinases and their tissue inhibitors in human brain tumors. Am J Pathol 153:429–437PubMed
25.
Gagliano N, Moscheni C, Torri C, Magnani I, Bertelli AA, Gioia M (2005) Effect of resveratrol on matrix metalloproteinase-2 (MMP-2) and Secreted Protein Acidic and Rich in Cysteine (SPARC) on human cultured glioblastoma cells. Biomed Pharmacother 59:359–364CrossRefPubMed
26.
Kunishio K, Okada M, Matsumoto Y, Nagao S (2003) Matrix metalloproteinase-2 and -9 expression in astrocytic tumors. Brain Tumor Pathol 20:39–45CrossRefPubMed
27.
Hormigo A, Gu B, Karimi S, Riedel E, Panageas KS, Edgar MA, Tanwar MK, Rao JS, Fleisher M, DeAngelis LM, Holland EC (2006) YKL-40 and matrix metalloproteinase-9 as potential serum biomarkers for patients with high-grade gliomas. Clin Cancer Res 12:5698–5704CrossRefPubMed
28.
Choe G, Park JK, Jouben-Steele L, Kremen TJ, Liau LM, Vinters HV, Cloughesy TF, Mischel PS (2002) Active matrix metalloproteinase 9 expression is associated with primary glioblastoma subtype. Clin Cancer Res 8:2894–2901PubMed
29.
Beliveau R, Delbecchi L, Beaulieu E, Mousseau N, Kachra Z, Berthelet F, Moumdjian R, Del Maestro R (1999) Expression of matrix metalloproteinases and their inhibitors in human brain tumors. Ann N Y Acad Sci 886:236–239CrossRefPubMed
30.
Kachra Z, Beaulieu E, Delbecchi L, Mousseau N, Berthelet F, Moumdjian R, Del Maestro R, Beliveau R (1999) Expression of matrix metalloproteinases and their inhibitors in human brain tumors. Clin Exp Metastasis 17:555–566CrossRefPubMed
31.
Chintala SK, Tonn JC, Rao JS (1999) Matrix metalloproteinases and their biological function in human gliomas. Int J Dev Neurosci 17:495–502CrossRefPubMed
32.
Groft LL, Muzik H, Rewcastle NB, Johnston RN, Knauper V, Lafleur MA, Forsyth PA, Edwards DR (2001) Differential expression and localization of TIMP-1 and TIMP-4 in human gliomas. Br J Cancer 85:55–63CrossRefPubMed
33.
Nakada M, Kita D, Futami K, Yamashita J, Fujimoto N, Sato H, Okada Y (2001) Roles of membrane type 1 matrix metalloproteinase and tissue inhibitor of metalloproteinases 2 in invasion and dissemination of human malignant glioma. J Neurosurg 94:464–473CrossRefPubMed
34.
Chang CY, Li MC, Liao SL, Huang YL, Shen CC, Pan HC (2005) Prognostic and clinical implication of IL-6 expression in glioblastoma multiforme. J Clin Neurosci 12:930–933CrossRefPubMed
35.
Fischer I, Gagner JP, Law M, Newcomb EW, Zagzag D (2005) Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol 15:297–310PubMedCrossRef
36.
Brat DJ, Bellail AC, Van Meir EG (2005) The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol 7:122–133CrossRefPubMed
37.
Loeffler S, Fayard B, Weis J, Weissenberger J (2005) Interleukin-6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1. Int J Cancer 115:202–213CrossRefPubMed
38.
Hutchinson PJ, O’Connell MT, Al-Rawi PG, Maskell LB, Kett-White R, Gupta AK, Richards HK, Hutchinson DB, Kirkpatrick PJ, Pickard JD (2000) Clinical cerebral microdialysis: a methodological study. J Neurosurg 93:37–43CrossRefPubMed
39.
Durkan GC, Nutt JE, Marsh C, Rajjayabun PH, Robinson MC, Neal DE, Lunec J, Mellon JK (2003) Alteration in urinary matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio predicts recurrence in nonmuscle-invasive bladder cancer. Clin Cancer Res 9:2576–2582PubMed
40.
Gohji K, Fujimoto N, Fujii A, Komiyama T, Okawa J, Nakajima M (1996) Prognostic significance of circulating matrix metalloproteinase-2 to tissue inhibitor of metalloproteinases-2 ratio in recurrence of urothelial cancer after complete resection. Cancer Res 56:3196–3198PubMed
41.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMed
42.
43.
Kelly PJ, Daumas-Duport C, Kispert DB, Kall BA, Scheithauer BW, Illig JJ (1987) Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg 66:865–874CrossRefPubMed
44.
Price SJ, Jena R, Burnet NG, Hutchinson PJ, Dean AF, Pena A, Pickard JD, Carpenter TA, Gillard JH (2006) Improved delineation of glioma margins and regions of infiltration with the use of diffusion tensor imaging: an image-guided biopsy study. AJNR Am J Neuroradiol 27:1969–1974PubMed
45.
Berens ME, Giese A (1999) “.those left behind”. Biology and oncology of invasive glioma cells. Neoplasia 1:208–219CrossRefPubMed
46.
Luyten PR, Marien AJ, Heindel W, van Gerwen PH, Herholz K, den Hollander JA, Friedmann G, Heiss WD (1990) Metabolic imaging of patients with intracranial tumors: H-1 MR spectroscopic imaging and PET. Radiology 176:791–799PubMed
47.
Padma MV, Said S, Jacobs M, Hwang DR, Dunigan K, Satter M, Christian B, Ruppert J, Bernstein T, Kraus G, Mantil JC (2003) Prediction of pathology and survival by FDG PET in gliomas. J Neurooncol 64:227–237CrossRefPubMed
48.
Ostergaard L, Hochberg FH, Rabinov JD, Sorensen AG, Lev M, Kim L, Weisskoff RM, Gonzalez RG, Gyldensted C, Rosen BR (1999) Early changes measured by magnetic resonance imaging in cerebral blood flow, blood volume, and blood-brain barrier permeability following dexamethasone treatment in patients with brain tumors. J Neurosurg 90:300–305CrossRefPubMed
49.
Herholz K, Heindel W, Luyten PR, denHollander JA, Pietrzyk U, Voges J, Kugel H, Friedmann G, Heiss WD (1992) In vivo imaging of glucose consumption and lactate concentration in human gliomas. Ann Neurol 31:319–327CrossRefPubMed
50.
51.
Hayashi Y, Edwards NA, Proescholdt MA, Oldfield EH, Merrill MJ (2007) Regulation and function of aquaporin-1 in glioma cells. Neoplasia 9:777–787CrossRefPubMed
52.
Bergenheim AT, Roslin M, Ungerstedt U, Waldenstrom A, Henriksson R, Ronquist G (2006) Metabolic manipulation of glioblastoma in vivo by retrograde microdialysis of L-2, 4 diaminobutyric acid (DAB). J Neurooncol 80:285–293CrossRefPubMed
53.
Bergenheim AT, Capala J, Roslin M, Henriksson R (2005) Distribution of BPA and metabolic assessment in glioblastoma patients during BNCT treatment: a microdialysis study. J Neurooncol 71:287–293CrossRefPubMed
54.
Rhen T, Cidlowski JA (2005) Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N Engl J Med 353:1711–1723CrossRefPubMed
55.
Kesari S, Paleologos NA, Vick NA (2008) Corticosteroids in neuro-oncology. In: Schiff D, Kesari S, Wen PY (eds). Current clinical oncology: cancer neurology in clinical practice, 2nd edn. Humana Press, Totowa, NJ, pp 47–56
56.
Brophy TR, McCafferty J, Tyrer JH, Eadie MJ (1983) Bioavailability of oral dexamethasone during high dose steroid therapy in neurological patients. Eur J Clin Pharmacol 24:103–108CrossRefPubMed
57.
O’Sullivan BT, Cutler DJ, Hunt GE, Walters C, Johnson GF, Caterson ID (1997) Pharmacokinetics of dexamethasone and its relationship to dexamethasone suppression test outcome in depressed patients and healthy control subjects. Biol Psychiatry 41:574–584CrossRefPubMed
58.
Chalk JB, Ridgeway K, Brophy T, Yelland JD, Eadie MJ (1984) Phenytoin impairs the bioavailability of dexamethasone in neurological and neurosurgical patients. J Neurol Neurosurg Psychiatry 47:1087–1090CrossRefPubMed
59.
Fulham MJ, Brunetti A, Aloj L, Raman R, Dwyer AJ, Di Chiro G (1995) Decreased cerebral glucose metabolism in patients with brain tumors: an effect of corticosteroids. J Neurosurg 83:657–664CrossRefPubMed
60.
Hutchinson PJ, O’Connell MT, Seal A, Nortje J, Timofeev I, Al-Rawi PG, Coles JP, Fryer TD, Menon DK, Pickard JD, Carpenter KL (2009) A combined microdialysis and FDG-PET study of glucose metabolism in head injury. Acta Neurochir (Wien) 151:51–61CrossRef
61.
Saad MF, Riad-Gabriel MG, Khan A, Sharma A, Michael R, Jinagouda SD, Boyadjian R, Steil GM (1998) Diurnal and ultradian rhythmicity of plasma leptin: effects of gender and adiposity. J Clin Endocrinol Metab 83:453–459CrossRefPubMed
62.
Simon C, Weibel L, Brandenberger G (2000) Twenty-four-hour rhythms of plasma glucose and insulin secretion rate in regular night workers. Am J Physiol Endocrinol Metab 278:E413–E420PubMed
63.
Breen GA, de Vellis J (1974) Regulation of glycerol phosphate dehydrogenase by hydrocortisone in dissociated rat cerebral cell cultures. Dev Biol 41:255–266CrossRefPubMed
64.
McGinnis JF, De Vellis J (1974) Cortisol induction of glycerol phosphate dehydrogenase in a rat brain tumour cell line. Nature 250:422–424CrossRefPubMed
65.
Hutchinson PJ, O’Connell MT, Nortje J, Smith P, Al-Rawi PG, Gupta AK, Menon DK, Pickard JD (2005) Cerebral microdialysis methodology–evaluation of 20 kDa and 100 kDa catheters. Physiol Meas 26:423–428CrossRefPubMed
66.
Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477:267–283PubMed
67.
Van Meir E, Sawamura Y, Diserens AC, Hamou MF, de Tribolet N (1990) Human glioblastoma cells release interleukin 6 in vivo and in vitro. Cancer Res 50:6683–6688PubMed
68.
Kawashima A, Harada T, Imada K, Yano T, Mizuguchi K (2008) Eicosapentaenoic acid inhibits interleukin-6 production in interleukin-1beta-stimulated C6 glioma cells through peroxisome proliferator-activated receptor-gamma. Prostaglandins Leukot Essent Fatty Acids 79:59–65CrossRefPubMed
69.
Sasaki A, Ishiuchi S, Kanda T, Hasegawa M, Nakazato Y (2001) Analysis of interleukin-6 gene expression in primary human gliomas, glioblastoma xenografts, and glioblastoma cell lines. Brain Tumor Pathol 18:13–21CrossRefPubMed
70.
Lin YM, Jan HJ, Lee CC, Tao HY, Shih YL, Wei HW, Lee HM (2008) Dexamethasone reduced invasiveness of human malignant glioblastoma cells through a MAPK phosphatase-1 (MKP-1) dependent mechanism. Eur J Pharmacol 593:1–9CrossRefPubMed
71.
Forster C, Kahles T, Kietz S, Drenckhahn D (2007) Dexamethasone induces the expression of metalloproteinase inhibitor TIMP-1 in the murine cerebral vascular endothelial cell line cEND. J Physiol 580:937–949CrossRefPubMed
72.
Ronquist G, Hugosson R, Sjolander U, Ungerstedt U (1992) Treatment of malignant glioma by a new therapeutic principle. Acta Neurochir (Wien) 114:8–11CrossRef
73.
74.
Helmy A, Carpenter KL, Hutchinson PJ (2007) Microdialysis in the human brain and its potential role in the development and clinical assessment of drugs. Curr Med Chem 14:1525–1537CrossRefPubMed
75.
Blakeley JO, Olson J, Grossman SA, He X, Weingart J, Supko JG (2009) Effect of blood brain barrier permeability in recurrent high grade gliomas on the intratumoral pharmacokinetics of methotrexate: a microdialysis study. J Neurooncol 91:51–58CrossRefPubMed
Metadata
Title
In vivo assessment of high-grade glioma biochemistry using microdialysis: a study of energy-related molecules, growth factors and cytokines
Authors
Hani J. Marcus
Keri L. H. Carpenter
Stephen J. Price
Peter J. Hutchinson
Publication date
01-03-2010
Publisher
Springer US
Published in
Journal of Neuro-Oncology / Issue 1/2010
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-009-9990-5

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