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Methyl-[11C]-l-methionine uptake as measured by positron emission tomography correlates to microvessel density in patients with glioma

  • Lutz W. Kracht
  • Michael Friese
  • Karl Herholz
  • Roland Schroeder
  • Bernd Bauer
  • Andreas Jacobs
  • Wolf-Dieter HeissEmail author
Original Article

Abstract

Positron emission tomography (PET) using methyl-[11C]-l-methionine ([11C]MET) is a useful tool in the diagnosis of brain tumours. The main mechanism of [11C]MET uptake is probably increased transport via the L-transporter system located in the endothelial cell membrane. We used [11C]MET-PET and microvessel count in glioma specimens to investigate whether the increased amino acid uptake is related to angiogenesis. Twenty-one patients with newly diagnosed and histologically confirmed glioma were investigated with [11C]MET-PET before open surgery. [11C]MET uptake was determined within an 8-mm region of interest in the area of the tumour showing the highest uptake, and the ratio to uptake in the corresponding contralateral region was calculated. To measure angiogenesis, immunostaining with factor VIII antibody was applied to sections from tumour tissue, and highlighted microvessels were counted in the area of highest vascularisation. In the entire patient group, a positive correlation was found between microvessel count and [11C]MET uptake (Spearman: r=0.89, P<0.001). This correlation was also significant in subgroups of patients [patients with grade II and III astrocytomas (Spearman: r=0.77, P<0.01) and patients with glioblastoma (Spearman: r=0.64, P<0.05)]. Angiogenesis, as assessed by microvessel count, and increased amino acid uptake, as assessed by [11C]MET-PET, are closely related events in gliomas. [11C]MET-PET offers a direct measure of amino acid transport and an indirect measure of microvessel density. [11C]MET-PET might be a useful tool to select potential responders to anti-angiogenic therapy and to monitor patients during such therapy.

Keywords

PET [11C]Methionine Angiogenesis Glioma Molecular imaging 

References

  1. 1.
    Herholz K, Holzer T, Bauer B, Schroder R, Voges J, Ernestus RI, Mendoza G, Weber-Luxenburger G, Lottgen J, Thiel A, Wienhard K, Heiss WD.11C-methionine PET for differential diagnosis of low-grade gliomas. Neurology 1998; 50:1316–1322.Google Scholar
  2. 2.
    Weber WA, Wester HJ, Grosu AL, Herz M, Dzewas B, Feldmann HJ, Molls M, Stocklin G, Schwaiger M. O-(2-[18F]fluoroethyl)-l-tyrosine and l-[methyl-11C]methionine uptake in brain tumours: initial results of a comparative study. Eur J Nucl Med 2000; 27:542–549.Google Scholar
  3. 3.
    Derlon JM, Bourdet C, Bustany P, Chatel M, Theron J, Darcel F, Syrota A. [11C]l-methionine uptake in gliomas. Neurosurgery 1989; 25:720–728.Google Scholar
  4. 4.
    Lilja A, Lundqvist H, Olsson Y, Spannare B, Gullberg P, Langstrom B. Positron emission tomography and computed tomography in differential diagnosis between recurrent or residual glioma and treatment-induced brain lesions. Acta Radiol 1989; 30:121–128.Google Scholar
  5. 5.
    Ericson K, Lilja A, Bergstrom M, Collins VP, Eriksson L, Ehrin E, von Holst H, Lundqvist H, Langsrom BB, Mosskin M. Positron emission tomography with ([11C]methyl)-l-methionine, [11C]d-glucose, and [68Ga]EDTA in supratentorial tumors. J Comput Assist Tomogr 1985; 9:683–689.Google Scholar
  6. 6.
    Bergstrom M, Collins VP, Ehrin E, Ericson K, Eriksson L, Greitz T, Halldin C, von Holst H, Langstrom B, Lilja A. Discrepancies in brain tumor extent as shown by computed tomography and positron emission tomography using [68Ga]EDTA, [11C]glucose, and [11C]methionine. J Comput Assist Tomogr 1983; 7:1062–1066.Google Scholar
  7. 7.
    Chung JK, Kim YK, Kim SK, Lee YJ, Paek S, Yeo JS, Jeong JM, Lee DS, Jung HW, Lee MC. Usefulness of11C-methionine PET in the evaluation of brain lesions that are hypo- or isometabolic on 18F-FDG PET. Eur J Nucl Med Mol Imaging 2002; 29:176–182.Google Scholar
  8. 8.
    Kaschten B, Stevenaert A, Sadzot B, Deprez M, Degueldre C, Del Fiore G, Luxen A, Reznik M. Preoperative evaluation of 54 gliomas by PET with fluorine-18-fluorodeoxyglucose and/or carbon-11-methionine. J Nucl Med 1998; 39:778–785.Google Scholar
  9. 9.
    Ogawa T, Shishido F, Kanno I, Inugami A, Fujita H, Murakami M, Shimosegawa E, Ito H, Hatazawa J, Okudera T. Cerebral glioma: evaluation with methionine PET. Radiology 1993; 186:45–53.Google Scholar
  10. 10.
    Ogawa T, Inugami A, Hatazawa J, Kanno I, Murakami M, Yasui N, Mineura K, Uemura K. Clinical positron emission tomography for brain tumors: comparison of fludeoxyglucose F 18 and l-methyl-11C-methionine. AJNR Am J Neuroradiol 1996; 17:345–353.Google Scholar
  11. 11.
    Sasaki M, Kuwabara Y, Yoshida T, Nakagawa M, Fukumura T, Mihara F, Morioka T, Fukui M, Masuda K. A comparative study of thallium-201 SPET, carbon-11 methionine PET and fluorine-18 fluorodeoxyglucose PET for the differentiation of astrocytic tumours. Eur J Nucl Med 1998; 25:1261–1269.Google Scholar
  12. 12.
    Langen KJ, Muhlensiepen H, Holschbach M, Hautzel H, Jansen P, Coenen HH. Transport mechanisms of 3-[123I]iodo-alpha-methyl-l-tyrosine in a human glioma cell line: comparison with [3H]methyl]-l-methionine. J Nucl Med 2000; 41:1250–1255.Google Scholar
  13. 13.
    Sato N, Suzuki M, Kuwata N, Kuroda K, Wada T, Beppu T, Sera K, Sasaki T, Ogawa A. Evaluation of the malignancy of glioma using11C-methionine positron emission tomography and proliferating cell nuclear antigen staining. Neurosurg Rev 1999; 22:210–214.Google Scholar
  14. 14.
    Kubota R, Kubota K, Yamada S, Tada M, Takahashi T, Iwata R, Tamahashi N. Methionine uptake by tumor tissue: a microautoradiographic comparison with FDG. J Nucl Med 1995; 36:484–492.Google Scholar
  15. 15.
    Jacobs A. Amino acid uptake in ischemically compromised brain tissue. Stroke 1995; 26:1859–1866.Google Scholar
  16. 16.
    Wienhard K, Herholz K, Coenen HH, Rudolf J, Kling P, Stocklin G, Heiss WD. Increased amino acid transport into brain tumors measured by PET ofl-(2-18F)fluorotyrosine. J Nucl Med 1991; 32:1338–1346.Google Scholar
  17. 17.
    Heiss P, Mayer S, Herz M, Wester HJ, Schwaiger M, Senekowitsch-Schmidtke R. Investigation of transport mechanism and uptake kinetics of O-(2-[18F]fluoroethyl)-l-tyrosine in vitro and in vivo. J Nucl Med 1999; 40:1367–1373.Google Scholar
  18. 18.
    Bergstrom M, Lundqvist H, Ericson K, Lilja A, Johnstrom P, Langstrom B, von Holst H, Eriksson L, Blomqvist G. Comparison of the accumulation kinetics of l-(methyl-11C)-methionine and d-(methyl-11C)-methionine in brain tumors studied with positron emission tomography. Acta Radiol 1987; 28:225–229.Google Scholar
  19. 19.
    Miyagawa T, Oku T, Uehara H, Desai R, Beattie B, Tjuvajev J, Blasberg R. "Facilitated" amino acid transport is upregulated in brain tumors. J Cereb Blood Flow Metab 1998; 18:500–509.Google Scholar
  20. 20.
    Leon SP, Folkerth RD, Black PM. Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 1996; 77:362–372.Google Scholar
  21. 21.
    Chan AS, Leung SY, Wong MP, Yuen ST, Cheung N, Fan YW, Chung LP. Expression of vascular endothelial growth factor and its receptors in the anaplastic progression of astrocytoma, oligodendroglioma, and ependymoma. Am J Surg Pathol 1998; 22:816–826.Google Scholar
  22. 22.
    Kracht LW, Bauer A, Herholz K, Terstegge K, Friese M, Schroder R, Heiss WD. Positron emission tomography in a case of intracranial hemangiopericytoma. J Comput Assist Tomogr 1999; 23:365–368.Google Scholar
  23. 23.
    Pathology and genetics of tumours of the nervous system (WHO). Lyon: International Agency for Research on Cancer (IARC Press), 2000.Google Scholar
  24. 24.
    Wienhard K, Eriksson L, Grootoonk S, Casey M, Pietrzyk U, Heiss WD. Performance evaluation of the positron scanner ECAT EXACT. J Comput Assist Tomogr 1992; 16:804–813.Google Scholar
  25. 25.
    Wienhard K, Dahlbom M, Eriksson L, Michel C, Bruckbauer T, Pietrzyk U, Heiss WD. The ECAT EXACT HR: performance of a new high resolution positron scanner. J Comput Assist Tomogr 1994; 18:110–118.Google Scholar
  26. 26.
    Berger G, Maziere M, Knipper R, Prenant C, Comar D. Automated synthesis of11C-labelled radiopharmaceuticals: imipramine, chlorpromazine, nicotine and methionine. Int J Appl Radiat Isot 1979; 30:393–399.Google Scholar
  27. 27.
    Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med 1991; 324:1–8.Google Scholar
  28. 28.
    Christensen HN. Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev 1990; 70:43–77.Google Scholar
  29. 29.
    Knudsen GM, Pettigrew KD, Patlak CS, Hertz MM, Paulson OB. Asymmetrical transport of amino acids across the blood-brain barrier in humans. J Cereb Blood Flow Metab 1990; 10:698–706.Google Scholar
  30. 30.
    Sanchez del Pino MM, Peterson DR, Hawkins RA. Neutral amino acid transport characterization of isolated luminal and abluminal membranes of the blood-brain barrier. J Biol Chem 1995; 270:14913–14918.Google Scholar
  31. 31.
    Souba WW, Pacitti AJ. How amino acids get into cells: mechanisms, models, menus, and mediators. JPEN J Parenter Enteral Nutr 1992; 16:569–578.Google Scholar
  32. 32.
    Bading JR, Kan-Mitchell J, Conti PS. System A amino acid transport in cultured human tumor cells: implications for tumor imaging with PET. Nucl Med Biol 1996; 23:779–786.Google Scholar
  33. 33.
    Plate KH, Breier G, Risau W. Molecular mechanisms of developmental and tumor angiogenesis. Brain Pathol 1994; 4:207–218.Google Scholar
  34. 34.
    Fujisawa H, Reis RM, Nakamura M, Colella S, Yonekawa Y, Kleihues P, Ohgaki H. Loss of heterozygosity on chromosome 10 is more extensive in primary (de novo) than in secondary glioblastomas. Lab Invest 2000; 80:65–72.Google Scholar
  35. 35.
    Vaquero J, Zurita M, Coca S, Oya S, Morales C. Prognostic significance of clinical and angiogenesis-related factors in low-grade oligodendrogliomas. Surg Neurol 2000; 54:229–234.Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Lutz W. Kracht
    • 1
  • Michael Friese
    • 3
  • Karl Herholz
    • 2
  • Roland Schroeder
    • 3
  • Bernd Bauer
    • 1
  • Andreas Jacobs
    • 2
  • Wolf-Dieter Heiss
    • 1
    • 2
    Email author
  1. 1.Max-Planck-Institut für neurologische ForschungCologneGermany
  2. 2.Klinik und Poliklinik für Neurologie der Universität zu KölnGermany
  3. 3.Institut für Pathologie der Universität zu KölnGermany

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