Journal of Neuro-Oncology

, Volume 76, Issue 2, pp 105–109

Immunohistochemical Analysis of Platelet-derived Growth Factor Receptor-α, -β, c-kit, c-abl, and Arg Proteins in Glioblastoma: Possible Implications for Patient Selection for Imatinib Mesylate Therapy

  • C. Haberler
  • E. Gelpi
  • C. Marosi
  • K. Rössler
  • P. Birner
  • H. Budka
  • J. A. Hainfellner
Laboratory Investigation

Summary

Inhibition of tyrosine kinase (TK) receptors by synthetic small molecules has become a promising new therapy option in oncology. The TK inhibitor imatinib mesylate selectively targets PDGFR-α, -β, c-kit, c-abl and arg and has proven successful in the treatment of chronic myeloid leukaemia. In recurrent glioblastoma, phase II therapy trials using imatinib mesylate have been initiated. As only a fraction of patients seems to benefit from imatinib mesylate therapy and due to potential side effects and high costs of imatinib mesylate therapy, selection of the right patients is important. The goal of our study was to assess systematically immunohistochemical expression of the major TKs targeted by imatinib mesylate in glioblastoma, as expression of these factors could be used to select patients for imatinib mesylate therapy.

In a cohort of 101 glioblastoma patients, anti-PDGFR-α, -β, c-kit, c-abl and arg protein immunohistochemistry was performed. Expression of these proteins was assessed semi-quantitatively and correlated with patient survival.

PDGFR-α and arg expression in tumor cells was widespread in 1/101 cases, respectively. Focal PDGFR-α, -β, c-kit, c-abl and arg immunolabeling was detected in 25/101, 19/101, 4/101, 7/101 and 31/101 cases, respectively. Statistical analysis did not reveal any correlation between expression of the TKs and patient survival.

We show here for the first time in a large series of glioblastomas that PDGFR-α, -β, c-kit, c-abl and arg expression is immunohistochemically detectable in a fraction of cases. The value of anti-tyrosine kinase immunolabeling as predictive factor for patient selection remains to be clarified by comparative analysis of tumor tissue of therapy-responders versus non-responders.

Keywords

glioblastoma platelet-derived growth factor receptor-α -β c-kit c-abl and arg targeted therapy 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Hubbard, SR, Till, JH 2000Protein tyrosine kinase structure and functionAnnu Rev Biochem69373398CrossRefPubMedGoogle Scholar
  2. 2.
    Heinrich, MC, Griffith, DJ, Druker, BJ, Wait, CL, Ott, KA, Zigler, AJ 2000Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitorBlood96925932PubMedGoogle Scholar
  3. 3.
    Buchdunger, E, Cioffi, CL, Law, N, Stover, D, Ohno-Jones, S, Druker, BJ, Lydon, NB 2000Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptorsJ Pharmacol Exp Ther295139145PubMedGoogle Scholar
  4. 4.
    Melo, JV 1996The molecular biology of chronic myeloid leukaemiaLeukemia10751756PubMedGoogle Scholar
  5. 5.
    Rowley, JD 1973A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa stainingNature243290293CrossRefPubMedGoogle Scholar
  6. 6.
    Daley, GQ, Etten, RA, Baltimore, D 1990Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosomeScience247824830PubMedGoogle Scholar
  7. 7.
    Druker, BJ 2002Imatinib and chronic myeloid leukemia: validating the promise of molecularly targeted therapyEur J Cancer38S70S76PubMedGoogle Scholar
  8. 8.
    Miettinen, M, Majidi, M, Lasota, J 2002Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): a reviewEur J Cancer38S39S51PubMedGoogle Scholar
  9. 9.
    Demetri, GD 2002Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinib mesylate (STI571)Eur J Cancer38S52S59PubMedGoogle Scholar
  10. 10.
    Raymond E, Brandes. A, Van Oosterom A, Dittrich C, Fumoleau P, Coudert C, Twelves C, De Balincourt C, Lacombe D, Van den Bent M: Multicentre phase II study of imatinib mesylate in patients with recurrent glioblastoma: An EORTC: NDDG/BTG Intergroup Study. J Clin Oncol 22: 1501, 2004 (abstract)Google Scholar
  11. 11.
    Fleming, TP, Saxena, A, Clark, WC, Robertson, JT, Oldfield, EH, Aaronson, SA, Ali, IU 1992Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumorsCancer Res5245504553PubMedGoogle Scholar
  12. 12.
    Hermanson, M, Funa, K, Hartman, M, Claesson-Welsh, L, Heldin, CH, Westermark, B, Nister, M 1992Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loopsCancer Res5232133219PubMedGoogle Scholar
  13. 13.
    Kleihues, P, Ohgaki, H 1999Primary and secondary glioblastomas: from concept to clinical diagnosisNeuro-Oncol14451PubMedGoogle Scholar
  14. 14.
    Kilic, T, Alberta, JA, Zdunek, PR, Acar, M, Iannarelli, P, O’Reilly, T, Buchdunger, E, Black, PM, Stiles, CD 2000Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine classCancer Res6051435150PubMedGoogle Scholar
  15. 15.
    Dowsett, M, Bartlett, J, Ellis, IO, Salter, J, Hills, M, Mallon, E, Watters, AD, Cooke, T, Paish, C, Wencyk, PM, Pinder, SE 2003Correlation between immunohistochemistry (HercepTest) and fluorescence in situ hybridization (FISH) for HER-2 in 426 breast carcinomas from 37 centresJ Pathol199418423CrossRefPubMedGoogle Scholar
  16. 16.
    Birner, P, Piribauer, M, Fischer, I, Gatterbauer, B, Marosi, C, Ambros, PF, Ambros, IM, Bredel, M, Oberhuber, G, Rossler, K, Budka, H, Harris, AL, Hainfellner, JA 2003Vascular patterns in glioblastoma influence clinical outcome and associate with variable expression of angiogenic proteins: evidence for distinct angiogenic subtypesBrain Pathol1313343PubMedGoogle Scholar
  17. 17.
    Hermanson, M, Funa, K, Koopmann, J, Maintz, D, Waha, A, Westermark, B, Heldin, CH, Wiestler, OD, Louis, DN, von-Deimling, A, Nister, M 1996Association of loss of heterozygosity on chromosome 17p with high platelet-derived growth factor alpha receptor expression in human malignant gliomasCancer Res56164171PubMedGoogle Scholar
  18. 18.
    Das, A, Tan, WL, Teo, J, Smith, DR 2002Glioblastoma multiforme in an Asian population: evidence for a distinct genetic pathwayJ Neuro-Oncol6011725CrossRefGoogle Scholar
  19. 19.
    Plate, KH, Breier, G, Farrell, CL, Risau, W 1992Platelet-derived growth factor receptor-beta is induced during tumor development and upregulated during tumor progression in endothelial cells in human gliomasLab Invest67529534PubMedGoogle Scholar
  20. 20.
    Stanulla, M, Welte, K, Hadam, MR, Pietsch, T 1995Coexpression of stem cell factor and its receptor c-Kit in human malignant glioma cell linesActa neuropathol89158165PubMedGoogle Scholar
  21. 21.
    Tada, M, Diserens, AC, Desbaillets, I, de-Tribolet, N 1994Analysis of cytokine receptor messenger RNA expression in human glioblastoma cells and normal astrocytes by reverse-transcription polymerase chain reactionJ Neurosurg8010631073PubMedGoogle Scholar
  22. 22.
    Berdel, WE, De-Vos, S, Maurer, J, Oberberg, D, Von-Marschall, Z, Schroeder, JK, Li, J, Ludwig, WD, Kreuser, ED, Thiel, E, Herrmann, F 1992Recombinant human stem cell factor stimulates growth of a human glioblastoma cell line expressing c-kit protooncogeneCancer Res5234983502PubMedGoogle Scholar
  23. 23.
    Blin, N, Muller-Brechlin, R, Carstens, C, Meese, E, Zang, KD 1987Enhanced expression of four cellular oncogenes in a human glioblastoma cell lineCancer Genet Cytogenet25285292CrossRefPubMedGoogle Scholar
  24. 24.
    Etten, RA 1999Cycling, stressed-out and nervous: cellular functions of c-AblTrends Cell Biol9179186PubMedGoogle Scholar
  25. 25.
    Koleske, AJ, Gifford, AM, Scott, ML, Nee, M, Bronson, RT, Miczek, KA, Baltimore, D 1998Essential roles for the Abl and Arg tyrosine kinases in neurulationNeuron2112591272CrossRefPubMedGoogle Scholar
  26. 26.
    Medeiros, F, Corless, CL, Duensing, A, Hornick, JL, Oliveira, AM, Heinrich, MC, Fletcher, JA, Fletcher, CD 2004KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implicationsAm J Surg Pathol28889894PubMedGoogle Scholar
  27. 27.
    Buchdunger, E, O’Reilly, T, Wood, J 2002Pharmacology of imatinib (STI571)Eur J Cancer38S28S36PubMedGoogle Scholar
  28. 28.
    Borg,  2004Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effectsJ Clin Invest114379388CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • C. Haberler
    • 1
  • E. Gelpi
    • 1
  • C. Marosi
    • 2
  • K. Rössler
    • 3
  • P. Birner
    • 4
  • H. Budka
    • 1
  • J. A. Hainfellner
    • 1
    • 5
  1. 1.Institute of NeurologyMedical University of ViennaAustria
  2. 2.Department of Internal Medicine IMedical University of ViennaAustria
  3. 3.Department of NeurosurgeryMedical University of ViennaAustria
  4. 4.Department of Clinical PathologyMedical University of ViennaAustria
  5. 5.Institute of NeurologyUniversity of ViennaWienAustria

Personalised recommendations