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TRAIL-receptor expression is an independent prognostic factor for survival in patients with a primary glioblastoma multiforme

  • Clinical–patient studies
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Summary

Purpose

In order to improve the survival of patients with a glioblastoma multiforme tumor (GBM), new therapeutic strategies must be developed. The use of a death inducing ligand such as TRAIL (TNF Related Apoptosis Inducing Ligand) seems a promising innovative therapy. The aim of this study was to quantify the expression of the death regulating receptors TRAIL-R1, TRAIL-R2 and TRAIL on primary GBM specimens and to correlate this expression with survival.

Experimental design

Expression of TRAIL and TRAIL-receptors was assessed by immunohistochemistry, both quantitatively (% of positive tumor cells) and semi-quantitatively (staining intensity) within both the perinecrotic and intermediate tumor zones of primary GBM specimens. RT-PCR of GBM tissue was performed to show expression of TRAIL receptor mRNA.

Results

Immunohistochemistry showed a slight diffuse intracytoplasmic and a stronger membranous staining for TRAIL and TRAIL receptors in tumor cells. Semi-quantitative expression of TRAIL showed a significantly higher expression of TRAIL in the perinecrotic zone than in the intermediate zone of the tumor (P=0.0001). TRAIL-R2 expression was significantly higher expressed than TRAIL-R1 (P=0.005). The antigenic load of TRAIL-R2 was positively correlated with survival (P=0.02). Multivariate analysis of TRAIL-R1 within the study group (n=62) showed that age, gender, staining intensity, antigenic load, % of TRAIL-R1 expression, were not statistically correlated with survival however radiotherapy was significantly correlated (multivariate analysis: age: P=0.15; gender: P=0.64; staining intensity: P=0.17; antigenic load: P=0.056; % of TRAIL-R1 expression: P=0.058; radiotherapy: P=0.0001). Subgroup analysis of patients who had received radiotherapy (n=47) showed a significant association of % of TRAIL-R1 expression and the antigenic load of TRAIL-R1 with survival (multivariate analysis: P=0.036, respectively, P=0.023).

Multivariate analysis of TRAIL-R2 staining intensity and antigenic load, within the study group (P=0.004, respectively, P=0.03) and the subgroup (P=0.002, respectively, P=0.004), showed a significant association with survival. RT-PCR analysis detected a negative relation between the amount of TRAIL-R1 mRNA and the WHO grade of astrocytic tumors (P=0.03).

Conclusions

TRAIL-R1 and TRAIL-R2 expression on tumor cells are independent prognostic factors for survival in patients with a glioblastoma multiforme. Both receptors could be targets for TRAIL therapy. As TRAIL-R2 is more expressed, in comparison with TRAIL-R1, on GBM tumor cells, TRAIL-R2 seems to be of more importance as a target for future TRAIL therapy than TRAIL-R1.

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References

  1. DeAngelis LM. (2001) Brain tumorsN Engl J Med 344:114–123

    Article  PubMed  CAS  Google Scholar 

  2. 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 glioblastomaN Engl J Med 352:987–996

    Article  PubMed  CAS  Google Scholar 

  3. Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z, Schwall RH. (1999) Safety and antitumor activity of recombinant soluble Apo2 ligandJ Clin Invest 104:155–162

    Article  PubMed  CAS  Google Scholar 

  4. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA, (1995) Identification and characterization of a new member of the TNF family that induces apoptosisImmunity 3: 673–682

    Article  PubMed  CAS  Google Scholar 

  5. Nitsch R, Bechmann I, Deisz RA, Haas D, Lehmann TN, Wendling U, Zipp F. (2000) Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL)Lancet 356: 827–828

    Article  PubMed  CAS  Google Scholar 

  6. Jo M, Kim TH, Seol DW, Esplen JE, Dorko K, Billiar TR, Strom SC. (2000) Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligandNat Med 6: 564–567

    Article  PubMed  CAS  Google Scholar 

  7. de Vries EG, van der Graaf WT, Heijenbrok FJ, Hoekstra HJ, de Jong S: Don’t blaze the trailblazer TRAIL too early. Lancet 356: 2014, 2000

  8. Knight MJ, Riffkin CD, Muscat AM, Ashley DM, Hawkins CJ: Analysis of FasL and TRAIL induced apoptosis pathways in glioma cells. Oncogene 13: 5789–5798, 2001

    Google Scholar 

  9. Grotzer MA, Eggert A, Zuzak TJ, Janss AJ, Marwaha S, Wiewrodt BR, Ikegaki N, Brodeur GM, Phillips PC. (2000) Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expressionOncogene 19: 4604–4610

    Article  PubMed  CAS  Google Scholar 

  10. Dorr J, Waiczies S, Wendling U, Seeger B, Zipp F. (2002) Induction of TRAIL-mediated glioma cell death by human T cellsJ Neuroimmunol 122: 117–124

    Article  PubMed  CAS  Google Scholar 

  11. Rohn TA, Wagenknecht B, Roth W, Naumann U, Gulbins E, Krammer PH, Walczak H, Weller M. (2001) CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c releaseOncogene 20: 4128–4137

    Article  PubMed  CAS  Google Scholar 

  12. Frank S, Kohler U, Schackert G, Schackert HK. (1999) Expression of TRAIL and its receptors in human brain tumorsBiochem Biophys Res Commun 257: 454–459

    Article  PubMed  CAS  Google Scholar 

  13. Kleihues P, Cavenee WK: Pathology & Genetics of Tumours of the Nervous System, 2000

  14. Sondergaard KL, Hilton DA, Penney M, Ollerenshaw M, Demaine AG (2002) Expression of hypoxia-inducible factor 1alpha in tumours of patients with glioblastomaNeuropathol Appl Neurobiol 28: 210–217

    Article  PubMed  CAS  Google Scholar 

  15. Plate KH, Breier G, Weich HA, Risau W (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivoNature 359: 845–848

    Article  PubMed  CAS  Google Scholar 

  16. Shweiki D, Itin A, Soffer D, Keshet E. (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesisNature 359: 843–845

    Article  PubMed  CAS  Google Scholar 

  17. Strater J, Hinz U, Walczak H, Mechtersheimer G, Koretz K, Herfarth C, Moller P, Lehnert T (2002) Expression of TRAIL and TRAIL receptors in colon carcinoma: TRAIL-R1 is an independent prognostic parameterClin Cancer Res 8: 3734–3740

    PubMed  Google Scholar 

  18. Spierings DC, de Vries EG, Vellenga E, van den Heuvel FA, Koornstra JJ, Wesseling J, Hollema H, de Jong S (2004) Tissue distribution of the death ligand TRAIL and its receptorsJ Histochem Cytochem 52: 821–831

    Article  PubMed  CAS  Google Scholar 

  19. Golstein P, (1997) Cell death: TRAIL and its receptorsCurr Biol 7:R750–R753

    Article  PubMed  CAS  Google Scholar 

  20. Wajant H, Moosmayer D, Wuest T, Bartke T, Gerlach E, Schonherr U, Peters N, Scheurich P, Pfizenmaier K (2001) Differential activation of TRAIL-R1 and -2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of TRAIL-R2 by a soluble TRAIL derivativeOncogene 20: 4101–4106

    Article  PubMed  CAS  Google Scholar 

  21. Nakamura M, Rieger J, Weller M, Kim J, Kleihues P, Ohgaki H (2000) APO2L/TRAIL expression in human brain tumorsActa Neuropathol (Berl) 99: 1–6

    Article  CAS  Google Scholar 

  22. Dorr J, Bechmann I, Waiczies S, Aktas O, Walczak H, Krammer PH, Nitsch R, Zipp F: Lack of tumor necrosis factor-related apoptosis-inducing ligand but presence of its receptors in the human brain. J Neurosci 22: RC209, 2002

  23. Rieger J, Ohgaki H, Kleihues P, Weller M. (1999) Human astrocytic brain tumors express AP02L/TRAILActa Neuropathol (Berl) 97: 1–4

    Article  CAS  Google Scholar 

  24. Gratas C, Tohma Y, Van Meir EG, Klein M, Tenan M, Ishii N, Tachibana O, Kleihues P, Ohgaki H (1997) Fas ligand expression in glioblastoma cell lines and primary astrocytic brain tumorsBrain Pathol 7: 863–869

    Article  PubMed  CAS  Google Scholar 

  25. Tartaglia LA, Goeddel DV (1992) Two TNF receptorsImmunol Today 13: 151–153

    Article  PubMed  CAS  Google Scholar 

  26. Nagata S, (1997) Apoptosis by death factorCell 88: 355–365

    Article  PubMed  CAS  Google Scholar 

  27. Bremer E, Kuijlen J, Samplonius D, Walczak H, de Leij L, Helfrich W (2004) Target cell-restricted and -enhanced apoptosis induction by a scFv:sTRAIL fusion protein with specificity for the pancarcinoma-associated antigen EGP2Int J Cancer 109: 281–290

    Article  PubMed  CAS  Google Scholar 

  28. Bremer E, Samplonius DF, van Genne L, Dijkstra MH, Kroesen BJ, de Leij LF, Helfrich W (2005) Simultaneous inhibition of epidermal growth factor receptor (EGFR) signaling and enhanced activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis induction by an scFv:sTRAIL fusion protein with specificity for human EGFRJ Biol Chem 280: 10025–10033

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by KWF research grant for clinical residents.

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Authors and Affiliations

  1. Department of Neurosurgery, University Hospital Groningen, Groningen, The Netherlands

    Jos MA Kuijlen, Jan Jakob A Mooij & Eelco W Hoving

  2. Department of Pathology and Laboratory Medicine, University Hospital Groningen, Groningen, The Netherlands

    Inge Platteel, Harry Hollema & Wilfred FA den Dunnen

  3. Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands

    Winette TA van der Graaf

  4. Department of Medical Technology Assessment, University Hospital Groningen, Groningen, The Netherlands

    Mark M Span

  5. Department of Neurosurgery, University Medical Centre Groningen, University of Groningen, 30.001, 9700 RB, Groningen, The Netherlands

    Jos MA Kuijlen

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  1. Jos MA Kuijlen
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Correspondence to Jos MA Kuijlen.

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Kuijlen, J., Mooij, J.J.A., Platteel, I. et al. TRAIL-receptor expression is an independent prognostic factor for survival in patients with a primary glioblastoma multiforme. J Neurooncol 78, 161–171 (2006). https://doi.org/10.1007/s11060-005-9081-1

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  • DOI: https://doi.org/10.1007/s11060-005-9081-1

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