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


METHODS
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.
Department of Neurosurgery, University Hospital Groningen, Groningen, The Netherlands. j.m.a.kuijlen@nchir.umcg.nl
Jos M A
JM
Kuijlen
Jan Jakob A
JJ
Mooij
Inge
I
Platteel
Eelco W
EW
Hoving
Winette T A
WT
van der Graaf
Mark M
MM
Span
Harry
H
Hollema
Wilfred F A
WF
den Dunnen
D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha