Etiology and Pathogenesis > Caspases  

Meeting Abstract

Loss of caspase-8 protein expression correlates with unfavorable survival outcome in childhood medulloblastoma

Michael A. Grotzer, Carmen Meier, Tarek Shalaby, Doris Lang

Neuro-Oncology Program, University, Zurich, Switzerland

[Background & Methods.] Upon binding of TNF-related apoptosis inducing ligand (TRAIL), the agonistic TRAIL receptors DR4 and DR5 activate caspase-8 leading to apoptosis. 
In medulloblastoma (MB) cell lines, resistance toward TRAIL-induced apoptosis was recently shown to correlate with loss of caspase-8 mRNA expression (Grotzer MA et al. Oncogene 2000;19:4604-4610) due to aberrant gene methalytion (Zuzak T et al. Eur J Cancer 2002;38:83-91). 
In this study, we analyzed the protein expression of caspase-8 in formalin-fixed paraffin-embedded tumor samples from 77 clinically well characterized MB patients utilizing immunohistochemistry. 
Comparison of caspase-8 expression with clinical variables was performed using univariate and multivariate Cox regression analysis. 

Results. Weak expression of caspase-8 was found to be associated with lower 5-year cumulative progression-free survival rate than was moderate/high caspase-8 expression (31% v 75%, log rank p=0.003). 
When compared with established clinical prognostic factors, caspase-8 expression, by univariate analysis, was found to be the single most powerful predictor of outcome. 
In multivariate analysis, the hazards ratio remained significant (p=0.004). 
Treatment of caspase-8 deficient MB cell lines with interferon-gamma resulted in dose-dependent restoration of caspase-8 mRNA. 

Conclusion. Loss of caspase-8 is common in MB and appears to be a powerful independent prognostic factor, suggesting that suppression of death receptor induced apoptosis may play an important role in the pathogenesis of this common childhood brain tumor. 
Accordingly, restoration of caspase-8 might be a target for novel experimental therapies in childhood MB. 

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