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Loss
of Caspase-8 Protein Expression Correlates with Unfavorable Survival Outcome in
Childhood Medulloblastoma
Carmen Pingoud-Meier1, Doris Lang1,
Anna J. Janss2, Lucy B.
Rorke3, Peter C. Phillips2,
Tarek Shalaby1 and Michael
A. Grotzer1
1Neuro-Oncology Program, Department of Oncology, University Children’s Hospital
of Zurich, Zurich, Switzerland; 2 Division of Neuro-Oncology and 3
Department of Pathology, Children’s Hospital of Philadelphia, Philadelphia,
Pennsylvania
Purpose. Escaping apoptosis is a hallmark of cancer.
In medulloblastoma (MB) cell lines, resistance to tumor necrosis
factor-related apoptosis-inducing ligand-induced apoptosis was
recently shown to correlate with loss of caspase-8 mRNA expression,
because of aberrant gene methylation (M. A. Grotzer et al.,
Oncogene, 19: 4604–4610, 2000).
Loss of caspase-8 mRNA expression has been demonstrated in a subset
of primary MB (T. J. Zuzak et al., Eur. J. Cancer, 38:
83–91, 2002).
In this study, we analyzed primary MB samples to test whether loss of
caspases correlates with survival outcome.
Experimental
Design. We used immunohistochemistry to analyze the protein expression of the
key initiator caspase-8 and caspase-9 in paraffin-embedded tumor
samples from 77 well characterized MB patients and compared the
expression levels of caspase-8 and caspase-9 with apoptosis indices,
clinical variables, and survival outcomes.
Results.
Weak expression of caspase-8 and caspase-9 was found in 16 and 24% of
the MB samples evaluated, respectively.
Weak expression of caspase-8 was an independent significant
prognostic factor for unfavorable progression-free survival outcome
and was more predictive than standard clinical factors.
In contrast, caspase-9 expression was not a prognostic factor.
Treatment of caspase-8-deficient MB cells with IFN-γ
resulted in dose-dependent restoration of caspase-8 mRNA and protein
expression and restoration of tumor necrosis factor-related
apoptosis-inducing ligand sensitivity.
Conclusions.
Loss of initiator caspase-8 is associated with an unfavorable
survival outcome.
Restoration of caspase-8 (e.g., by treatment with IFN-γ)
might, therefore, represent a novel experimental therapy in childhood
MB.
©
2003 American
Association for Cancer Research
Source: http://clincancerres.aacrjournals.org/cgi/content/abstract/9/17/6401?etoc
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