Published online before print April 13, 2007

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(American Journal of Pathology. 2007;170:1917-1930.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060993

Interferon- Sensitizes Resistant Ewing’s Sarcoma Cells to Tumor Necrosis Factor Apoptosis-Inducing Ligand-Induced Apoptosis by Up-Regulation of Caspase-8 Without Altering Chemosensitivity

Andrej Lissat^*, Thomas Vraetz^*, Maria Tsokos, Ruth Klein^*, Matthias Braun^*, Nino Koutelia^*, Paul Fisch, Maria E. Romero, Lauren Long, Peter Noellke^*, Crystal L. Mackall, Charlotte M. Niemeyer^* and Udo Kontny^*

From the Division of Pediatric Hematology and Oncology,^* Department of Pediatrics and Adolescent Medicine, and the Institute of Pathology, Albert-Ludwigs-University, Freiburg, Germany; the Laboratory of Pathology, and the Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Ewing’s sarcoma cells are highly susceptible to apoptosis via tumor necrosis factor apoptosis-inducing ligand (TRAIL). Resistance to TRAIL has been linked to deficient expression of caspase-8 in vitro. Here, we report on the status of caspase-8 expression in tumors from patients with Ewing’s sarcoma, the effect of interferon- on caspase-8 expression and apoptosis, and the role of caspase-8 for TRAIL- and chemotherapy-mediated apoptosis in Ewing’s sarcoma. Using immunohistochemistry, we show that low expression of caspase-8 is seen in about 24% of tumors. Interferon- induces expression of caspase-8 at concentrations achievable in humans and sensitizes cells to TRAIL. Transfection of wild type but not mutant caspase-8 into caspase-8-deficient Ewing’s sarcoma cells restored sensitivity to TRAIL, indicating that up-regulation of caspase-8 is sufficient to restore TRAIL sensitivity. In contrast, no role for caspase-8 in chemotherapy-induced apoptosis was identified, because 1) transfection of caspase-8 or treatment with interferon- did not alter the sensitivity of caspase-8-deficient cells to chemotherapeutics, 2) application of chemotherapy did not select for caspase-8-negative tumor cells in vivo, and 3) the caspase-8 status of tumors did not influence survival after chemotherapy-based protocols. In conclusion, our data provide a rationale for the inclusion of interferon- in upcoming clinical trials with TRAIL.