Title: Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium
Authors: Van Hauwermeiren, Filip ×
Armaka, Marietta
Karagianni, Niki
Kranidioti, Ksanthi
Vandenbroucke, Roosmarijn E
Loges, Sonja
Van Roy, Maarten
Staelens, Jan
Puimège, Leen
Palagani, Ajay
Berghe, Wim Vanden
Victoratos, Panayiotis
Carmeliet, Peter
Libert, Claude
Kollias, George #
Issue Date: Jun-2013
Publisher: American Society for Clinical Investigation
Series Title: Journal of Clinical Investigation vol:123 issue:6 pages:2590-2603
Article number: 10.1172/JCI65624
Abstract: TNF has remarkable antitumor activities; however, therapeutic applications have not been possible because of the systemic and lethal proinflammatory effects induced by TNF. Both the antitumor and inflammatory effects of TNF are mediated by the TNF receptor p55 (p55TNFR) (encoded by the Tnfrsf1a gene). The antitumor effect stems from an induction of cell death in tumor endothelium, but the cell type that initiates the lethal inflammatory cascade has been unclear. Using conditional Tnfrsf1a knockout or reactivation mice, we found that the expression level of p55TNFR in intestinal epithelial cells (IECs) is a crucial determinant in TNF-induced lethal inflammation. Remarkably, tumor endothelium and IECs exhibited differential sensitivities to TNF when p55TNFR levels were reduced. Tumor-bearing Tnfrsf1a+/- or IEC-specific p55TNFR-deficient mice showed resistance to TNF-induced lethality, while the tumor endothelium remained fully responsive to TNF-induced apoptosis and tumors regressed. We demonstrate proof of principle for clinical application of this approach using neutralizing anti-human p55TNFR antibodies in human TNFRSF1A knockin mice. Our results uncover an important cellular basis of TNF toxicity and reveal that IEC-specific or systemic reduction of p55TNFR mitigates TNF toxicity without loss of antitumor efficacy.
ISSN: 0021-9738
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Angiogenesis and Vascular Metabolism (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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