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Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

Filip Van Hauwermeiren, Marietta Armaka, Niki Karagianni, Ksanthi Kranidioti, Roosmarijn Vandenbroucke UGent, Sonja Loges, Maarten Van Royen UGent, Jan Staelens, Leen Puimège, Ajay Palagani, et al. (2013) JOURNAL OF CLINICAL INVESTIGATION. 123(6). p.2590-2603
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
NF-KAPPA-B, IFN-GAMMA, TUMOR-NECROSIS-FACTOR, ANTIBODY-RESPONSES, INDUCED LETHALITY, INDUCED APOPTOSIS, RECOMBINANT HUMAN, FACTOR RECEPTOR-1, INTERFERON-GAMMA, MICE
journal title
JOURNAL OF CLINICAL INVESTIGATION
J. Clin. Invest.
volume
123
issue
6
pages
2590 - 2603
Web of Science type
Article
Web of Science id
000320093100029
JCR category
MEDICINE, RESEARCH & EXPERIMENTAL
JCR impact factor
13.765 (2013)
JCR rank
5/124 (2013)
JCR quartile
1 (2013)
ISSN
0021-9738
DOI
10.1172/JCI65624
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
4106418
handle
http://hdl.handle.net/1854/LU-4106418
date created
2013-07-23 17:13:31
date last changed
2018-06-22 08:18:41
@article{4106418,
  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.},
  author       = {Van Hauwermeiren, Filip and Armaka, Marietta and Karagianni, Niki and Kranidioti, Ksanthi and Vandenbroucke, Roosmarijn and Loges, Sonja and Van Royen, Maarten and Staelens, Jan and Puim{\`e}ge, Leen and Palagani, Ajay and Vanden Berghe, Wim and Victoratos, Panayiotis and Carmeliet, Peter and Libert, Claude and Kollias, George},
  issn         = {0021-9738},
  journal      = {JOURNAL OF CLINICAL INVESTIGATION},
  keyword      = {NF-KAPPA-B,IFN-GAMMA,TUMOR-NECROSIS-FACTOR,ANTIBODY-RESPONSES,INDUCED LETHALITY,INDUCED APOPTOSIS,RECOMBINANT HUMAN,FACTOR RECEPTOR-1,INTERFERON-GAMMA,MICE},
  language     = {eng},
  number       = {6},
  pages        = {2590--2603},
  title        = {Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium},
  url          = {http://dx.doi.org/10.1172/JCI65624},
  volume       = {123},
  year         = {2013},
}

Chicago
Van Hauwermeiren, Filip, Marietta Armaka, Niki Karagianni, Ksanthi Kranidioti, Roosmarijn Vandenbroucke, Sonja Loges, Maarten Van Royen, et al. 2013. “Safe TNF-based Antitumor Therapy Following p55TNFR Reduction in Intestinal Epithelium.” Journal of Clinical Investigation 123 (6): 2590–2603.
APA
Van Hauwermeiren, F., Armaka, M., Karagianni, N., Kranidioti, K., Vandenbroucke, R., Loges, S., Van Royen, M., et al. (2013). Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium. JOURNAL OF CLINICAL INVESTIGATION, 123(6), 2590–2603.
Vancouver
1.
Van Hauwermeiren F, Armaka M, Karagianni N, Kranidioti K, Vandenbroucke R, Loges S, et al. Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium. JOURNAL OF CLINICAL INVESTIGATION. 2013;123(6):2590–603.
MLA
Van Hauwermeiren, Filip, Marietta Armaka, Niki Karagianni, et al. “Safe TNF-based Antitumor Therapy Following p55TNFR Reduction in Intestinal Epithelium.” JOURNAL OF CLINICAL INVESTIGATION 123.6 (2013): 2590–2603. Print.