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

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

in: J CLIN INVEST, Jahrgang 123, Nr. 6, 03.06.2013, S. 2590-603.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Van Hauwermeiren, F, Armaka, M, Karagianni, N, Kranidioti, K, Vandenbroucke, RE, Loges, S, Van Roy, M, Staelens, J, Puimège, L, Palagani, A, Berghe, WV, Victoratos, P, Carmeliet, P, Libert, C & Kollias, G 2013, 'Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium', J CLIN INVEST, Jg. 123, Nr. 6, S. 2590-603. https://doi.org/10.1172/JCI65624

APA

Van Hauwermeiren, F., Armaka, M., Karagianni, N., Kranidioti, K., Vandenbroucke, R. E., Loges, S., Van Roy, M., Staelens, J., Puimège, L., Palagani, A., Berghe, W. V., Victoratos, P., Carmeliet, P., Libert, C., & Kollias, G. (2013). Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium. J CLIN INVEST, 123(6), 2590-603. https://doi.org/10.1172/JCI65624

Vancouver

Van Hauwermeiren F, Armaka M, Karagianni N, Kranidioti K, Vandenbroucke RE, Loges S et al. Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium. J CLIN INVEST. 2013 Jun 3;123(6):2590-603. https://doi.org/10.1172/JCI65624

Bibtex

@article{4e0acbfc139b4e93bffe3111e988dc76,
title = "Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium",
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.",
keywords = "Animals, Antibodies, Monoclonal, Antineoplastic Agents, Apoptosis, Cytokines, Drug Screening Assays, Antitumor, Endothelium, Gene Expression, Gene Knock-In Techniques, Humans, Inflammation, Interferon-gamma, Intestinal Mucosa, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Transplantation, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Tumor Necrosis Factor-alpha",
author = "{Van Hauwermeiren}, Filip and Marietta Armaka and Niki Karagianni and Ksanthi Kranidioti and Vandenbroucke, {Roosmarijn E} and Sonja Loges and {Van Roy}, Maarten and Jan Staelens and Leen Puim{\`e}ge and Ajay Palagani and Berghe, {Wim Vanden} and Panayiotis Victoratos and Peter Carmeliet and Claude Libert and George Kollias",
year = "2013",
month = jun,
day = "3",
doi = "10.1172/JCI65624",
language = "English",
volume = "123",
pages = "2590--603",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",

}

RIS

TY - JOUR

T1 - Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

AU - Van Hauwermeiren, Filip

AU - Armaka, Marietta

AU - Karagianni, Niki

AU - Kranidioti, Ksanthi

AU - Vandenbroucke, Roosmarijn E

AU - Loges, Sonja

AU - Van Roy, Maarten

AU - Staelens, Jan

AU - Puimège, Leen

AU - Palagani, Ajay

AU - Berghe, Wim Vanden

AU - Victoratos, Panayiotis

AU - Carmeliet, Peter

AU - Libert, Claude

AU - Kollias, George

PY - 2013/6/3

Y1 - 2013/6/3

N2 - 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.

AB - 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.

KW - Animals

KW - Antibodies, Monoclonal

KW - Antineoplastic Agents

KW - Apoptosis

KW - Cytokines

KW - Drug Screening Assays, Antitumor

KW - Endothelium

KW - Gene Expression

KW - Gene Knock-In Techniques

KW - Humans

KW - Inflammation

KW - Interferon-gamma

KW - Intestinal Mucosa

KW - Melanoma, Experimental

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Neoplasm Transplantation

KW - Receptors, Tumor Necrosis Factor, Type I

KW - Signal Transduction

KW - Tumor Necrosis Factor-alpha

U2 - 10.1172/JCI65624

DO - 10.1172/JCI65624

M3 - SCORING: Journal article

C2 - 23676465

VL - 123

SP - 2590

EP - 2603

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 6

ER -