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Research Article Free access | 10.1172/JCI29900

TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis

Niklas Finnberg,1 Andres J.P. Klein-Szanto,2 and Wafik S. El-Deiry1

1Laboratory of Molecular Oncology and Cell Cycle Regulation, Department of Medicine, Division of Hematology/Oncology, Department of Genetics, Department of Pharmacology, Institute for Translational Medicine and Therapeutics, and Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 2Division of Medical Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

Address correspondence to: Wafik S. El-Deiry, Department of Medicine, University of Pennsylvania School of Medicine, 415 Curie Blvd., CRB 437, Philadelphia, Pennsylvania 19104, USA. Phone: (215) 898-9015; Fax: (215) 573-9139; E-mail: wafik@mail.med.upenn.edu.

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1Laboratory of Molecular Oncology and Cell Cycle Regulation, Department of Medicine, Division of Hematology/Oncology, Department of Genetics, Department of Pharmacology, Institute for Translational Medicine and Therapeutics, and Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 2Division of Medical Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

Address correspondence to: Wafik S. El-Deiry, Department of Medicine, University of Pennsylvania School of Medicine, 415 Curie Blvd., CRB 437, Philadelphia, Pennsylvania 19104, USA. Phone: (215) 898-9015; Fax: (215) 573-9139; E-mail: wafik@mail.med.upenn.edu.

Find articles by Klein-Szanto, A. in: PubMed | Google Scholar

1Laboratory of Molecular Oncology and Cell Cycle Regulation, Department of Medicine, Division of Hematology/Oncology, Department of Genetics, Department of Pharmacology, Institute for Translational Medicine and Therapeutics, and Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 2Division of Medical Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

Address correspondence to: Wafik S. El-Deiry, Department of Medicine, University of Pennsylvania School of Medicine, 415 Curie Blvd., CRB 437, Philadelphia, Pennsylvania 19104, USA. Phone: (215) 898-9015; Fax: (215) 573-9139; E-mail: wafik@mail.med.upenn.edu.

Find articles by El-Deiry, W. in: PubMed | Google Scholar

Published December 13, 2007 - More info

J Clin Invest. https://doi.org/10.1172/JCI29900.
© 2007 The American Society for Clinical Investigation
Published December 13, 2007 - Version history
Received: July 31, 2006; Accepted: October 18, 2007
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Abstract

Preclinical data support the potential of the death-signaling receptors for TRAIL as targets for cancer therapy. However, it is unclear whether these death-signaling receptors suppress the emergence and growth of malignant tumors in vivo. Herein we show that TNF-related apoptosis-inducing ligand receptor (TRAIL-R), the only proapoptotic death-signaling receptor for TRAIL in the mouse, suppresses inflammation and tumorigenesis. Loss of a single TRAIL-R allele on the lymphoma-prone Eμ-myc genetic background significantly reduced median lymphoma-free survival. TRAIL-R–deficient lymphomas developed with equal frequency irrespective of mono- or biallelic loss of TRAIL-R, had increased metastatic potential, and showed apoptotic defects relative to WT littermates. In addition, TRAIL-R–/– mice showed decreased long-term survival following a sublethal dose of ionizing radiation. Histological evaluation of moribund irradiated TRAIL-R–/– animals showed hallmarks of bronchopneumonia as well as tumor formation with increased NF-κB p65 expression. TRAIL-R also suppressed diethylnitrosamine-induced (DEN-induced) hepatocarcinogenesis, as an increased number of large tumors with apoptotic defects developed in the livers of DEN-treated TRAIL-R–/– mice. Thus TRAIL-R may function as an inflammation and tumor suppressor in multiple tissues in vivo.

Version history
  • Version 1 (December 13, 2007): No description
  • Version 2 (January 2, 2008): No description
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