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PMID: 18079962 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

The Journal of clinical investigation ·Vol. 118 ·No. 1 ·2008-01-00 ·Pages 111-23

Finnberg N, Klein-Szanto AJ, El-Deiry WS

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 Emu-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-kappaB 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.

MeSH Terms
Alkylating Agents/toxicity Animals Bronchitis/chemically induced,genetics,metabolism,pathology Cell Line, Tumor Cell Transformation, Neoplastic/drug effects,genetics,metabolism,pathology,radiation effects Chronic Disease Diethylnitrosamine/toxicity Humans Inflammation/chemically induced,genetics,metabolism,pathology Liver Neoplasms/chemically induced,genetics,metabolism,pathology Lymphoma/chemically induced,genetics,metabolism,pathology Mice Mice, Knockout Pneumonia/chemically induced,genetics,metabolism,pathology Radiation, Ionizing Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics,metabolism Transcription Factor RelA/genetics,metabolism Tumor Suppressor Proteins/genetics,metabolism Whole-Body Irradiation/adverse effects
Chemicals
Alkylating Agents Receptors, TNF-Related Apoptosis-Inducing Ligand Tnfrsf10b protein, mouse Transcription Factor RelA Tumor Suppressor Proteins Diethylnitrosamine
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Finnberg Niklas
Laboratory of Molecular Oncology and Cell Cycle Regulation, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Klein-Szanto Andres J P
El-Deiry Wafik S
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI29900
Published
2008-01-00
Pages
111-23
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2129232
Subset
IM
Grants
NCI NIH HHS · P01 CA075138 · United States
NCI NIH HHS · P01 CA098101 · United States
NCI NIH HHS · CA75138 · United States
NCI NIH HHS · CA98101 · United States
External Links
PubMed source DOI: 10.1172/JCI29900 PMC Full Text View journal details
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