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

• Published in: The Journal of clinical investigation 2008-01, Vol.118 (1), p.111-123
• Main Authors: Finnberg, Niklas, Klein-Szanto, Andres J P, El-Deiry, Wafik S
• Format: Article
• Language: English
• Subjects: Alkylating Agents - toxicity; Animals; Apoptosis; Biomedical research; Bronchitis - chemically induced; Bronchitis - genetics; Bronchitis - metabolism; Bronchitis - pathology; Cancer; Cancer therapies; Cell death; Cell Line, Tumor; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cell Transformation, Neoplastic - radiation effects; Chronic Disease; Diethylnitrosamine - toxicity; Genetic aspects; Health aspects; Humans; Inflammation; Inflammation - chemically induced; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Ligands; Liver cancer; Liver Neoplasms - chemically induced; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lymphoma; Lymphoma - chemically induced; Lymphoma - genetics; Lymphoma - metabolism; Lymphoma - pathology; Metastasis; Mice; Mice, Knockout; Pneumonia - chemically induced; Pneumonia - genetics; Pneumonia - metabolism; Pneumonia - pathology; Radiation, Ionizing; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Risk factors; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Tumor necrosis factor; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumorigenesis; Tumors; Whole-Body Irradiation - adverse effects
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI29900

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.