TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis
Niklas Finnberg, … , Andres J.P. Klein-Szanto, Wafik S. El-Deiry
Niklas Finnberg, … , Andres J.P. Klein-Szanto, Wafik S. El-Deiry
Published December 13, 2007
Citation Information: J Clin Invest. 2008;118(1):111-123. https://doi.org/10.1172/JCI29900.
View: Text | PDF
Research Article Article has an altmetric score of 14

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

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.

Authors

Niklas Finnberg, Andres J.P. Klein-Szanto, Wafik S. El-Deiry

×

Figure 5

TRAIL-R–/– animals show decreased survival following exposure to a single sublethal dose (4 Gy) of ionizing radiation.

Options: View larger image (or click on image) Download as PowerPoint
TRAIL-R–/– animals show decreased survival following exposure to a sing...
(A) Survival following 4 Gy of whole-body irradiation was decreased in the TRAIL-R–/– group (n = 23) at 28–52 weeks following irradiation in comparison with the group of WT (n = 14) animals and TRAIL-R+/– (n = 13) animals (Kaplan-Meier log-rank analysis, P = 0.010). (B) However, decreased body weight was observed in both TRAIL-R+/– (n = 3) and TRAIL-R–/– (n = 4) animals relative to WT (n = 4) animals at 28 weeks following 4 Gy of ionizing irradiation (P < 0.05, Mann-Whitney U test). No weight difference was detected between genotypes in nonirradiated animals (data not shown). (C) A representative H&E staining of the lungs from lethargic TRAIL-R–/– animals irradiated with 4 Gy at 39 weeks prior to sacrifice. Extensive inflammatory emboli in the respiratory bronchioles and increased cellularity in the interstitial space was observed (C; ×20, lower left and right panels). Lungs were histochemically stained with Masson’s trichrome (D) in order to detect the presence of collagen (bright blue) and were analyzed by immunofluorescence for fibronectin (E; Cy3, red). Lungs from irradiated and lethargic TRAIL-R–/– animals showed severe pneumonitis (D) and extensive deposition of collagen and fibronectin (E).