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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Alkylating Agents / toxicity
-
Animals
-
Bronchitis / chemically induced
-
Bronchitis / genetics
-
Bronchitis / metabolism*
-
Bronchitis / pathology
-
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
-
Humans
-
Inflammation / chemically induced
-
Inflammation / genetics
-
Inflammation / metabolism
-
Inflammation / pathology
-
Liver Neoplasms / chemically induced
-
Liver Neoplasms / genetics
-
Liver Neoplasms / metabolism*
-
Liver Neoplasms / pathology
-
Lymphoma / chemically induced
-
Lymphoma / genetics
-
Lymphoma / metabolism*
-
Lymphoma / pathology
-
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*
-
Transcription Factor RelA / genetics
-
Transcription Factor RelA / metabolism
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / metabolism*
-
Whole-Body Irradiation / adverse effects
Substances
-
Alkylating Agents
-
Receptors, TNF-Related Apoptosis-Inducing Ligand
-
Tnfrsf10b protein, mouse
-
Transcription Factor RelA
-
Tumor Suppressor Proteins
-
Diethylnitrosamine