TRAIL death receptors as tumor suppressors and drug targets

Various ways of targeting TRAIL-death receptors for the treatment of a diverse set of malignancies are being explored in ongoing clinical trials. Recent data of ours and others suggest that loss of the only death signaling receptor in mice ( TRAIL-R) is associated with susceptibility to various stages of lymphomagenesis and carcinogenesis, perhaps in a complex cell- and model-specific manner. 1,2 Myc-overexpressing B cell lymphomas with an intact TRAIL-R locus displayed a number of gene expression changes indicating resistance to TRAIL-R signaling. Herein we show some data on the use of recombinant human TRAIL (rhTRAIL) and gamma-radiation (10 Gy) in combination in an autochthonous mouse model for hepatocellular carcinoma. As cell death signaling through the death receptors is evolutionary conserved from zebra fish to man, novel genetically engineered mouse tumor models may prove useful in establishing in vivo models that excel our fundamental understanding of resistance to TRAIL-death receptor signaling, off-target effects from TRAIL-death receptor targeting compounds and help in identifying a clinically cogent rationale for efficient targeting of TRAIL death receptors in patients. Once established, mouse tumor models may prove to be a useful tool in understanding TRAIL-death receptor signaling.