TRAIL-R3/R4 and Inhibition of TRAIL Signalling in Cancer
Lubna Danish, Daniela Stöhr, Peter Scheurich, and Nadine Pollak
in TRAIL, Fas Ligand, TNF and TLR3 in Cancer, Springer International Publishing; DOI 10.1007/978-3-319-56805-8_2
The tumour necrosis factor (TNF) ligand family member TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis predominantly in tumour cells, but not in normal tissues, representing therefore an attractive candidate for cancer therapy. The human TRAIL/TRAIL receptor system is very complex, four different membrane receptors bind the ligand. Two of these receptors, TRAIL-R1 and TRAIL-R2, transmit apoptotic but also non-apoptotic signals, whereas the other two, TRAIL-R3 and TRAIL-R4, act as inhibitors. Most tumour cells co-express several TRAIL receptors, allowing receptor interference. Several molecular mechanisms have been proposed by which TRAIL-R3 and TRAIL-R4 may counteract proapoptotic TRAIL signalling at the plasma membrane level, but possibly also intracellularly. A detailed understanding of the role of the individual TRAIL receptors and their interplay will be advantageous for the development of new TRAIL receptor agonists for cancer therapy. In fact, new TRAIL formulations will be needed since first clinical studies with soluble TRAIL or receptor agonistic antibodies showed only limited success. This review summarizes the complex TRAIL/TRAIL receptor system and the mechanisms by which TRAIL-R3 and TRAIL-R4 may interfere with TRAIL-mediated apoptosis induction. In addition, we discuss the prognostic and predictive value of TRAIL receptor expression in patients’ tumour material.