Peer-Reviewed Journal Details
Mandatory Fields
O'Leary L, van der Sloot A, Serrano L, Reis C, Cool R, Quax WJ, Deegan S, Murillo L, Thompson K, de Sampaio P, Ryan AE, Singh Dhami SP, Murphy G, Szegezdi E
Decoy receptors block TRAIL sensitivity at supra-cellular level: the role of stromal cells in controlling tumour TRAIL-sensitivity
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Optional Fields
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand cytokine known for its cytotoxic activity against malignantly transformed cells. TRAIL induces cell death through binding to death receptors DR4 and DR5. The inhibitory decoy receptors (DcR1 and DcR2) co-expressed with death receptor 4 (DR4)/DR5 on the same cell can block the transmission of the apoptotic signal. Here, we show that DcRs also regulate TRAIL sensitivity at a supracellular level and thus represent a mechanism by which the microenvironment can diminish tumour TRAIL sensitivity. Mathematical modelling and layered or spheroid stroma-extracellular matrix-tumour cultures were used to model the tumour microenvironment. By engineering TRAIL to escape binding by DcRs, we found that DcRs do not only act in a cell-autonomous or cis-regulatory manner, but also exert trans-cellular regulation originating from stromal cells and affect tumour cells, highlighting the potent inhibitory effect of DcRs in the tumour tissue and the necessity of selective targeting of the two death-inducing TRAIL receptors to maximise efficacy.
Grant Details
Enterprise Ireland, National Development Plan of Ireland, Commercialisation Fund to AS and ES (CFTD/06/112), SFI SIRG award to ES (09/SIRG /B1575) and Millennium Grant to ES from the National University of Ireland, Galway (NUIG)
Publication Themes
Biomedical Science and Engineering