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Oncogene. 2016 Mar 10;35(10):1261-70. doi: 10.1038/onc.2015.180. Epub 2015 Jun 8.

Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity.

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Apoptosis Research Centre, National University of Ireland, Galway, Ireland.
EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain.
Institute for Research in Immunology and Cancer, University of Montreal, 2950, Chemin de Polytechnique Pavillon Marcelle-Coutu, Dock 20, Montréal, Québec, Canada.
Department of Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland.
Department of Oncology, University of Cambridge, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
Centre for Microscopy and Imaging, National University of Ireland, Galway, Ireland.


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.

[Indexed for MEDLINE]

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