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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism
  • Humans
  • Models, Biological
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Mutation
  • Protein Conformation
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, Tumor Necrosis Factor, Member 10c / genetics
  • Receptors, Tumor Necrosis Factor, Member 10c / metabolism*
  • Stromal Cells / metabolism
  • Stromal Cells / pathology*
  • TNF-Related Apoptosis-Inducing Ligand / chemistry
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Tumor Necrosis Factor Decoy Receptors / genetics
  • Tumor Necrosis Factor Decoy Receptors / metabolism*


  • GPI-Linked Proteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor, Member 10c
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10C protein, human
  • TNFRSF10D protein, human
  • Tumor Necrosis Factor Decoy Receptors