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Updated: Dec 19, 2025
In Vivo Immunogenicity Screening of Tumor-Derived Extracellular Vesicles by Flow Cytometry of Splenic T Cells
Published on: September 23, 2021
Death Receptor 5 Displayed on Extracellular Vesicles Decreases TRAIL Sensitivity of Colon Cancer Cells
Rita Setroikromo1, Baojie Zhang1, Carlos R Reis1
1Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, Netherlands.
Abstract:
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is considered to be a promising antitumor drug because of its selective proapoptotic properties on tumor cells. However, the clinical application of TRAIL is until now limited because of the resistance of several cancer cells, which can occur at various levels in the TRAIL signaling pathway. The role of decoy receptors that can side-track TRAIL, thereby preventing the formation of an activated death receptor, has been extensively studied. In this study, we have focused on extracellular vesicles (EVs) that are known to play a role in cell-to-cell communication and that can be released by donor cells into the medium transferring their components to recipient cells. TRAIL-induced apoptotic signaling is triggered upon the binding of two death receptors, DR4 and DR5. Here, we found that DR5 but not DR4 is present in the conditioned medium (CM)-derived from various cancer cells. Moreover, we observed that DR5 was exposed on EVs and can act as "decoy receptor" for binding to TRAIL. This results in a strongly reduced number of apoptotic cells upon treatment with DR5-specific TRAIL variant DHER in CM. This reduction happened with EVs containing either the long or short isoform of DR5. Taken together, we demonstrated that colon rectal tumor cells can secrete DR5-coated EVs, and this can cause TRAIL resistance. This is to our knowledge a novel finding and provides new insights into understanding TRAIL sensitivity.
Insights
Cancer cells can develop resistance to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) therapy. This study reveals that cancer cells release extracellular vesicles coated with DR5, a decoy receptor, which hinders TRAIL
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise as an antitumor drug due to its selective proapoptotic effects on cancer cells.
- Cancer cell resistance to TRAIL limits its clinical application, with resistance mechanisms occurring at various points in the TRAIL signaling pathway.
- Decoy receptors are known to interfere with TRAIL signaling by binding TRAIL and preventing death receptor activation.
Purpose of the Study:
- To investigate the role of extracellular vesicles (EVs) in mediating TRAIL resistance in cancer cells.
- To determine if death receptor 5 (DR5) is present on EVs and if it functions as a decoy receptor for TRAIL.
- To elucidate a novel mechanism of TRAIL resistance involving cancer cell-secreted EVs.
Main Methods:
- Analysis of conditioned medium (CM) from various cancer cell lines for the presence of death receptors DR4 and DR5.
- Characterization of EVs isolated from CM to identify surface-expressed proteins, specifically DR5.
- Treatment of cancer cells with a DR5-specific TRAIL variant (DHER) in the presence of CM-derived EVs to assess apoptosis induction.
Main Results:
- DR5, but not DR4, was detected in the conditioned medium of various cancer cells.
- DR5 was found to be exposed on extracellular vesicles (EVs) released by cancer cells.
- EVs containing DR5 significantly reduced TRAIL-induced apoptosis, indicating DR5 acts as a decoy receptor on EVs.
- Both long and short isoforms of DR5 on EVs contributed to TRAIL resistance.
Conclusions:
- Colon rectal tumor cells secrete DR5-coated extracellular vesicles.
- These DR5-expressing EVs function as decoy receptors, sequestering TRAIL and conferring resistance to TRAIL-based therapies.
- This finding presents a novel mechanism contributing to TRAIL resistance and offers new insights into managing TRAIL sensitivity in cancer treatment.
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