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Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy | Nature Reviews Cancer
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Clinical trials testing activators of tumour necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) signalling in cancer have not met expectations. This Review discusses new insights that might explain clinical failure, but also provide the basis for harnessing TRAIL-Rs for cancer therapy. The discovery that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis of cancer cells without causing toxicity in mice has led to the in-depth study of pro-apoptotic TRAIL receptor (TRAIL-R) signalling and the development of biotherapeutic drug candidates that activate TRAIL-Rs. The outcome of clinical trials with these TRAIL-R agonists has, however, been disappointing so far. Recent evidence indicates that many cancers, in addition to being TRAIL resistant, use the endogenous TRAIL–TRAIL-R system to their own advantage. However, novel insight on two fronts — how resistance of cancer cells to TRAIL-based pro-apoptotic therapies might be overcome, and how the pro-tumorigenic effects of endogenous TRAIL might be countered — gives reasonable hope that the TRAIL system can be harnessed to treat cancer. In this Review we assess the status quo of our understanding of the biology of the TRAIL–TRAIL-R system — as well as the gaps therein — and discuss the opportunities and challenges in effectively targeting this pathway.
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tnf-alpha-related apoptosis-inducing ligand releases tumour-necrosis factor-alpha nature portfolio journals tnf-related apoptosis-inducing ligand trail-r2/killer/dr5 mrna isoforms permissions reprints privacy policy nature portfolio european research council advertising open-label study il6/stat3-dependent trail expression cancer research uk c-jun n-terminal kinase apoptosis-inducing ligand belonging trail/apo2l gene-deficient mice trail-mediated dr5-disc formation trail-based pro-apoptotic therapies social media tumor necrosis factor tumour necrosis factor rankl/opg/trail plasma levels agonistic trail-r2-specific antibody cycloheximide-sensitive factor occurs death-inducing signalling complex membrane-targeted death ligand modern research death receptor–ligand systems endotoxin-induced serum factor trail/dr5-dependent suppression induced trail-induced programmed necrosis cell-surface death ligand cyclooxygenase-dependent tumor growth myeloid-derived suppressor cells membrane-bound fas ligand tumor-cell-derived interleukin-4 trail-r2-targeting nanobody tas266 death receptor-induced apoptosis retinoic acid-induced apoptosis scientific adviser ifn-gamma-dependent suppression antonella montinaro & henning walczak modulates fasl-induced cytotoxicity author correspondence tumor-supportive immune microenvironment proapoptotic ligand apo2l/trail trail-induced apoptosis mediated university college london trail-r2- mediated apoptosis trail-r-mediated apoptosis
Questions {❓}
- Bortezomib and TRAIL: a perfect match for apoptotic elimination of tumour cells?
- Is TRAIL the holy grail of cancer therapy?
- Metastasis suppressor function of tumor necrosis factor-related apoptosis-inducing ligand-R in mice: implications for TRAIL-based therapy in humans?
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Clinical trials testing activators of tumour necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) signalling in cancer have not met expectations. This Review discusses new insights that might explain clinical failure, but also provide the basis for harnessing TRAIL-Rs for cancer therapy. The discovery that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis of cancer cells without causing toxicity in mice has led to the in-depth study of pro-apoptotic TRAIL receptor (TRAIL-R) signalling and the development of biotherapeutic drug candidates that activate TRAIL-Rs. The outcome of clinical trials with these TRAIL-R agonists has, however, been disappointing so far. Recent evidence indicates that many cancers, in addition to being TRAIL resistant, use the endogenous TRAILâTRAIL-R system to their own advantage. However, novel insight on two fronts â how resistance of cancer cells to TRAIL-based pro-apoptotic therapies might be overcome, and how the pro-tumorigenic effects of endogenous TRAIL might be countered â gives reasonable hope that the TRAIL system can be harnessed to treat cancer. In this Review we assess the status quo of our understanding of the biology of the TRAILâTRAIL-R system â as well as the gaps therein â and discuss the opportunities and challenges in effectively targeting this pathway.
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