Abstract
Cell therapy is a promising new treatment option for cancer. In particular, mesenchymal stem cells (MSCs) have shown potential in delivering therapeutic genes in various tumour models and are now on the verge of being tested in the clinic. A number of therapeutic genes have been examined in this context, including the death ligand TRAIL. For cell therapy, it can be used in its natural form as a full-length and membrane-bound protein (FL-TRAIL) or as an engineered version commonly referred to as soluble TRAIL (sTRAIL). As to which is more therapeutically efficacious, contradicting results have been reported. We discovered that MSCs producing sTRAIL have significantly higher apoptosis-inducing activity than cells expressing FL-TRAIL and found that FL-TRAIL, in contrast to sTRAIL, is not secreted. We also demonstrated that TRAIL does induce the expression of pro-metastatic cytokines in prostate cancer cells, but that this effect could be overcome through combination with an AKT inhibitor. Thus, a combination consisting of small-molecule drugs specifically targeting tumour cells in combination with MSC.sTRAIL, not only provides a way of sensitising cancer cells to TRAIL, but also reduces the issue of side-effect-causing cytokine production. This therapeutic strategy therefore represents a novel targeted treatment option for advanced prostate cancer and other difficult to treat tumours.
Highlights
The tumour necrosis factor related apoptosis-inducing ligand (TRAIL), known as Apo2L, CD253 or TNFSF10, can induce apoptosis in cancer cells while sparing normal cells
For the soluble TRAIL (sTRAIL) construct, the TRAIL ectodomain was fused to an Isoleucine Zipper (ILZ)
Our results demonstrate that in the context of cell therapy an engineered, secreted version of TRAIL has more anti-cancer potency than full-length TRAIL that remains membrane-bound and is not secreted into the extracellular space
Summary
The tumour necrosis factor related apoptosis-inducing ligand (TRAIL), known as Apo2L, CD253 or TNFSF10, can induce apoptosis in cancer cells while sparing normal cells. Since p53 is frequently inactivated in human tumours, TRAIL is able to induce apoptosis in cancer cells that are normally hard to treat. TRAIL is a member of the TNF superfamily, which forms multimers that interact with cognate receptors on the cell surface [8,9,10]. It binds to four membrane-bound death receptors and one soluble receptor, TRAIL-R1/DR4, TRAIL-R2/DR5, TRAIL-R3/ DcR1, TRAIL-R4/DcR2 and osteoprotegerin (OPG). Following binding of TRAIL, a protein complex, Cancers 2019, 11, 568; doi:10.3390/cancers11040568 www.mdpi.com/journal/cancers
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