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Review
. 2018 Jul 27;19(8):2188.
doi: 10.3390/ijms19082188.

Mesenchymal Stem Cell Expressing TRAIL as Targeted Therapy against Sensitised Tumour

Kamal Shaik Fakiruddin  1   2 , Nadiah Ghazalli  3 , Moon Nian Lim  4 , Zubaidah Zakaria  5 , Syahril Abdullah  6   7
Affiliations
Review

Mesenchymal Stem Cell Expressing TRAIL as Targeted Therapy against Sensitised Tumour

Kamal Shaik Fakiruddin et al. Int J Mol Sci. .

Abstract

Tapping into the ability of engineered mesenchymal stem cells (MSCs) to mobilise into the tumour has expanded the scope of cancer treatment. Engineered MSCs expressing tumour necrosis factor (TNF)-related apoptosis inducing ligand (MSC-TRAIL) could serve as a platform for an efficient and targeted form of therapy. However, the presence of cancer stem cells (CSCs) that are resistant to TRAIL and apoptosis may represent a challenge for effective treatment. Nonetheless, with the discovery of small molecular inhibitors that could target CSCs and tumour signalling pathways, a higher efficacy of MSC-TRAIL mediated tumour inhibition can be achieved. This might pave the way for a more effective form of combined therapy, which leads to a better treatment outcome. In this review, we first discuss the tumour-homing capacity of MSCs, its effect in tumour tropism, the different approach behind genetically-engineered MSCs, and the efficacy and safety of each agent delivered by these MSCs. Then, we focus on how sensitisation of CSCs and tumours using small molecular inhibitors can increase the effect of these cells to either TRAIL or MSC-TRAIL mediated inhibition. In the conclusion, we address a few questions and safety concerns regarding the utilization of engineered MSCs for future treatment in patients.

Keywords: TRAIL; apoptosis; cancer stem cells; mesenchymal stem cells; sensitisation; tumours.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Engineered mesenchymal stem cells (MSCs) act to support and inhibit tumour growth. MSCs could induce apoptosis in some tumours, while others have reported that MSCs might also inhibit apoptosis. MSCs could promote vascularization in the tumour microenvironment by secreting growth factors and might also lead to tumour inhibition by inducing cyclin dependent kinases (CDKs) and cyclins block that leads to cell cycle arrest. These ambiguous roles of MSCs suggested that more studies are needed to elucidate the exact function of MSCs in different tumour models for a safer treatment outcome. TRAIL—tumour necrosis factor-related apoptosis inducing ligand; VEGF—vascular endothelial growth factor; PDGF—platelet-derived growth factor; FGF—fibroblast growth factors; IFN—interferon; IGF—insulin-like growth factor; TGF—transforming growth factor; IDO—indoleamine 2,3-dioxygenase; HGF—hepatocyte growth factor; EGF—epidermal growth factor; PDGF—platelet-derived growth factor; WNT—proto-oncogene protein; IL—interleukin; SDF—stromal derived factor one alpha; AKT—serine/threonine kinase; PTEN—phosphatase and tensin homolog.
Figure 2
Figure 2
Sensitisation of tumour or cancer stem cells (CSC) to MSC-TRAIL induced apoptosis. An increase in the anti-apoptotic molecules (e.g., X-linked inhibitor of apoptosis proteins [XIAPs], cellular FLICE-like inhibitory protein [cFLIP], and B-cell lymphoma 2 [BCL-2]) upon TRAIL activation can be circumvented using specific inhibitors, as illustrated above. Through tumour sensitisation by anti-apoptosis gene silencing or specific DR5 receptor enhancement, and the utilization of MSCs as a vehicle for TRAIL delivery, a better treatment outcome could be achieved. SMAC—second mitochondria-derived activator of caspases; FADD—fas-associated protein with death domain; Cas—caspase; BID—BH3 interacting-domain death agonist; BAK—BCL-2 antagonist killer 1; BAX—BCL-2 associated X. Inhibitors: SAHA—suberoylanilide hydroxamic acid; shRNA—short hairpin RNA; siRNA—small interfering RNA; RNAi—RNA interference. The arrow and t-bar represent activated and inhibitory interactions respectively.
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References

    1. Bray F., Ferlay J., Laversanne M., Brewster D.H., Gombe Mbalawa C., Kohler B., Pineros M., Steliarova-Foucher E., Swaminathan R., Antoni S., et al. Cancer incidence in five continents: Inclusion criteria, highlights from Volume X and the global status of cancer registration. Int. J. Cancer. 2015;137:2060–2071. doi: 10.1002/ijc.29670. - DOI - PubMed
    1. Hanahan D., Weinberg R.A. The hallmarks of cancer. Cell. 2000;100:57–70. doi: 10.1016/S0092-8674(00)81683-9. - DOI - PubMed
    1. Jemal A., Bray F., Center M.M., Ferlay J., Ward E., Forman D. Global cancer statistics. CA Cancer J. Clin. 2011;61:69–90. doi: 10.3322/caac.20107. - DOI - PubMed
    1. Chen K., Huang Y.H., Chen J.L. Understanding and targeting cancer stem cells: Therapeutic implications and challenges. Acta Pharmacol. Sin. 2013;34:732–740. doi: 10.1038/aps.2013.27. - DOI - PMC - PubMed
    1. Pittenger M.F., Mackay A.M., Beck S.C., Jaiswal R.K., Douglas R., Mosca J.D., Moorman M.A., Simonetti D.W., Craig S., Marshak D.R. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–147. doi: 10.1126/science.284.5411.143. - DOI - PubMed

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