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Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptotic pathways in cancer immunosurveillance: molecular mechanisms and prospects for therapy

Authors James B, Griffith T

Received 1 October 2014

Accepted for publication 12 November 2014

Published 22 December 2014 Volume 2015:5 Pages 1—10


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Professor Nikolay Dokholyan

Britnie R James,1 Thomas S Griffith1–4

1Department of Urology, 2Microbiology, Immunology, and Cancer Biology Graduate Program, 3Center for Immunology, 4Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA

Abstract: Since first described in 1995, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has generated considerable interest as a cancer therapeutic because of its ability to induce apoptosis in a range of tumor cell types while having little activity on normal cells and tissues. Since then, the vast majority of studies published on TRAIL and anti-TRAIL receptor monoclonal antibodies have focused on the tumoricidal activity of these molecules, with the intention of developing TRAIL-receptor agonists into potent cancer therapeutic agents. As promising as these agonists have proved to be in vitro and in various in vivo preclinical models, there have been a number of obstacles identified likely contributing to the underwhelming clinical trial data obtained – including a high frequency of TRAIL-resistant tumors – and reduced excitement about using TRAIL-receptor agonists as monotherapy for cancer. Consequently, it is important to understand the various mechanisms used by tumor cells to maintain TRAIL resistance and develop novel combinatorial approaches to restore TRAIL sensitivity in tumor cells. This review highlights the complexities of the TRAIL–TRAIL-receptor system, explores various methods for inducing TRAIL-induced death of tumor cells, and discusses some of the mechanisms that regulate tumor resistance to TRAIL and the way in which this resistance can be countered.

Keywords: TRAIL, TRAIL-R, TRAIL-receptor agonists, TRAIL resistance, cell death, tumor

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