Abstract
Death ligands such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; TNFSF10) and their corresponding death receptors (e.g., DR5) not only initiate apoptosis through activation of the extrinsic apoptotic pathway but also exert non-apoptotic biological functions such as regulation of inflammation and cancer metastasis. The involvement of the TRAIL/death receptor signaling pathway in the regulation of cancer invasion and metastasis is complex as both positive and negative roles have been reported. The underlying molecular mechanisms are even more complicated. This review will focus on discussing current knowledge in our understanding of the involvement of TRAIL/death receptor-mediated signaling in the regulation of cancer cell invasion and metastasis.
Highlights
Based on our findings [42,96], we suggest that the activation of DR5 normally favors the formation of the death-inducing signaling complex (DISC), resulting in induction of apoptosis or anoikis as well as other potential biological consequences; this will lead to direct killing of detached cancer cells and restrict the formation of another complex named the metastasis and invasion signaling complex (MISC), eventually resulting in the suppression of cancer cell invasion and metastasis
Death receptor-mediated signaling complex proteins can serve as an important platform to regulate cancer apoptosis, inflammation, and metastasis depending on cell types or contexts
Under tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant or apoptosiscompromising conditions, activation of TRAIL/death receptor signaling may likely favor the positive regulation of cancer cell invasion and metastasis
Summary
This review will primarily focus on discussing current knowledge in our understanding of the involvement of the extrinsic apoptotic pathway, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/death receptor-mediated signaling, in the regulation of cancer cell metastasis. These TRAIL gene-targeted mice were more susceptible to experimental and spontaneous tumor metastasis and more sensitive to the chemical carcinogen methylcholanthrene, further supporting TRAIL as an important natural effector molecule used in the host defense against transformed cells and cancer cell metastasis [24] These early studies strongly suggest that TRAIL expressed in immune cells, such as NK cells, contributes to the natural suppression of tumor development and metastasis, likely via TRAIL-mediated apoptosis
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