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Circulating Tumor Cells Develop Resistance to TRAIL-Induced Apoptosis Through Autophagic Removal of Death Receptor 5: Evidence from an In Vitro Model

Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA
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Cancers 2019, 11(1), 94; https://doi.org/10.3390/cancers11010094
Received: 15 November 2018 / Revised: 8 January 2019 / Accepted: 8 January 2019 / Published: 15 January 2019
(This article belongs to the Special Issue TRAIL Signaling in Cancer Cells)
Circulating tumor cells (CTCs) in the peripheral blood are the precursors to distant metastasis but the underlying mechanisms are poorly understood. This study aims at understanding the molecular features within CTCs, in relation to their metastatic potential. Using in vitro CTC models, in which breast cancer cell lines were cultured in non-adherent conditions simulating the microenvironment in the blood stream, we found that the suspension culture resulted in resistance to TNF-related apoptosis inducing ligand (TRAIL)-mediated cell death. Such a resistance was directly correlated with a reduction in surface and total levels of DR5 protein. In the non-adherent state, the cells underwent a rapid autophagic flux, characterized by an accumulation of autophagosome organelles. Notably, DR5 was translocated to the autophagosomes and underwent a lysosomal degradation. Our data suggest that CTCs may evade the TNF cytokine-mediated immune surveillance through a downregulation of the death receptor (DR) expression. The data warrants further studies in cancer patients to find the status of DRs and other molecular features within primary CTCs, in relation to disease progression or chemoresistance. View Full-Text
Keywords: circulating tumor cells; CTCs; breast cancer; metastasis; death receptor; TRAIL; apoptosis; in vitro model circulating tumor cells; CTCs; breast cancer; metastasis; death receptor; TRAIL; apoptosis; in vitro model
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Twomey, J.D.; Zhang, B. Circulating Tumor Cells Develop Resistance to TRAIL-Induced Apoptosis Through Autophagic Removal of Death Receptor 5: Evidence from an In Vitro Model. Cancers 2019, 11, 94.

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