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

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 bre...

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Published inCancers Vol. 11; no. 1; p. 94
Main Authors Twomey, Julianne D, Zhang, Baolin
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 15.01.2019
MDPI
Subjects
Apoptosis
Autophagy
Breast cancer
Cancer therapies
Cell culture
Cell death
Chemoresistance
circulating tumor cells
CTCs
Cytokines
death receptor
DR5 protein
Hemopoiesis
Immunosurveillance
in vitro model
Ligands
Lysosomes
Medical prognosis
Metastases
Metastasis
Microenvironments
Organelles
Peripheral blood
Phagosomes
Proteins
Suspension culture
TRAIL
TRAIL protein
Tumor cell lines
Tumor cells
Tumor necrosis factor
Tumor necrosis factor-TNF
Tumors
in vitro model
TRAIL
metastasis
apoptosis
breast cancer
circulating tumor cells
CTCs
death receptor
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Summary: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.
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ISSN:2072-6694
2072-6694
DOI:10.3390/cancers11010094