Abstract
BackgroundCancer stem cells (CSCs) play a critical role in tumor development and progression and are involved in cancer metastasis. The role of reactive oxygen species (ROS) in CSCs and cancer metastasis remains controversial. The aim of the present study was to investigate the correlation between ROS level of CSCs and cancer metastasis and to explore the possible underlying molecular mechanisms.MethodsFour different cell lines were used to isolate tumor spheres and to analyze intrinsic properties of tumor sphere cells including proliferation, self-renewal potential, differentiation, drug-resistance and cancer metastasis in vitro and in vivo. ROS assays were used to detect the intracellular ROS level of tumor spheres cells. Gene expression analysis and western blot were used to investigate the underlying mechanisms of ROS in regulating cancer metastasis.ResultsTumor spheres possessed the characteristic features of CSCs, and ROS-high tumor spheres (RH-TS) displayed elevated mitochondrial ROS level exclusively drove metastasis formation. The gene expression analysis showed elevated fatty acid β-oxidation, downregulation of epithelial marker upregulation of mesenchymal markers, and the activation of MAP kinase cascades. Furthermore, 14 up-regulated genes in RH-TS cells were associated with reduced overall survival of different cancer patients.ConclusionsOur findings demonstrate that CSCs characterized by elevated mitochondrial ROS level potentiate cancer metastasis. Mechanistically, elevated mitochondrial ROS via fatty acid β-oxidation, activates the MAPK cascades, resulting in the epithelial-mesenchymal transition (EMT) process of RH-TS cells, thereby potentiating caner invasion and metastasis. Therefore, targeting mitochondrial ROS might provide a promising approach to prevent and alleviate cancer metastasis induced by RH-TS cells.
Highlights
Cancer stem cells (CSCs) play a critical role in tumor development and progression and are involved in cancer metastasis
We further replated dissociated single tumor sphere cells in a 96-well plate in an average density of 1 cell per well to analyze the self-renewal ability. 3833 single clones were obtained from tumor sphere 1° cells from 20 clones, and the percentages of tumor sphere was 90.1% ± 1.3%; 747 single clones were obtained from tumor sphere 2° cells from 5 clones, and the percentages of tumor sphere was 89.3% ± 1.1%; 673 single clones were obtained from tumor sphere 3° cells from 5 clones, and the percentages of tumor sphere was 89.5% ± 1.6%
It revealed that about 90% of sphere derived single cells grew into new tumor spheres, and the percentage of self-renewing sphere-forming cells remained remarkably stable over 3 rounds of single cell replating experiments (Fig. 1b)
Summary
Cancer stem cells (CSCs) play a critical role in tumor development and progression and are involved in cancer metastasis. The role of reactive oxygen species (ROS) in CSCs and cancer metastasis remains controversial. CSCs, an integral part of tumor mass, are generally supposed to be a sub-population of quiescent cells endowed with selfrenewal and differentiation properties and strongly influence tumor propagation and cancer metastasis [3,4,5]. The discovery of cancer stem cells has significantly changed our concepts about the mechanisms of multi-step tumorigenesis and metastasis, since these self-renewing cells (or closely related progenitor cells), rather than the bulk populations of cancer cells, may be the objects of genetic alteration and clonal selection
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