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Sci Rep. 2018 Aug 1;8(1):11573. doi: 10.1038/s41598-018-29947-w.

Stroma-derived IL-6, G-CSF and Activin-A mediated dedifferentiation of lung carcinoma cells into cancer stem cells.

Author information

1
Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-517, Coimbra, Portugal.
2
Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3001-301, Coimbra, Portugal.
3
Faculty of Medicine (FMUC), University of Coimbra, 3000-548, Coimbra, Portugal.
4
Centro Hospitalar e Universitário de Coimbra (CHUC), 3000-075, Coimbra, Portugal.
5
Nuffield Laboratory of Ophthalmology, NDCN & NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 9DU, United Kingdom.
6
Laboratory of Cytogenetics and Genomics, Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal.
7
Faculty of Pharmacy (FFUC), University of Coimbra, 3000-548, Coimbra, Portugal.
8
Centre for Biotechnology, Brock University, St. Catharines, Ontario, L2S 3A1, Canada.
9
Pharmacology and Experimental Therapeutics - Institute of Biomedical Research in Light and Image (IBILI), Faculty of Medicine, University of Coimbra, 3000-354, Coimbra, Portugal.
10
Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, 3000-354, Coimbra, Portugal.
11
Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-517, Coimbra, Portugal. mcalpoim@bioq.uc.pt.
12
Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3001-301, Coimbra, Portugal. mcalpoim@bioq.uc.pt.
13
Department of Life Sciences, Faculty of Science and Technology (FCTUC), University of Coimbra, 3000-456, Coimbra, Portugal. mcalpoim@bioq.uc.pt.

Abstract

Cancer stem cells (CSCs) are a small population of resistant cells inhabiting the tumors. Although comprising only nearly 3% of the tumor mass, these cells were demonstrated to orchestrate tumorigenesis and differentiation, underlie tumors' heterogeneity and mediate therapy resistance and tumor relapse. Here we show that CSCs may be formed by dedifferentiation of terminally differentiated tumor cells under stress conditions. Using a elegant co-culture cellular system, we were able to prove that nutrients and oxygen deprivation activated non-malignant stromal fibroblasts, which in turn established with tumor cells a paracrine loop mediated by Interleukine-6 (IL-6), Activin-A and Granulocyte colony-stimulating factor (G-CSF), that drove subsequent tumor formation and cellular dedifferentiation. However, by scavenging these cytokines from the media and/or blocking exosomes' mediated communication it was possible to abrogate dedifferentiation thus turning these mechanisms into potential therapeutic targets against cancer progression.

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