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Nat Commun. 2014 Mar 25;5:3472. doi: 10.1038/ncomms4472.

Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling.

Author information

1
1] Graduate Institute of Oncology, National Taiwan University Medical College, Taipei 10051, Taiwan [2] Graduate Institute of Toxicology, National Taiwan University Medical College, Taipei 10051, Taiwan [3] Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan.
2
Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei 10051, Taiwan.
3
Department of Pathology and Graduate Institute of Pathology, National Taiwan University Medical College, Taipei 10051, Taiwan.
4
Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan.
5
Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Medical College, Taipei 10051, Taiwan.
6
Department of Pharmacology, National Taiwan University Medical College, Taipei 10051, Taiwan.
7
Graduate Institute of Medical Genomics and Proteomics, National Taiwan University Medical College, Taipei 10051, Taiwan.
8
Graduate Institute of Oral Biology, National Taiwan University Dentistry College, Taipei 10051, Taiwan.
9
Graduate Institute of Chemistry, Academia Sinica, Taipei 10051, Taiwan.
10
1] Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan [2] Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
11
Graduate Institute of Toxicology, National Taiwan University Medical College, Taipei 10051, Taiwan.
12
1] Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan [2] Department of Statistics, University of California, Los Angeles, California 90095, USA.
13
1] Graduate Institute of Toxicology, National Taiwan University Medical College, Taipei 10051, Taiwan [2] Genome and Systems Biology Degree Program, National Taiwan University, Taipei 10051, Taiwan.
14
1] Graduate Institute of Oncology, National Taiwan University Medical College, Taipei 10051, Taiwan [2] Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei 10051, Taiwan [3] Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.

Abstract

Cancer stem cells (CSCs) are a promising target for treating cancer, yet how CSC plasticity is maintained in vivo is unclear and is difficult to study in vitro. Here we establish a sustainable primary culture of Oct3/4(+)/Nanog(+) lung CSCs fed with CD90(+) cancer-associated fibroblasts (CAFs) to further advance our knowledge of preserving stem cells in the tumour microenvironment. Using transcriptomics we identify the paracrine network by which CAFs enrich CSCs through de-differentiation and reacquisition of stem cell-like properties. Specifically, we find that IGF1R signalling activation in cancer cells in the presence of CAFs expressing IGF-II can induce Nanog expression and promote stemness. Moreover, this paracrine signalling predicts overall and relapse-free survival in stage I non-small cell lung cancer (NSCLC) patients. IGF-II/IGF1R signalling blockade inhibits Nanog expression and attenuates cancer stem cell features. Our data demonstrate that CAFs constitute a supporting niche for cancer stemness, and targeting this paracrine signalling may present a new therapeutic strategy for NSCLC.

PMID:
24668028
DOI:
10.1038/ncomms4472
[Indexed for MEDLINE]

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