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

Wan-Jiun Chen; Chao-Chi Ho; Yih-Leong Chang; Hsuan-Yu Chen; Chih-An Lin; Thai-Yen Ling; Sung-Liang Yu; Shin-Sheng Yuan; Yu-Ju Louisa Chen; Chien-Yu Lin; Szu-Hua Pan; Han-Yi Elizabeth Chou; Yu-Ju Chen; Gee-Chen Chang; Wen-Cheng Chu; Yee-Ming Lee; Jen-Yi Lee; Pei-Jung Lee; Ker-Chau Li; Huei-Wen Chen; Pan-Chyr Yang

doi:10.1038/ncomms4472

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

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

Authors

Wan-Jiun Chen¹, Chao-Chi Ho², Yih-Leong Chang³, Hsuan-Yu Chen⁴, Chih-An Lin⁵, Thai-Yen Ling⁶, Sung-Liang Yu⁵, Shin-Sheng Yuan⁴, Yu-Ju Louisa Chen⁴, Chien-Yu Lin⁴, Szu-Hua Pan⁷, Han-Yi Elizabeth Chou⁸, Yu-Ju Chen⁹, Gee-Chen Chang¹⁰, Wen-Cheng Chu¹¹, Yee-Ming Lee¹¹, Jen-Yi Lee¹¹, Pei-Jung Lee¹¹, Ker-Chau Li¹², Huei-Wen Chen¹³, Pan-Chyr Yang¹⁴

Affiliations

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.

PMID: 24668028
DOI: 10.1038/ncomms4472

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics*
Adenocarcinoma / metabolism
Aged
Aged, 80 and over
Animals
Carcinoma, Squamous Cell / genetics*
Carcinoma, Squamous Cell / metabolism
Cells, Cultured
Female
Fibroblasts / metabolism*
Gene Expression Profiling
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Insulin-Like Growth Factor II / genetics
Insulin-Like Growth Factor II / metabolism
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Male
Mice
Middle Aged
Nanog Homeobox Protein
Neoplasm Transplantation
Neoplastic Stem Cells / metabolism*
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
Paracrine Communication*
Receptor, IGF Type 1
Receptors, Somatomedin / genetics
Receptors, Somatomedin / metabolism
Small Cell Lung Carcinoma / genetics*
Small Cell Lung Carcinoma / metabolism
Thy-1 Antigens / metabolism
Tumor Microenvironment

Substances

Homeodomain Proteins
IGF1R protein, human
NANOG protein, human
Nanog Homeobox Protein
Octamer Transcription Factor-3
POU5F1 protein, human
Receptors, Somatomedin
Thy-1 Antigens
Insulin-Like Growth Factor II
Receptor, IGF Type 1

Associated data

GEO/GSE38678