Cancer-associated Fibroblasts Regulate the Plasticity of Lung Cancer Stemness via Paracrine Signalling

Nat Commun. 2014 Mar 25;5:3472. 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*
  • 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

Associated data

  • GEO/GSE38678