Wnt Activity Defines Colon Cancer Stem Cells and Is Regulated by the Microenvironment

Nat Cell Biol. 2010 May;12(5):468-76. doi: 10.1038/ncb2048. Epub 2010 Apr 25.

Abstract

Despite the presence of mutations in APC or beta-catenin, which are believed to activate the Wnt signalling cascade constitutively, most colorectal cancers show cellular heterogeneity when beta-catenin localization is analysed, indicating a more complex regulation of Wnt signalling. We explored this heterogeneity with a Wnt reporter construct and observed that high Wnt activity functionally designates the colon cancer stem cell (CSC) population. In adenocarcinomas, high activity of the Wnt pathway is observed preferentially in tumour cells located close to stromal myofibroblasts, indicating that Wnt activity and cancer stemness may be regulated by extrinsic cues. In agreement with this notion, myofibroblast-secreted factors, specifically hepatocyte growth factor, activate beta-catenin-dependent transcription and subsequently CSC clonogenicity. More significantly, myofibroblast-secreted factors also restore the CSC phenotype in more differentiated tumour cells both in vitro and in vivo. We therefore propose that stemness of colon cancer cells is in part orchestrated by the microenvironment and is a much more dynamic quality than previously expected that can be defined by high Wnt activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Coculture Techniques
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Fibroblasts / pathology
  • Hepatocyte Growth Factor / metabolism
  • Hepatocyte Growth Factor / physiology
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Proteins
  • Neoplasms, Experimental
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Paracrine Communication*
  • Signal Transduction
  • Transplantation, Heterologous
  • Wnt Proteins / metabolism*
  • beta Catenin

Substances

  • Neoplasm Proteins
  • Wnt Proteins
  • beta Catenin
  • Hepatocyte Growth Factor