Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation

Cancer Cell. 2012 Nov 13;22(5):571-84. doi: 10.1016/j.ccr.2012.08.013.

Abstract

A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-β pathway, yet, paradoxically, they are characterized by elevated TGF-β production. Here, we unveil a prometastatic program induced by TGF-β in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-β on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-β-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-β stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / pathology*
  • Cytokine Receptor gp130 / genetics
  • Cytokine Receptor gp130 / metabolism
  • Cytokine Receptor gp130 / physiology
  • HT29 Cells
  • Humans
  • Interleukin-11 / genetics
  • Interleukin-11 / metabolism
  • Interleukin-11 / physiology
  • Mice
  • Neoplasm Metastasis / drug therapy
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors
  • Recurrence
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • STAT3 Transcription Factor / physiology
  • Signal Transduction
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / physiology*
  • Tumor Cells, Cultured
  • Tumor Microenvironment

Substances

  • Il6st protein, mouse
  • Interleukin-11
  • Receptors, Transforming Growth Factor beta
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Transforming Growth Factor beta
  • Cytokine Receptor gp130
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse