Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species

J Cell Sci. 2006 Jul 1;119(Pt 13):2727-38. doi: 10.1242/jcs.03011. Epub 2006 Jun 6.


Myofibroblasts, pivotal for tumor progression, populate the microecosystem of reactive stroma. Using an in vitro tumor-stroma model of skin carcinogenesis, we report here that tumor-cell-derived transforming growth factor beta1 (TGFbeta1) initiates reactive oxygen species-dependent expression of alpha-smooth muscle actin, a biomarker for myofibroblastic cells belonging to a group of late-responsive genes. Moreover, protein kinase C (PKC) is involved in lipid hydroperoxide-triggered molecular events underlying transdifferentiation of fibroblasts to myofibroblasts (mesenchymal-mesenchymal transition, MMT). In contrast to fibroblasts, myofibroblasts secrete large amounts of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6), resulting in a significant increase in the invasive capacity of tumor cells. The thiol N-acetyl-L-cysteine, the micronutrient selenite as well as selenoprotein P and the lipid peroxidation inhibitors alpha-tocopherol and butylated hydroxytoluene significantly lower both the number of TGFbeta1-initiated myofibroblasts and the secretion of HGF, VEGF and IL-6, correlating with a diminished invasive capacity of tumor cells. This novel concept of stromal therapy, namely the protection of stromal cells against the dominating influence of tumor cells in tumor-stroma interaction by antioxidants and micronutrients, may form the basis for prevention of MMT in strategies for chemoprevention of tumor invasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Antioxidants / pharmacology
  • Cell Differentiation*
  • Cells, Cultured
  • Chromans / pharmacology
  • Disease Progression
  • Fibroblasts / pathology*
  • Humans
  • Lipid Peroxidation / drug effects
  • Models, Biological
  • Muscle Fibers, Skeletal / metabolism
  • Neoplasm Invasiveness / physiopathology*
  • Neoplasm Invasiveness / prevention & control
  • Protein Kinase C / physiology
  • Reactive Oxygen Species / metabolism
  • Skin / cytology*
  • Smad Proteins / metabolism
  • Sodium Selenite / pharmacology
  • Transforming Growth Factor beta / physiology
  • Transforming Growth Factor beta1


  • Antioxidants
  • Chromans
  • Reactive Oxygen Species
  • Smad Proteins
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Protein Kinase C
  • Sodium Selenite
  • 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
  • Acetylcysteine