Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species.
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.
Cat
Bahar
B
Institute for Biochemistry and Molecular Biology I, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
Stuhlmann
Dominik
D
Steinbrenner
Holger
H
Alili
Lirija
L
Holtkötter
Olaf
O
Sies
Helmut
H
Brenneisen
Peter
P
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D018450:Disease Progression; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000503:physiopathology* / Q000517:prevention & control; D011493:Protein Kinase C / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000166:cytology*; D051785:Smad Proteins / Q000378:metabolism; D018038:Sodium Selenite / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology; D053773:Transforming Growth Factor beta1
D000975:Antioxidants; D002839:Chromans; D017382:Reactive Oxygen Species; D051785:Smad Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D011493:Protein Kinase C; D018038:Sodium Selenite; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D000111:Acetylcysteine