title: Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species.
abstract: 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.
authors.affiliation: Institute for Biochemistry and Molecular Biology I, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors.forename: Bahar
authors.initials: B
authors.lastname: Cat
authors.forename: Dominik
authors.initials: D
authors.lastname: Stuhlmann
authors.forename: Holger
authors.initials: H
authors.lastname: Steinbrenner
authors.forename: Lirija
authors.initials: L
authors.lastname: Alili
authors.forename: Olaf
authors.initials: O
authors.lastname: Holtkötter
authors.forename: Helmut
authors.initials: H
authors.lastname: Sies
authors.forename: Peter
authors.initials: P
authors.lastname: Brenneisen
mesh_terms: 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
chemical_list: 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