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First published online 6 June 2006
doi: 10.1242/jcs.03011

Journal of Cell Science 119, 2727-2738 (2006)
Published by The Company of Biologists 2006
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Research Article

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

Bahar Cat1, Dominik Stuhlmann1, Holger Steinbrenner1, Lirija Alili1, Olaf Holtkötter2, Helmut Sies1 and Peter Brenneisen1,*

1 Institute for Biochemistry and Molecular Biology I, Heinrich-Heine-University, 40225 Düsseldorf, Germany
2 Henkel KGaA, 40191 Düsseldorf, Germany

* Author for correspondence (e-mail: PeterBrenneisen{at}web.de)

Accepted 30 March 2006

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 ß1 (TGFß1) 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 TGFß1-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.

Key words: Myofibroblast, Reactive oxygen species, Transforming growth factor ß, Tumor invasion, Tumor-stroma interaction


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