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

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

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 -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 -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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