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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
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JCS ePress
online publication date 6 Jun 2006
doi: 10.1242/jcs.03011
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Research Article
Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species
* Author for correspondence (e-mail: PeterBrenneisen{at}web.de)
1 (TGF
1) 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 TGF
1-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.
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C. Werth, D. Stuhlmann, B. Cat, H. Steinbrenner, L. Alili, H. Sies, and P. Brenneisen
Stromal resistance of fibroblasts against oxidative damage: involvement of tumor cell-secreted platelet-derived growth factor (PDGF) and phosphoinositide 3-kinase (PI3K) activation
Carcinogenesis,
February 1, 2008;
29(2):
404 - 410.
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A. K. Sasser, N. J. Sullivan, A. W. Studebaker, L. F. Hendey, A. E. Axel, and B. M. Hall
Interleukin-6 is a potent growth factor for ER-{alpha}-positive human breast cancer
FASEB J,
November 1, 2007;
21(13):
3763 - 3770.
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