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Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(2):404-410; doi:10.1093/carcin/bgm296
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Stromal resistance of fibroblasts against oxidative damage: involvement of tumor cell-secreted platelet-derived growth factor (PDGF) and phosphoinositide 3-kinase (PI3K) activation

Christel Werth, Dominik Stuhlmann, Bahar Cat, Holger Steinbrenner, Lirija Alili, Helmut Sies and Peter Brenneisen*

Institute of Biochemistry and Molecular Biology I, Heinrich-Heine-University, D-40225 Düsseldorf, Germany

* To whom correspondence should be addressed. Tel: +49 211 811 2715; Fax: +49 211 811 3029; Email: peterbrenneisen{at}web.de

A critical step in tumor progression is the interaction of malignant and stromal cells via paracrine mechanisms. Stromal cells, particularly fibroblasts, support cancer cells in invasion of the surrounding tissue for access to the vascular system. Here, the question is addressed of whether tumor cells induce ‘stromal resistance’, i.e. protect the microenvironment from oxidative damage. The supernatant of cultured skin-derived tumor cells was added to fibroblasts and was shown to protect the fibroblasts from hydrogen peroxide-mediated cell toxicity. The platelet-derived growth factor secreted from the cancer cells was identified as trigger of this protection in fibroblasts via the phosphoinositide 3-kinase pathway. These data suggest that prosurvival signals in stromal fibroblasts as initiated by tumor cells constitute a strategy of ‘stromal resistance’, illustrating a novel biological role of fibroblasts for the tumor microenvironment.

Abbreviations: cGPx, cytosolic glutathione peroxidase; CM, conditioned medium; EGF, epidermal growth factor; HDF, human dermal fibroblasts; NHEK, normal human epidermal keratinocytes; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; SCL, squamous cell line; SFM, serum-free medium; TGF, transforming growth factor

Received September 4, 2007; revised December 17, 2007; accepted December 17, 2007.


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