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

• Published in: Carcinogenesis (New York) 2008-02, Vol.29 (2), p.404-410
• Main Authors: Werth, Christel, Stuhlmann, Dominik, Cat, Bahar, Steinbrenner, Holger, Alili, Lirija, Sies, Helmut, Brenneisen, Peter
• Format: Article
• Language: English
• Subjects: Aged, 80 and over; Antioxidants - metabolism; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Enzyme Activation; Female; Fibroblasts - metabolism; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Male; Medical sciences; Neoplasms - metabolism; Oxidative Stress; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Platelet-Derived Growth Factor - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgm296

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.