title: Fibroblast-to-myofibroblast switch is mediated by NAD(P)H oxidase generated reactive oxygen species.
abstract: Tumour-stroma interaction is a prerequisite for tumour progression in skin cancer. Hereby, a critical step in stromal function is the transition of tumour-associated fibroblasts to MFs (myofibroblasts) by growth factors, for example TGFβ (transforming growth factor beta(). In this study, the question was addressed of whether fibroblast-associated NAD(P)H oxidase (NADH/NADPH oxidase), known to be activated by TGFβ1, is involved in the fibroblast-to-MF switch. The up-regulation of αSMA (alpha smooth muscle actin), a biomarker for MFs, is mediated by a TGFβ1-dependent increase in the intracellular level of ROS (reactive oxygen species). This report demonstrates two novel aspects of the TGFβ1 signalling cascade, namely the generation of ROS due to a biphasic NAD(P)H oxidase activity and a ROS-dependent downstream activation of p38 leading to a transition of dermal fibroblasts to MFs that can be inhibited by the selective NAD(P)H oxidase inhibitor apocynin. These data suggest that inhibition of NAD(P)H oxidase activity prevents the fibroblast-to-MF switch and may be important for chemoprevention in context of a 'stromal therapy' which was described earlier.
authors.affiliation: Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany lirija.alili@web.de.
authors.forename: Lirija
authors.initials: L
authors.lastname: Alili
authors.affiliation: Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Sack
authors.affiliation: Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Puschmann
authors.affiliation: Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brenneisen
mesh_terms: D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D032446:Myoblasts / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: MAPK; NAD(P)H oxidase; TGFβ1; myofibroblast; reactive oxygen species; tumour–stroma interaction