Table of Contents

Genetic network dynamics of cell migration and proliferation

Secreted growth factors such as GM-CSF and HGF are pivotal modulators of epithelial carcinogenesis and tissue regeneration (Breuhahn et al., 2002 Res Adv in Cancer; Breuhahn et al., 2000 Cell Growth Differ; Mann et al., 2001 Cancer Res; Mann et al., 2001 J Invest Dermatol). Especially, mesenchymal cell-derived hepatocyte growth factor (HGF) is a central regulator of epidermal wound healing. In order to analyze the pro-migratory effects of HGF on keratinocytes, we utilized heterologous cocultures combining primary human keratinocytes and genetically modified murine fibroblasts. Time-resolved expression series of keratinocytes stimulated with HGF disclosed known but also previously not described target genes regulating HGF-dependent motility (Schnickmann et al., 2009 J Invest Dermatol). In addition, by inverse modeling of kinetic gene expression data followed by experimental validation, dynamic regulatory pathways involved in the control of HGF-mediated keratinocyte migration was identified (Busch et al., 2008. Mol Syst Biol). Since efficient wound closure is based on strict spatio-temporal HGF stimulation of keratinocytes, we are currently analyzing decision making processes that discriminate between keratinocyte proliferation and migration.

Scheme showing that time ordered sequential events after growth factor stimulation of keratinocytes control cell decisions and functions

Scheme showing that time ordered sequential events after growth factor stimulation of keratinocytes control cell decisions and functions. CEACAM1: carcinoembryogenic antigen-related cell adhesion molecule1; CTGF: connective tissue growth factor; GM-CSF: granulocyte-macrophage colony stimulating factor; HGF: hepatocyte growth factor; KGF: keratinocyte growth factor; IL-1: interleukin-1; MMP: matrix metalloproteinase; PTN: pleiotrophin; SDF-1: stromal cell-derived factor-1; TGF: transforming growth factor; uPA: urokinase plasminogen activator; uPAR: uPA-receptor; VEGF: vascular endothelial growth factor.

Staff Members

Literature

• Breuhahn K, Mann A, Müller G, Wilhelmi A, Schirmacher P, Enk A, Blessing M. (2000) Epidermal overexpression of granulocyte-macrophage colony-stimulating factor induces both keratinocyte proliferation and apoptosis. Cell Growth Differ 11:111-21
• Mann A, Breuhahn K, Schirmacher P, Wilhelmi A, Beyer C, Rosenau A, Ozbek S, Rose-John S, Blessing M. (2001) Up- and down-regulation of granulocyte/macrophage-colony stimulating factor activity in murine skin increase susceptibility to skin carcinogenesis by independent mechanisms. Cancer Res 61:2311-9
• Mann A, Breuhahn K, Schirmacher P, Blessing M. (2001) Keratinocyte-derived granulocyte-macrophage colony stimulating factor accelerates wound healing: Stimulation of keratinocyte proliferation, granulation tissue formation, and vascularization. J Invest Dermatol 117:1382-90
• Breuhahn K, Kern MA, Blessing M, Schirmacher P (2002) Growth factors in the modulation of skin carcinogenesis in transgenic murine models. Res. Adv. in Cancer 2: 255-264
• Busch H, Camacho-Trullio D, Rogon Z, Breuhahn K, Angel P, Eils R, Szabowski A. (2008) Gene network dynamics controlling keratinocyte migration. Mol Syst Biol 199:1-15
• Stephanie Schnickmann, David Camacho, Michaela Bissinger, Roland Eils, Peter Angel, Peter Schirmacher, Axel Szabowski, Kai Breuhahn. (2009) AP-1 controlled hepatocyte growth factor (HGF) activation promotes keratinocyte migration via CEACAM1 and uPA/uPAR. J Invest Dermatol 129:1140-8