Role of stromal MMP14 and MMP3 in skin homeostasis

The pleiotropic functions of MMP14 were underscored in mice with global deletion which suffered from multiple defects leading to death within three weeks after birth. Cell-type specific deletions of MMP14 enabled further analysis its functions in development and pathology. Mice with constitutive MMP14 deletion in endothelial cells (MMP14EC-/-) developed and bred normal with no obvious phenotype. However, growth and lung metastasis of B16F1 melanoma in MMP14EC-/- mice was reduced. This was accompanied by decreased vascular permeability, likely a consequence of enhanced pericytes coverage, VE-cadherin expression and reduced nitric oxide production resulting from less eNOS expression. These results indicated that endothelial-derived MMP14 may be effective in reducing melanoma metastasis and enhance vessel stabilization. In a second model mice with fibroblast-specific deletion of MMP14 (MMP14Sf-/-) developed a fibrosis-like phenotype, however cutaneous repair was normal in these mice. Protein and RNA analysis of the skin and isolated fibroblasts identified upregulated MMP3 expression in MMP14Sf-/- mice. To address the functional significance for MMP3 in that context, we generated mice with MMP3 deletion in addition to fibroblast-specific loss of MMP14 (MMP3-/-/MMP14Sf-/- mice). These mice resembled the fibrotic phenotype of MMP14Sf-/- mice. In contrast, skin repair showed delayed wound closure and enhanced granulation tissue formation in double deficient mice, accompanied by a myofibroblast phenotype in all knockout mice. In early wound myofibroblast population of the wound tissue was reduced, but persisted longer in later wounds compared to wild type mice. Although we did not find altered TGFβ1 in wound tissue, and isolated skin fibroblasts from all mice genotypes were functionally able to respond to TGFβ1 and to mechanical stimuli, we cannot exclude that in vivo release of ECM-bound TGFβ1 in single and double MMP3-/-/MMP14Sf-/- knockout mice is altered, this needs further investigations. Reduced myofibroblast clearance from later wounds was accompanied by reduced apoptosis in all knockouts. These studies provide new cell type-specific regulatory functions of MMP14 and MMP3 in mediating skin repair through the regulation of myofibroblasts homeostasis in wounds. Defense date: April 20th 202

p120ctn and P-Cadherin but Not E-Cadherin Regulate Cell Motility and Invasion of DU145 Prostate Cancer Cells

Adherens junctions consist of transmembrane cadherins, which interact intracellularly with p120ctn, beta-catenin and alpha-catenin. p120ctn is known to regulate cell-cell adhesion by increasing cadherin stability, but the effects of other adherens junction components on cell-cell adhesion have not been compared with that of p120ctn.We show that depletion of p120ctn by small interfering RNA (siRNA) in DU145 prostate cancer and MCF10A breast epithelial cells reduces the expression levels of the adherens junction proteins, E-cadherin, P-cadherin, beta-catenin and alpha-catenin, and induces loss of cell-cell adhesion. p120ctn-depleted cells also have increased migration speed and invasion, which correlates with increased Rap1 but not Rac1 or RhoA activity. Downregulation of P-cadherin, beta-catenin and alpha-catenin but not E-cadherin induces a loss of cell-cell adhesion, increased migration and enhanced invasion similar to p120ctn depletion. However, only p120ctn depletion leads to a decrease in the levels of other adherens junction proteins.Our data indicate that P-cadherin but not E-cadherin is important for maintaining adherens junctions in DU145 and MCF10A cells, and that depletion of any of the cadherin-associated proteins, p120ctn, beta-catenin or alpha-catenin, is sufficient to disrupt adherens junctions in DU145 cells and increase migration and cancer cell invasion

Trastuzumab (Herceptin (R)): Monoclonal antibody in the treatment of HER2/neu-overexpressing breast cancer in the metastatic and (neo)adjuvant situation

Trastuzumab (Herceptin (R)) is a humanized monoclonal antibody that specifically targets HER2/neu (human epidermal growth factor receptor-2) breast cancer cells, which are overexpressed in about 25-30% of breast carcinomas. After phase I and II trials, several phase III studies of trastuzumab alone or in combination with various chemotherapies were conducted. Patients with HER2/neu overexpression levels of 3+ determined by immunohistochemical assay or gene amplification (fluorescence in situ hybridization) derive most clinical benefit from trastuzumab. Taking into consideration efficacy and side effect profile, the combination of trastuzumab and paclitaxel showed an improvement of all clinical parameters, including overall survival, for the first time in the history of palliative breast cancer therapy. The application of trastuzumab has meanwhile become an established part of systemic therapy of metastastic breast cancer, and excellent data of its application in the adjuvant setting now exist (NSABP-B31, NCCTG-N9831, HERA), with significantly better relapse-free survival in the treatment arms with trastuzumab. Ongoing trials investigate the role of trastuzumab in the neoadjuvant setting. Trastuzumab is generally well tolerated. Cardiotoxicity is the main concern, thus monitoring of cardiac function is recommended

Medien der Weltbeschreibung im 16. Jahrhundert: Teil 1: Kostüm- und Trachtenbücher

Das 16. Jahrhundert ist eine Zeit des Wandels für Europa – darüber ist man sich jenseits aller berechtigten Kritik an der Epochenscheide um 1500 immer noch weithin einig. Wenn man sich auch füglich darüber streiten kann, wie sehr sich das Weltbild der Europäer in dieser Zeit wirklich verändern mag; eines ändert sich in jedem Fall: die Beschreibung der bekannten Welt. Denn die wird im 16. Jahrhundert größer. Und so verändern sich auch die Medien, in denen diese Welt beschrieben, geordnet und sich zu Eigen gemacht wird. In einer Reihe von Artikeln werden über die nächsten Ausgaben der ZEITARBEIT unterschiedliche Quellengattungen vorgestellt, in denen das besonders deutlich wird

Editorial

Ein kleines bisschen Programmatik vorweg: ZEITARBEIT – Was wir sind und was wir sein wollen