%0 Journal Article
%A Meides, Alice
%A Gutschalk, Claudia M
%A Devel, Laurent
%A Beau, Fabrice
%A Czarny, Bertrand
%A Hensler, Sabine
%A Neugebauer, Julia
%A Dive, Vincent
%A Angel, Peter
%A Mueller, Margareta M
%T Effects of selective MMP-13 inhibition in squamous cell carcinoma depend on estrogen.
%J International journal of cancer
%V 135
%N 12
%@ 0020-7136
%C Bognor Regis
%I Wiley-Liss
%M DKFZ-2017-03957
%P 2749 - 2759
%D 2014
%X Matrix metalloproteinases like MMP-13 cleave and remodel the extracellular matrix and thereby play a crucial role in tumor progression in vivo. Using a highly selective inhibitor to block MMP-13 protein activity, we demonstrate a striking inhibitory effect on invasive tumor growth and vascularization in murine skin squamous cell carcinoma (SCC). Therapy outcome critically depends on animal age in C57Bl/6 mice and was successful in old female but not in young female mice. Treatment success was recovered by ovariectomy in young and abolished by 17ß-estradiol supplementation in old mice, suggesting a hormone dependent inhibitor effect. Responsiveness of the tumorigenic keratinocytes BDVII and fibroblasts to 17ß-estradiol was confirmed in vitro, where MMP-13 inhibitor treatment led to a reduction of cell invasion and vascular endothelial growth factor (VEGF) release. This correlated well with a less invasive and vascularized tumor in treated mice in vivo. 17ß-estradiol supplementation also reduced invasion and VEGF release in vitro with no additional reduction on MMP-13 inhibitor treatment. This suggests that low 17ß-estradiol levels in old mice in vivo lead to enhanced MMP-13 levels and VEGF release, allowing a more effective inhibitor treatment compared to young mice. In our study, we present a strong link between lower estrogen levels in old female mice, an elevated MMP-13 level, which results in a more effective MMP-13 inhibitor treatment in fibroblasts and SCC cells in vitro and in vivo.
%K Estrogens (NLM Chemicals)
%K Matrix Metalloproteinase Inhibitors (NLM Chemicals)
%K Vascular Endothelial Growth Factor A (NLM Chemicals)
%K Estradiol (NLM Chemicals)
%K Matrix Metalloproteinase 13 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:24676718
%R 10.1002/ijc.28866
%U https://inrepo02.dkfz.de/record/127935