TY  - JOUR
AU  - Meides, Alice
AU  - Gutschalk, Claudia M
AU  - Devel, Laurent
AU  - Beau, Fabrice
AU  - Czarny, Bertrand
AU  - Hensler, Sabine
AU  - Neugebauer, Julia
AU  - Dive, Vincent
AU  - Angel, Peter
AU  - Mueller, Margareta M
TI  - Effects of selective MMP-13 inhibition in squamous cell carcinoma depend on estrogen.
JO  - International journal of cancer
VL  - 135
IS  - 12
SN  - 0020-7136
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2017-03957
SP  - 2749 - 2759
PY  - 2014
AB  - 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.
KW  - Estrogens (NLM Chemicals)
KW  - Matrix Metalloproteinase Inhibitors (NLM Chemicals)
KW  - Vascular Endothelial Growth Factor A (NLM Chemicals)
KW  - Estradiol (NLM Chemicals)
KW  - Matrix Metalloproteinase 13 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24676718
DO  - DOI:10.1002/ijc.28866
UR  - https://inrepo02.dkfz.de/record/127935
ER  -