Journal Article

DKFZ-2017-03957

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Effects of selective MMP-13 inhibition in squamous cell carcinoma depend on estrogen.

Meides, A. (First author)DKFZ* ; Gutschalk, C. M.DKFZ* ; Devel, L. ; Beau, F. ; Czarny, B. ; Hensler, S. ; Neugebauer, J.DKFZ* ; Dive, V. ; Angel, P.DKFZ* ; Mueller, M. M. (Last author)DKFZ*

2014
Wiley-Liss Bognor Regis

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Please use a persistent id in citations: doi:10.1002/ijc.28866

Abstract: 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.

Keyword(s): Estrogens ; Matrix Metalloproteinase Inhibitors ; Vascular Endothelial Growth Factor A ; Estradiol ; Matrix Metalloproteinase 13

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Contributing Institute(s):

1. Tumor- und Mikroumgebung (A101)
2. Signaltransduktion/Wachstumskontrolle (A100)

Research Program(s):

1. 311 - Signalling pathways, cell and tumor biology (POF3-311) (POF3-311)

Appears in the scientific report 2014

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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