Effects of selective MMP‐13 inhibition in squamous cell carcinoma depend on estrogen. Issue 12 (7th August 2014)

• Record Type: Journal Article
• Authors: Meides, Alice; Gutschalk, Claudia M.; Devel, Laurent; Beau, Fabrice; Czarny, Bertrand; Hensler, Sabine; Neugebauer, Julia; Dive, Vincent; Angel, Peter; Mueller, Margareta M.
• Is Part Of: International journal of cancer. Volume 135:Issue 12(2014:Dec. 15)
• Page Start: 2749
• Page End: 2759
• Publication Date: 2014-08-07
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.28866
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Matrix metalloproteinases like MMP‐13 cleave and remodel the extracellular matrix and thereby play a crucial role in tumor progression <italic>in vivo</italic>. 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 <italic>in vitro</italic>, 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 <italic>in vivo</italic>. 17ß‐estradiol supplementation also reduced invasion and VEGF release <italic>in vitro</italic> with no additional reduction on MMP‐13 inhibitor treatment. This suggests that low 17ß‐estradiol levels in old mice <italic>in vivo</italic> 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 <italic>in vitro</italic> and <italic>in vivo</italic>.</p> </abstract>