title: Effects of selective MMP-13 inhibition in squamous cell carcinoma depend on estrogen.
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.
authors.affiliation: Group Tumor and Microenvironment, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
authors.forename: Alice
authors.initials: A
authors.lastname: Meides
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Gutschalk
authors.forename: Laurent
authors.initials: L
authors.lastname: Devel
authors.forename: Fabrice
authors.initials: F
authors.lastname: Beau
authors.forename: Bertrand
authors.initials: B
authors.lastname: Czarny
authors.forename: Sabine
authors.initials: S
authors.lastname: Hensler
authors.forename: Julia
authors.initials: J
authors.lastname: Neugebauer
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
authors.forename: Peter
authors.initials: P
authors.lastname: Angel
authors.forename: Margareta M
authors.initials: MM
authors.lastname: Mueller
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005109:Extracellular Matrix / Q000201:enzymology; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D015603:Keratinocytes / Q000166:cytology; D053509:Matrix Metalloproteinase 13 / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D004967:Estrogens; D061965:Matrix Metalloproteinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; D053509:Matrix Metalloproteinase 13
keywords: MMP-13; SCC; angiogenesis; invasion