gms | German Medical Science

125. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

22. - 25.04.2008, Berlin

Intravital analysis of tumor-induced neovascularization in matrix metalloproteinase-19-deficient mice

Meeting Abstract

  • corresponding author A. Ring - Department of Surgery, Trauma Center, University Hospital Bergmannsheil Bochum, Germany
  • R. Sedlacek - Institute of Biochemistry, Christian-Albrechts-University of Kiel, Germany
  • O. Goertz - Department of Plastic and Hand Surgery, Burn Center, Sarcoma Reference Center, University Hospital Bergmannsheil Bochum, Germany
  • G. Muhr - Department of Surgery, Trauma Center, University Hospital Bergmannsheil Bochum, Germany
  • H.U. Steinau - Department of Plastic and Hand Surgery, Burn Center, Sarcoma Reference Center, University Hospital Bergmannsheil Bochum, Germany
  • S. Langer - Department of Plastic and Hand Surgery, Burn Center, Sarcoma Reference Center, University Hospital Bergmannsheil Bochum, Germany

Deutsche Gesellschaft für Chirurgie. 125. Kongress der Deutschen Gesellschaft für Chirurgie. Berlin, 22.-25.04.2008. Düsseldorf: German Medical Science GMS Publishing House; 2008. Doc08dgch9890

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgch2008/08dgch319.shtml

Veröffentlicht: 16. April 2008

© 2008 Ring et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Introduction: Pericellular proteolysis plays an important role in angiogenesis being required for remodelling of extracellular matrix (ECM) and endothelial cell migration. Major part in initiating the angiogenesis is attributed to zinc-dependent matrix metalloproteinases (MMP). MMP mediate the degradation of endothelial and interstitial matrix and control the activity of growth factors, chemokines and cytokines. Matrix metalloproteinase-19 (MMP-19) is also supposed to regulate neovascularization, which essentially occurred in tissue regeneration and wound healing, but in tumor growth too. Studies on isolated tissue indicated that in contrast to most MMP, the MMP-19 is down-regulated during malignant transformation and dedifferentiation. However, the function of MMP-19 as mediator in vascular neo-formation is poorly understood, and the contribution of MMP-19 during angiogenic processes remains controversial. To get new insights into specific function of MMP-19 during neovascularization in vivo, the tumor-induced angiogenic response of mutant mice lacking MMP-19 was analyzed in dorsal skinfold chamber model.

Material and methods: Mice genetically deficient in MMP-19 and corresponding wild type were used. Each group contained at least eight animals. Malignant keratinocytes were seeded on the top of striated skin muscle layer. Tumor-induced angiogenesis and neovascularization were evaluated in two independent sets of experiment. Experiments were done in accordance to guidelines of the Ruhr-University of Bochum regarding the care and use of laboratory animals. Statistical analysis was done by t-test. P<0.05 was considered as significant. Tumor-induced neovascularization was analyzed according to the neo-formed perfused capillary-like microvessel. Functional vessel density (FVD) served as parameter for neovascularization. Detection of neovascularization was performed by means of intravital fluorescent microscopy. Quantitative measurements of vessel growth were achieved by computer-assisted analysis.

Results: Tumor growth and neo-formation of blood vessels occurred in both groups. Tumor induced the development of vessel sprouts that rapidly infiltrated the tumor cell seeded muscle and invaded host tissue by remodelling the mature microvasculature. Neo-formation of capillary-like vasculature was comparatively disturbed in MMP-19-proficient animals. FVD was found significantly higher in MMP-19-deficient mice. In addition, there was a markedly difference in tumor progression, increased in MMP-19-deficient animals.

Conclusion: Based on direct dynamic visualization and quantification of FVD, we provide evidence that host MMP-19-deficiency is associated with an increased angiogenic response. Accelerated capillary-like outgrowth from pre-existing microvasculature of skin muscle and increased tumor progression was observed in knock-out mice. The findings point to important role of MMP-19 in tumor-induced neovascularization. Further studies on MMP-19 may contribute to development of new anti-angiogenic strategies in cancer therapy.