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Carcinogenesis Advance Access published online on November 5, 2009
Carcinogenesis, doi:10.1093/carcin/bgp248
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

MMP13 as a stromal mediator in controlling persistent angiogenesis in skin carcinoma

Wiltrud Lederle1,4, Bettina Hartenstein2, Alice Meides1, Heike Kunzelmann1, Zena Werb3, Peter Angel2 and Margareta M. Mueller1,*

1 Group: Tumour and Microenvironment (A101), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
2 Division of Signal Transduction and Growth Control (A100), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
3 Department of Anatomy and the Biomedical Sciences Program, University of California, San Francisco, CA 94143-0452, USA
4 Experimental Molecular Imaging, University of Aachen (RWTH), Pauwelsstraße 20, 52074 Aachen, Germany

* Author for Correspondence: German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany, Phone: ++49-6221-42-4533, Fax: ++49-6221-42-4551, E-mail: Ma.Mueller{at}dkfz.de

Matrix metalloproteinases (MMPs) such as MMP13 promote tumour growth and progression by mediating ECM reorganization and regulating the biological activity of cytokines. Using Mmp13-/- mice, we demonstrate an essential role of this single collagenase for highly malignant and invasive growth in skin squamous cell carcinoma (SCC). Lack of host MMP13 strongly impaired tumour growth of malignant SCC cells, leading to small, mostly avascular cysts. While initial stromal activation in tumour transplants of Mmp13+/+ and Mmp13-/- animals was similar, MMP13 was essential for maintenance of angiogenesis and for invasion. MMP13 was induced in fibroblasts of the wildtype animals at the onset of invasion and correlated with a strong increase in VEGF protein and its association with VEGFR-2 on endothelial cells in invasive areas. In contrast, VEGF protein in the stroma was barely detectable and tumour invasion was downregulated in Mmp13-/- animals, despite ongoing VEGF mRNA expression. Taken together with in vitro data showing the release of VEGF from the ECM by MMP13 expressing fibroblasts, these data strongly suggest a crucial role of MMP13 in promoting angiogenesis via releasing VEGF from the ECM and thus allowing the invasive growth of the SCC cells.

Key Words: MMP13 • angiogenesis • VEGF • invasion • SCC

Received May 6, 2009; revised September 8, 2009; accepted October 10, 2009.


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