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  • Original Paper
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Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity

Oncogene volume 23, pages 5487–5495 (2004)Cite this article

Abstract

S100A4(mts1) protein expression has been strongly associated with metastatic tumor progression. It has been suggested as a prognostic marker for a number of human cancers. It is proposed that extracellular S100A4 accelerates cancer progression by stimulating the motility of endothelial cells, thereby promoting angiogenesis. Here we show that in 3D culture mouse endothelial cells (SVEC 4-10) respond to recombinant S100A4 by stimulating invasive growth of capillary-like structures. The outgrowth is not dependent on the stimulation of cell proliferation, but rather correlates with the transcriptional modulation of genes involved in the proteolytic degradation of extracellular matrix (ECM). Treatment of SVEC 4-10 with the S100A4 protein leads to the transcriptional activation of collagenase 3 (MMP-13) mRNA followed by subsequent release of the protein from the cells. β-Casein zymography demonstrates enhancement of proteolytic activity associated with MMP-13. This observation indicates that extracellular S100A4 stimulates the production of ECM degrading enzymes from endothelial cells, thereby stimulating the remodeling of ECM. This could explain the angiogenic and metastasis-stimulating activity of S100A4(mts1).

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Acknowledgements

We thank Claus Christensen for fruitful discussions of both the experimental design and the content of the manuscript, and Birgitte Kaas and Inge Skibshøy for excellent technical assistance. This work was supported by grants from Danish Cancer Society, Danish Research Council and Dansk Kraeftforsknings Fond.

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Authors and Affiliations

  1. Department of Molecular Cancer Biology, Institute for Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen, DK-2100, Denmark

    Birgitte Schmidt-Hansen, Dorte Örnås, Mariam Grigorian, Jörg Klingelhöfer, Eugene Tulchinsky, Eugene Lukanidin & Noona Ambartsumian

  2. Department of Cancer Studies and Molecular Medicine, Robert Kilpatrick Clinical Sciences Building, University of Leicester, Leicester, LE 7 LX, UK

    Eugene Tulchinsky

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  1. Birgitte Schmidt-Hansen
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Correspondence to Noona Ambartsumian.

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Schmidt-Hansen, B., Örnås, D., Grigorian, M. et al. Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity. Oncogene 23, 5487–5495 (2004). https://doi.org/10.1038/sj.onc.1207720

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