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Cancers 2016, 8(6), 59; doi:10.3390/cancers8060059

S100A4 in Cancer Metastasis: Wnt Signaling-Driven Interventions for Metastasis Restriction

1
Experimental and Clinical Research Center, Charité University Medicine, Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany
2
German Cancer Consortium, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
Academic Editors: Renée van Amerongen and Walter Birchmeier
Received: 28 April 2016 / Revised: 27 May 2016 / Accepted: 9 June 2016 / Published: 20 June 2016
(This article belongs to the Special Issue Wnt Signaling in Cancer)
View Full-Text   |   Download PDF [702 KB, uploaded 20 June 2016]   |  

Abstract

The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most lethal event during the course of the disease and is directly linked to patient survival, critically limiting successful therapy. This review focuses on our studies of the metastasis-inducing gene S100A4, which we identified as transcriptional target of β-catenin. S100A4 increased migration and invasion in vitro and metastasis in mice. In patient CRC samples, high S100A4 levels predict metastasis and reduced patient survival. Our results link pathways important for tumor progression and metastasis: the Wnt signaling pathway and S100A4, which regulates motility and invasiveness. S100A4 suppression by interdicting Wnt signaling has potential for therapeutic intervention. As proof of principle, we applied S100A4 shRNA systemically and prevented metastasis in mice. Furthermore, we identified small molecule inhibitors from high-throughput screens of pharmacologically active compounds employing an S100A4 promoter-driven reporter. Best hits act, as least in part, via intervening in the Wnt pathway and restricted metastasis in mouse models. We currently translate our findings on restricting S100A4-driven metastasis into clinical practice. The repositioned FDA-approved drug niclosamide, targeting Wnt signaling, is being tested in a prospective phase II clinical trial for treatment of CRC patients. Our assay for circulating S100A4 transcripts in patient blood is used to monitor treatment success. View Full-Text
Keywords: Wnt signaling; colorectal cancer; metastasis; S100A4; intervention Wnt signaling; colorectal cancer; metastasis; S100A4; intervention
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Dahlmann, M.; Kobelt, D.; Walther, W.; Mudduluru, G.; Stein, U. S100A4 in Cancer Metastasis: Wnt Signaling-Driven Interventions for Metastasis Restriction. Cancers 2016, 8, 59.

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