RAGE mediates S100A4-induced cell motility via MAPK/ERK and hypoxia signaling and is a prognostic biomarker for human colorectal cancer metastasis
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Mathias Dahlmann1, Anna Okhrimenko1, Patrick Marcinkowski1, Marc Osterland1, Pia Herrmann1, Janice Smith2, Claus W. Heizmann3, Peter M. Schlag1,4, Ulrike Stein1
1 Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
2 Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
3 University Children’s Hospital, Division of Clinical Chemistry and Biochemistry, Steinwiesstrasse 75, 8032 Zürich, Switzerland
4 Charité Comprehensive Cancer Center, Charité University Medicine, Invalidenstraße 80, 10117 Berlin, Germany
Ulrike Stein, email:
Keywords: Colorectal cancer, metastasis, S100A4, RAGE, signaling
Received: February 03, 2014 Accepted: April 16, 2014 Published: April 17, 2014
Survival of colorectal cancer patients is strongly dependent on development of distant metastases. S100A4 is a prognostic biomarker and inducer for colorectal cancer metastasis. Besides exerting intracellular functions, S100A4 is secreted extracellularly. The receptor for advanced glycation end products (RAGE) is one of its interaction partners. The impact of the S100A4-RAGE interaction for cell motility and metastasis formation in colorectal cancer has not been elucidated so far. Here we demonstrate the RAGE-dependent increase in migratory and invasive capabilities of colorectal cancer cells via binding to extracellular S100A4. We show the direct interaction of S100A4 and RAGE, leading to hyperactivated MAPK/ERK and hypoxia signaling. The S100A4-RAGE axis increased cell migration (P<0.005) and invasion (P<0.005), which was counteracted with recombinant soluble RAGE and RAGE-specific antibodies. In colorectal cancer patients, not distantly metastasized at surgery, high RAGE expression in primary tumors correlated with metachronous metastasis, reduced overall (P=0.022) and metastasis-free survival (P=0.021).
In summary, interaction of S100A4-RAGE mediates S100A4-induced colorectal cancer cell motility. RAGE by itself represents a biomarker for prognosis of colorectal cancer. Thus, therapeutic approaches targeting RAGE or intervening in S100A4-RAGE-dependent signaling early in tumor progression might represent alternative strategies restricting S100A4-induced colorectal cancer metastasis.
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