Abstract
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.
Highlights
Colorectal cancer (CRC) is the third most common type of cancer worldwide, with more than 1.2 million new cases and over 600,000 deaths in the year 2008 [1]
We show the direct interaction of receptor for advanced glycation end products (RAGE) and recombinant S100A4 (rS100A4), leading to hyperactivation of the mitogen activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) pathway and of the hypoxia signaling pathway
In order to isolate the impact of RAGE in response to rS100A4, and to mimic the up-regulation of RAGE in cancer tissue, we ectopically overexpressed RAGE in HCT116, SW620 and DLD-1 cells.HCT116/RAGE cells showed a 12‐fold increase of RAGE mRNA expression, compared to the control cell lines HCT116 and HCT116/ vector
Summary
Colorectal cancer (CRC) is the third most common type of cancer worldwide, with more than 1.2 million new cases and over 600,000 deaths in the year 2008 [1]. The major cause for the high mortality of this disease is the formation of distant metastases. The small Ca2+ binding protein S100A4 has been reported to be highly expressed in different cancer tissues (reviewed in [3]). High S100A4 expression in tumors correlates with increased metastasis formation [4], which has been shown for CRC [5,6]. The reduction of S100A4 expression in CRC‐xenografted mice decreased the occurrence of metastases [7,8]. The occurrence www.impactjournals.com/oncotarget of S100A4 in the tumor‐stroma microenvironment aggravates metastasis formation, partially by remodeling the extracellular matrix or the recruitment of factors of the immune system [11,12,13]
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