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Clin Cancer Res. 2014 Feb 1;20(3):604-16. doi: 10.1158/1078-0432.CCR-13-0582. Epub 2013 Nov 19.

The disparate twins: a comparative study of CXCR4 and CXCR7 in SDF-1α-induced gene expression, invasion and chemosensitivity of colon cancer.

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Authors' Affiliations: Molecular Oncology of Solid Tumors, DKFZ (German Cancer Research Center); Department of Translational Oncology, National Center of Tumor Diseases (NCT) and DKFZ, Heidelberg; Department of Experimental Surgery, Medical Faculty Mannheim; Department of Radiation Oncology, University Medical Centre Mannheim, Medical Faculty Mannheim; Medical Research Center, University Medical Centre Mannheim; Centre for Biomedicine and Medical Technology Mannheim (CBTM), University Medical Centre Mannheim; Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Mannheim; KIT Karlsruhe Campus Nord, Eggenstein-Leopoldshafen; and Center for Tumor Diagnostics and Therapy, Paracelsus Klinik, Osnabrueck, Germany.



In colorectal cancer, increased expression of the CXC chemokine receptor 4 (CXCR4) has been shown to provoke metastatic disease due to the interaction with its ligand stromal cell-derived factor-1 (SDF-1). Recently, a second SDF-1 receptor, CXCR7, was found to enhance tumor growth in solid tumors. Albeit signaling cascades via SDF-1/CXCR4 have been intensively studied, the significance of the SDF-1/CXCR7-induced intracellular communication triggering malignancy is still only marginally understood.


In tumor tissue of 52 patients with colorectal cancer, we observed that expression of CXCR7 and CXCR4 increased with tumor stage and tumor size. Asking whether activation of CXCR4 or CXCR7 might result in a similar expression pattern, we performed microarray expression analyses using lentivirally CXCR4- and/or CXCR7-overexpressing SW480 colon cancer cell lines with and without stimulation by SDF-1α.


Gene regulation via SDF-1α/CXCR4 and SDF-1α/CXCR7 was completely different and partly antidromic. Differentially regulated genes were assigned by gene ontology to migration, proliferation, and lipid metabolic processes. Expressions of AKR1C3, AXL, C5, IGFBP7, IL24, RRAS, and TNNC1 were confirmed by quantitative real-time PCR. Using the in silico gene set enrichment analysis, we showed that expressions of miR-217 and miR-218 were increased in CXCR4 and reduced in CXCR7 cells after stimulation with SDF-1α. Functionally, exposure to SDF-1α increased invasiveness of CXCR4 and CXCR7 cells, AXL knockdown hampered invasion. Compared with controls, CXCR4 cells showed increased sensitivity against 5-FU, whereas CXCR7 cells were more chemoresistant.


These opposing results for CXCR4- or CXCR7-overexpressing colon carcinoma cells demand an unexpected attention in the clinical application of chemokine receptor antagonists such as plerixafor.

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