Abstract
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.
Highlights
The members of the human chemokine superfamily build up a network contributing to cancer metastasis, survival, and proliferation
Using the in silico gene set enrichment analysis, we showed that expressions of miR-217 and miR-218 were increased in CXC chemokine receptor 4 (CXCR4) and reduced in CXCR7 cells after stimulation with SDF-1a
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
Summary
The members of the human chemokine superfamily build up a network contributing to cancer metastasis, survival, and proliferation. High expression of CXCR4 was observed in primary tumors of patients with colorectal cancer (stage IV) and correlated with a significant reduction of median overall survival due to liver metastasis [5, 6]. A gradient of SDF-1 established by secretion from cells of lymph nodes, liver, and lung into the blood flow serves as an attractant for CXCR4-expressing metastatic colorectal cancer cells that have detached from the primary tumor [1, 7, 8]. Invasive but chemosensitive CXCR4 cells faced marginally invasive but chemoresistant CXCR7 cells These opposing results for CXCR4- or CXCR7-overexpressing colon carcinoma cells demand an unexpected attention in the clinical application of chemokine receptor antagonists, especially, when it comes to therapy of metastatic disease
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