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.
Clin Cancer Res. 2014 Feb 1;20(3):604-16. doi: 10.1158/1078-0432.CCR-13-0582. Epub 2013 Nov 19.
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.
在结直肠癌中，CXC 趋化因子受体 4（CXCR4）的表达增加已被证明会导致转移性疾病，这是由于其与配体基质细胞衍生因子-1（SDF-1）相互作用所致。最近，发现第二种 SDF-1 受体 CXCR7 可增强实体瘤中的肿瘤生长。尽管 SDF-1/CXCR4 的信号级联已被深入研究，但 SDF-1/CXCR7 诱导的细胞内通讯引发恶性肿瘤的意义仍知之甚少。
在 52 例结直肠癌患者的肿瘤组织中，我们观察到 CXCR7 和 CXCR4 的表达随着肿瘤分期和肿瘤大小的增加而增加。为了研究激活 CXCR4 或 CXCR7 是否会导致类似的表达模式，我们使用慢病毒过表达 CXCR4 和/或 CXCR7 的 SW480 结肠癌细胞系进行了微阵列表达分析，并用 SDF-1α 进行了刺激。
SDF-1α/CXCR4 和 SDF-1α/CXCR7 的基因调控完全不同，且部分呈反方向。通过基因本体论将差异调节的基因分配给迁移、增殖和脂质代谢过程。通过定量实时 PCR 验证了 AKR1C3、AXL、C5、IGFBP7、IL24、RRAS 和 TNNC1 的表达。通过计算机基因集富集分析，我们表明在 SDF-1α 刺激后，CXCR4 细胞的 miR-217 和 miR-218 表达增加，而 CXCR7 细胞的表达减少。功能上，SDF-1α 暴露增加了 CXCR4 和 CXCR7 细胞的侵袭性，AXL 敲低则阻碍了侵袭。与对照组相比，CXCR4 细胞对 5-FU 更敏感，而 CXCR7 细胞则更具耐药性。
这些 CXCR4 或 CXCR7 过表达结肠癌细胞的相反结果要求在趋化因子受体拮抗剂（如plerixafor）的临床应用中给予意外关注。
