The Disparate Twins: A Comparative Study of CXCR4 and CXCR7 in SDF-1α–Induced Gene Expression, Invasion and Chemosensitivity of Colon Cancer

Abstract

Purpose: 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.Experimental Design: 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-1a.Results: Gene regulation via SDF-1a/CXCR4 and SDF-1a/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-1a. Functionally, exposure to SDF-1a 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.Conclusions: 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. Clin Cancer Res; 20(3); 604-16. Ó2013 AACR.

Molecular characterization of cancer-associated fibroblasts isolated from human colorectal cancer as a major stromal cell component promoting metastasis

“…An elevated level of another SDF-1 receptor, CXCR7, has been reported in CRC brain metastasis as well as in certain classes of aggressive colon tumor. [24] Thus, the expression of CXCR7 in our study could reflect the metastatic status of the CRC patient.…”

Meta-analysis of CXCR7 Expression Related to Clinical Prognosis in Cancers

“…This study was initiated from the aspect of CXCR7 expression, and its correlation with tumor grade, tumor stage, and lymph node metastasis. In cervical cancer research [30], colorectal cancer research by Xu et al [19] cutaneous squamous cell carcinoma research by Hu et al [21] renal cancer research by Wang et al [26] and gallbladder cancer research by Yao et al [27] all of these studies have consistent results for tumor grade, stage and lymph node metastasis [30][31][32][33][34]. These significant clinicopathological relative factors revealed their roles in tumor development [35][36][37][38][39][40].…”

C-X-C motif receptor 7 in gastrointestinal cancer

“…CXCR7 expression, which was mediated by TLR4, promoted tumor cell proliferation and migration in human colorectal carcinoma (38). In addition, higher rates of CXCR7 expression were confirmed in colorectal carcinoma tissues compared with those in normal tissues, and the high CXCR7 expression was associated with aggressive tumor behavior, including large tumor size, high TNM stage, high histological grade, and lymph node metastasis (38,42). Guillemot et al (39) also demonstrated that CXCR7 and its ligands were overexpressed in human colorectal cancer and that CXCR7 facilitated the progression of colon cancer in the lungs of a pulmonary metastasis mouse model.…”

“…Previous studies have demonstrated that CXCR7 is differentially expressed in colorectal cancer at the transcriptional and protein levels, as well as in the cell membrane (38)(39)(40)(41)(42)(43). CXCR7 expression increased following lipopolysaccharide treatment in the SW480 and COLO 205 colorectal carcinoma cell lines, which express Toll-like receptor 4 (TLR4)/myeloid differential protein-2.…”

“…CCX662 is in preclinical development for the treatment of glioblastoma multiforme (1). In gastrointestinal tract cancer, several preclinical studies have demonstrated that targeting the CXCR7 pathway had an antitumor activity in vitro and in vivo (33,39,42,45,46,48,54,55). Maussang et al (33) reported that CXCR7-targeting nanobodies reduced the secretion of the anti-angiogenic factor and inhibited tumor growth in head-and-neck cancer.…”