Abstract
BackgroundInteractions between CXCR4 and its ligand CXCL12 have been shown to be involved in cancer progression in colorectal cancer (CRC). We performed a comparative CXCL12/CXCR4 expression analysis and assessed the effect of external CXCL12 stimulation on migration of CRC cells without and with CXCR4 inhibition.MethodsExpression of CXCL12/CXCR4 was assessed by quantitative real-time PCR, ELISA and immunohistochemistry in resection specimens of 50 CRC patients as well as in the corresponding normal tissues and in three human CRC cell lines with different metastatic potential (Caco-2, SW480 and HT-29). Migration assays were performed after stimulation with CXCL12 and CXCR4 was inhibited by siRNA and neutralizing antibodies.ResultsIn CRC tissues CXCL12 was significantly down-regulated and CXCR4 was significantly up-regulated compared to the corresponding normal tissues. In cell lines CXCR4 was predominantly expressed in SW480 and less pronounced in HT-29 cells. CXCL12 was only detectable in Caco-2 cells. CXCL12 stimulation had no impact on Caco-2 cells but significantly increased migration of CXCR4 bearing SW480 and HT-29 cells. This effect was significantly abrogated by neutralizing anti-CXCR4 antibody as well as by CXCR4 siRNAs (P < 0.05).ConclusionsCXCR4 expression was up-regulated in CRC and CXCL12 stimulation increased migration in CXCR4 bearing cell lines. Migration was inhibited by both neutralizing CXCR4 antibodies and CXCR4 siRNAs. Thus, the expression and functionality of CXCR4 might be associated with the metastatic potential of CRC cells and CXCL12/CXCR4 interactions might therefore constitute a promising target for specific treatment interventions.
Highlights
Interactions between CXCR4 and its ligand CXCL12 have been shown to be involved in cancer progression in colorectal cancer (CRC)
These results were verified for CXCL12 on the protein level as shown by enzyme-linked immunosorbent assays (ELISA) assays which demonstrated significant CXCL12 downregulation in CRC tissues compared to the corresponding normal tissues (Figure 1B)
Our results correlate with inhibition studies performed on SW480 cells [37], where chemotaxis induced by CXCL12 was shown to be blocked, not as complete as we have shown for both SW480 and HT-29 cells
Summary
Interactions between CXCR4 and its ligand CXCL12 have been shown to be involved in cancer progression in colorectal cancer (CRC). Various cancer-related studies demonstrated that specific chemokines and their receptors may be involved in the molecular mechanisms that control metastasis in the early stages of cancer development [2]. In this respect, the homeostatic chemokine CXCL12, a non-ELR+ CXC chemokine, has been implicated in promoting angiogenesis and metastasis [3,4]. CXCR4 expression was associated with advanced tumor stage and the development and recurrence of lymphatic or distant colorectal liver metastases (CRLM) [15,16,17]. It was shown that concomitant and high expression of CXCR4 and VEGF is a strong and independent predictor of early distant relapse in CRC [19] and recent evidence indicates that CXCR4 may play a role in tumor angiogenesis of CRC [20]
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