Colorectal cancer expression of chemokine receptor CXCR4 promotes liver metastasis

Abstract

3582 Background: Chemokines released from organs provide homing signals to specific receptor-bearing cells, conferring migrational and invasive properties to those cells. Our hypothesis is CXCR4 expression by colorectal cancer (CRC) cells facilitates metastasis to the liver. Methods: Premalignant and malignant CRC lesions (n=90: adenoma, n=4; AJCC stages I/II, n=33; AJCC stages III/IV, n=24; liver metastases, n=29) were identified from a CRC patient database. Microarray screening mRNA analysis was performed on 6 CRC tissue specimens from different stages. Initially, these gene expression arrays were performed for profiling known chemokine receptors. Specific gene mRNAs identified by the arrays were then verified by quantitative real-time PCR (qRT) analysis in 86 patients with CRC using paraffin-embedded tissues (n=49) and frozen tissues (n=37). Subset analysis of stage I/II patients was conducted to determine whether chemokine receptor expression levels correlated with local or distant metastasis (LDM). Results: Microarray analysis revealed expression of several chemokine receptors. CXCR4 was prominent and, thus, further assessed for differential gene expression. Comparison of CXCR4 expression levels by qRT in stage I/II CRC vs. liver metastases, primary stage III/IV CRC vs. liver metastases, and primary stage I-IV CRC vs. liver metastases revealed significant upregulation of CXCR4 expression in liver metastases in all comparisons (Chi-Square; p=0.025, p=0.032, and p=0.010, respectively). Subset analysis of stage I/II patients revealed that 30% (n=3/10) of patients with high CXCR4 expression developed LDM, whereas, no patients with low expression (n=0/23) developed LDM during a mean follow-up of 39 months (p=0.022). Conclusions: SDF-1, which is the ligand for CXCR4, is highly expressed in liver and may promote homing of CXCR4 (+) CRC cells. Therefore, our study suggests CXCR4 expression on CRC cells is a potential factor for facilitating metastasis. Furthermore, our study suggests the potential metastatic disposition of CRC cells with high CXCR4 expression in stage I/II patients. No significant financial relationships to disclose.