The Fractalkine-Receptor Axis Improves Human Colorectal Cancer Prognosis by Limiting Tumor Metastatic Dissemination

Human colorectal cancer (CRC) is a frequent neoplasia in Western countries, and its metastatic progression is a major cause of cancer-related death. In search of specific molecules upregulated in CRC, with possible clinical relevance, we performed a differential gene-profiling analysis in surgery-derived CRC samples and adjacent uninvolved intestinal mucosa. The chemokine CX 3 CL1 and its specific receptor CX 3 CR1 were significantly upregulated in tumors. Higher expression of CX 3 CL1 and CX 3 CR1 was confirmed by immunohistochemistry in 100 CRC tumor samples (stages I–III). Unexpectedly, high immune scores of CX 3 CL1 did not correlate with the density of tumor-infiltrating CD3 + T cells or CD68 + macrophages. Coexpression of ligand and receptor by tumor cells (axis-positive tumors) significantly associated with longer disease-free ( p = 0.01) and disease-specific survival ( p = 0.001). Conversely, axis-negative tumors (with low expression of both ligand and receptor) had increased risk of tumor relapse ( p = 0.02), and increased likelihood of metachronous metastasis ( p = 0.001), including after stage adjustment ( p = 0.006). Transduction of CX 3 CL1 and CX 3 CR1 in CRC tumor cell lines induced cell aggregation that strongly inhibited in vitro migration in chemotaxis assays. In a mouse model of spleen–liver metastases, cancer dissemination to liver was dramatically reduced in CX 3 CL1-CX 3 CR1–expressing tumors, and ligand–receptor interaction was confirmed in cancer cells in vivo by fluorescence resonance energy transfer analysis. In conclusion, tumoral expression of the CX 3 CL1-CX 3 CR1 chemokine axis functions as a retention factor, increasing homotypic cell adhesion and limiting tumor spreading to metastatic sites. Lack or low levels of expression of CX 3 CL1-CX 3 CR1 by tumor cells identifies a group of CRC patients at increased risk of metastatic progression.