부산대학교 도서관

Human colorectal cancer (CRC) is a frequent neoplasia in Western countries, and its metastatic progression is a major cause of cancerrelated death. In search of specific molecules upregulated in CRC, with possible clinical relevance, we performed a differential geneprofiling analysis in surgery-derived CRC samples and adjacent uninvolved intestinal mucosa. The chemokine CX3CLI and its specific receptor CX3CRI were significantly upregulated in tumors. Higher expression of CX3CLI and CX3CR1 was confirmed by immunohistoehemistry in 100 CRC tumor samples (stages I-III). Unexpectedly, high immune scores of CX3CLI 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 ip = 0.01) and disease-specific survival ip = 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 ip = 0.001), including after stage adjustment (p = 0.006). Transduction of CX3CLI and CX3CRI in CRC tumor cell lines induced cell aggregation that strongly inhibited in vitro migration in chemotaxis assays. In a mouse model of spleenliver metastases, cancer dissemination to liver was dramatically reduced in CX3CLI-CX3CRI-expressing tumors, and ligandreceptor interaction was confirmed in cancer cells in vivo by fluorescence resonance energy transfer analysis. In conclusion, tumoral expression of the CX3CLI-CX3CRI 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 CX3CLI-CX3CRI by tumor cells identifies a group of CRC patients at increased risk of metastatic progression. [ABSTRACT FROM AUTHOR]