TY - JOUR
T1 - The fractalkine-receptor axis improves human colorectal cancer prognosis by limiting tumor metastatic dissemination
AU - Erreni, Marco
AU - Siddiqui, Imran
AU - Marelli, Giulia
AU - Grizzi, Fabio
AU - Bianchi, Paolo
AU - Morone, Diego
AU - Marchesi, Federica
AU - Celesti, Giuseppe
AU - Pesce, Samantha
AU - Doni, Andrea
AU - Rumio, Cristiano
AU - Roncalli, Massimo G.
AU - Laghi, Luigi
AU - Mantovani, Alberto
AU - Allavena, Paola
PY - 2016/1/15
Y1 - 2016/1/15
N2 - Human colorectal cancer (CRC) is a frequent neoplasia inWestern 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 CX3CL1 and its specific receptor CX3CR1 were significantly upregulated in tumors. Higher expression of CX3CL1 and CX3CR1 was confirmed by immunohistochemistry in 100 CRC tumor samples (stages I-III). Unexpectedly, high immune scores of CX3CL1 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 CX3CL1 and CX3CR1 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 CX3CL1-CX3CR1-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 CX3CL1-CX3CR1 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 CX3CL1-CX3CR1 by tumor cells identifies a group of CRC patients at increased risk of metastatic progression.
AB - Human colorectal cancer (CRC) is a frequent neoplasia inWestern 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 CX3CL1 and its specific receptor CX3CR1 were significantly upregulated in tumors. Higher expression of CX3CL1 and CX3CR1 was confirmed by immunohistochemistry in 100 CRC tumor samples (stages I-III). Unexpectedly, high immune scores of CX3CL1 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 CX3CL1 and CX3CR1 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 CX3CL1-CX3CR1-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 CX3CL1-CX3CR1 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 CX3CL1-CX3CR1 by tumor cells identifies a group of CRC patients at increased risk of metastatic progression.
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U2 - 10.4049/jimmunol.1501335
DO - 10.4049/jimmunol.1501335
M3 - Article
C2 - 26673138
AN - SCOPUS:84954124515
VL - 196
SP - 902
EP - 914
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 2
ER -