title: The Fractalkine-Receptor Axis Improves Human Colorectal Cancer Prognosis by Limiting Tumor Metastatic Dissemination.
abstract: 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 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.
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; paola.allavena@humanitasresearch.it marco.erreni@humanitasresearch.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Erreni
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy;
authors.forename: Imran
authors.initials: I
authors.lastname: Siddiqui
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy;
authors.forename: Giulia
authors.identifier: http://orcid.org/0000-0002-5688-1009
authors.initials: G
authors.lastname: Marelli
authors.affiliation: Laboratory of Gastroenterology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy;
authors.forename: Fabio
authors.initials: F
authors.lastname: Grizzi
authors.affiliation: Laboratory of Gastroenterology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Bianchi
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy;
authors.forename: Diego
authors.initials: D
authors.lastname: Morone
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy;
authors.forename: Federica
authors.initials: F
authors.lastname: Marchesi
authors.affiliation: Laboratory of Gastroenterology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Celesti
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy;
authors.forename: Samantha
authors.initials: S
authors.lastname: Pesce
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Doni
authors.affiliation: Department of Pharmacology and Biomolecular Science, University of Milan, 20133 Milan, Italy;
authors.forename: Cristiano
authors.initials: C
authors.lastname: Rumio
authors.affiliation: Humanitas University, 20089 Rozzano, Milan, Italy; and Department of Pathology, Institute for Clinical Care and Scientific Research Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
authors.forename: Massimo G
authors.initials: MG
authors.lastname: Roncalli
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; Laboratory of Gastroenterology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy;
authors.forename: Luigi
authors.initials: L
authors.lastname: Laghi
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; Humanitas University, 20089 Rozzano, Milan, Italy; and.
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; paola.allavena@humanitasresearch.it marco.erreni@humanitasresearch.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Allavena
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1 / Q000096:biosynthesis*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D019707:Receptors, Chemokine / Q000096:biosynthesis*; D059467:Transcriptome
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D019707:Receptors, Chemokine