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The fractalkine-receptor axis improves human colorectal cancer prognosis by limiting tumor metastatic dissemination

Journal of Immunology, ISSN: 1550-6606, Vol: 196, Issue: 2, Page: 902-914
2016
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Article Description

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 CXCL1 and its specific receptor CXCR1 were significantly upregulated in tumors. Higher expression of CXCL1 and CXCR1 was confirmed by immunohistochemistry in 100 CRC tumor samples (stages I-III). Unexpectedly, high immune scores of CXCL1 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 CXCL1 and CXCR1 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 CXCL1-CXCR1-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 CXCL1-CXCR1 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 CXCL1-CXCR1 by tumor cells identifies a group of CRC patients at increased risk of metastatic progression.

Bibliographic Details

Erreni, Marco; Siddiqui, Imran; Marelli, Giulia; Grizzi, Fabio; Bianchi, Paolo; Morone, Diego; Marchesi, Federica; Celesti, Giuseppe; Pesce, Samantha; Doni, Andrea; Rumio, Cristiano; Roncalli, Massimo G.; Laghi, Luigi; Mantovani, Alberto; Allavena, Paola

Oxford University Press (OUP)

Medicine; Immunology and Microbiology

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