Blockade of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice

Boryana Konstantinova Popivanova, Feodora Ivanova Kostadinova, Kengo Furuichi, Mohamed M. Shamekh, Toshikazu Kondo, Takashi Wada, Kensuke Egashira, Naofumi Mukaida

    Research output: Contribution to journalArticlepeer-review

    138 Citations (Scopus)

    Abstract

    Accumulating evidence indicates the crucial contribution of chronic inflammation to various types of carcinogenesis, including colon carcinoma associated with ulcerative colitis and asbestosis-induced malignant mesothelioma. Ulcerative colitis-associated colon carcinogenesis can be recapitulated in mice by azoxymethane administration followed by repetitive dextran sulfate sodium ingestion. In the course of this carcinogenesis process, the expression of a macrophage-tropic chemokine, CCL2, was enhanced together with intracolonic massive infiltration of macrophages, which were a major source of cyclooxygenase (COX)-2, a crucial mediator of colon carcinogenesis. Mice deficient in CCL2-specific receptor, CCR2, exhibited less macrophage infiltration and lower tumor numbers with attenuated COX-2 expression. Moreover, CCL2 antagonists decreased intracolonic macrophage infiltration and COX-2 expression, attenuated neovascularization, and eventually reduced the numbers and size of colon tumors, even when given after multiple colon tumors have developed. These observations identify CCL2 as a crucial mediator of the initiation and progression of chronic colitis-associated colon carcinogenesis and suggest that targeting CCL2 may be useful in treating colon cancers, particularly those associated with chronic inflammation.

    Original languageEnglish
    Pages (from-to)7884-7892
    Number of pages9
    JournalCancer Research
    Volume69
    Issue number19
    DOIs
    Publication statusPublished - Oct 1 2009

    All Science Journal Classification (ASJC) codes

    • Oncology
    • Cancer Research

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