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Blockade of a Chemokine, CCL2, Reduces Chronic Colitis-Associated Carcinogenesis in Mice

Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Cancer Research (Impact Factor: 9.28). 09/2009; 69(19):7884-92. DOI: 10.1158/0008-5472.CAN-09-1451
Source: PubMed

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.

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    • "In an earlier trial we showed that this kind of intervention does not lead to increased survival in a murine model of mesothelioma [36]. There are several proposed strategies to counteract the M2 macrophages, including inhibiting M2 macrophage recruitment [37], M2 macrophage depletion [38] and blocking M2 tumor-promoting activity of TAMs [39]. However, since M2 macrophages remain the plasticity for polarization [40], re-polarization from M2 to M1-type could be the ideal method to tip the balance between M1 and M2 to a tumor-hostile situation. "
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    ABSTRACT: Hypothesis The tumor micro-environment and especially the different macrophage phenotypes appear to be of great influence on the behavior of multiple tumor types. M1 skewed macrophages possess anti-tumoral capacities, while the M2 polarized macrophages have pro-tumoral capacities. We analyzed if the macrophage count and the M2 to total macrophage ratio is a discriminative marker for outcome after surgery in malignant pleural mesothelioma (MPM) and studied the prognostic value of these immunological cells. Methods 8 MPM patients who received induction chemotherapy and surgical treatment were matched on age, sex, tumor histology, TNM stage and EORTC score with 8 patients who received chemotherapy only. CD8 positive T-cells and the total macrophage count, using the CD68 pan-macrophage marker, and CD163 positive M2 macrophage count were determined in tumor specimens prior to treatment. Results The number of CD68 and CD163 cells was comparable between the surgery and the non-surgery group, and was not related to overall survival (OS) in both the surgery and non-surgery group. However, the CD163/CD68 ratio did correlate with OS in both in the total patient group (Pearson r −0.72, p<0.05). No correlation between the number of CD8 cells and prognosis was found. Conclusions The total number of macrophages in tumor tissue did not correlate with OS in both groups, however, the CD163/CD68 ratio correlates with OS in the total patient group. Our data revealed that the CD163/CD68 ratio is a potential prognostic marker in epithelioid mesothelioma patients independent of treatment but cannot be used as a predictive marker for outcome after surgery.
    PLoS ONE 09/2014; 9(9):e106742. DOI:10.1371/journal.pone.0106742 · 3.23 Impact Factor
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    • "The resultant colonic tumors contain a large number of monocytes/macrophages expressing cyclooxygenase (COX)-2, an enzyme crucially involved in colon carcinogenesis [10]. Abundant CCL2 is detected in colon tissues, and CCL2 blockade reduces the infiltration of CCR2-positive COX-2 expressing monocytes/macrophages and eventually colonic tumor development and progression [10]. "
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    Mediators of Inflammation 05/2014; 2014:170381. DOI:10.1155/2014/170381 · 3.24 Impact Factor
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    • "NF-κB is activated by TNF-α, followed by CCL2-CCR2 axis-mediated macrophages infiltration. This ultimately progresses to colon cancer [17]. Simultaneously, there is a massive infiltration of neutrophils into the lamina propria and submucosa in the progression of UC-associated colon carcinogenesis [17]. "
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    PLoS ONE 12/2012; 7(12):e51848. DOI:10.1371/journal.pone.0051848 · 3.23 Impact Factor
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