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: 9.33). 09/2009; 69(19):7884-92. DOI: 10.1158/0008-5472.CAN-09-1451
Source: PubMed


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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    • "Monocytes recruited to tumors through the CCL2-CCR2 axis are polarized to TAMs, contributing to tumor cell survival (McClellan et al., 2012). Two prior studies suggested that CCL2 increased colon tumor numbers in mice through a CCL2-CCR2-dependent recruitment of myeloid cells (McClellan et al., 2012; Popivanova et al., 2009). The complete functional repertoire of colonic CCL2 remains unclear, and whether colonic CCL2 expression is elevated in human colitis-associated CRC is unknown. "
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    ABSTRACT: Our study reveals a non-canonical role for CCL2 in modulating non-macrophage, myeloid-derived suppressor cells (MDSCs) and shaping a tumor-permissive microenvironment during colon cancer development. We found that intratumoral CCL2 levels increased in patients with colitis-associated colorectal cancer (CRC), adenocarcinomas, and adenomas. Deletion of CCL2 blocked progression from dysplasia to adenocarcinoma and reduced the number of colonic MDSCs in a spontaneous mouse model of colitis-associated CRC. In a transplantable mouse model of adenocarcinoma and an APC-driven adenoma model, CCL2 fostered MDSC accumulation in evolving colonic tumors and enhanced polymorphonuclear (PMN)-MDSC immunosuppressive features. Mechanistically, CCL2 regulated T cell suppression of PMN-MDSCs in a STAT3-mediated manner. Furthermore, CCL2 neutralization decreased tumor numbers and MDSC accumulation and function. Collectively, our experiments support that perturbing CCL2 and targeting MDSCs may afford therapeutic opportunities for colon cancer interception and prevention. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 07/2015; 19(2). DOI:10.1016/j.celrep.2015.06.024 · 8.36 Impact Factor
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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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    ABSTRACT: Chemokines were initially identified as bioactive substances, which control the trafficking of inflammatory cells including granulocytes and monocytes/macrophages. Moreover, chemokines have profound impacts on other types of cells associated with inflammatory responses, such as endothelial cells and fibroblasts. These observations would implicate chemokines as master regulators in various inflammatory responses. Subsequent studies have further revealed that chemokines can regulate the movement of a wide variety of immune cells including lymphocytes, natural killer cells, and dendritic cells in both physiological and pathological conditions. These features endow chemokines with crucial roles in immune responses. Furthermore, increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of cancer cells. It is widely acknowledged that cancer develops and progresses to invade and metastasize in continuous interaction with noncancerous cells present in cancer tissues, such as macrophages, lymphocytes, fibroblasts, and endothelial cells. The capacity of chemokines to regulate both cancerous and noncancerous cells highlights their crucial roles in cancer development and progression. Here, we will discuss the roles of chemokines in carcinogenesis and the possibility of chemokine targeting therapy for the treatment of cancer.
    Mediators of Inflammation 05/2014; 2014(5):170381. DOI:10.1155/2014/170381 · 3.24 Impact Factor
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