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

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. [Cancer Res 2009;69(19):7884-92]

Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages

“…37 Similarly, mice deficient in CCR2, the receptor for the well-described macrophage chemoattractant CCL2, showed decreased colitis-associated carcinogenesis and decreased macrophage accumulation in the colon. 38 APC MIN/C mice deficient in CCL2 also had decreased intestinal tumorigenesis associated with decreased macrophage accumulation. 39 Furthermore, blockade of CSF-1R, the receptor for the macrophage chemoattractant CSF-1, decreased growth of transplanted MC38 colon cancers with a concomitant decrease in tumor macrophages.…”

Chemokines in tumor development and progression

“…Some research suggested that specific chemokine receptor-expressing tumor cells migrate to organs with high expression levels of the respective chemokines along a concentration gradient [37]. This hypothesis may explain the tissue tropism observed in certain [42]. Moreover, CXCL12 and a CCR7 ligand, CCL21, can reduce the sensitivity of cancer cells to anoikis, which is believed to be one of the major blocks in the metastatic spread of various types of cancer, by regulating pro-apoptotic Bmf and anti-apoptotic Bcl-xL proteins [43].…”

Chemokines, chemokine receptors and the gastrointestinal system

“…Consistent with a suppressor role for D6, lymphatic vessels expressing D6 were demonstrated in epithelium and connective tissue of both small and large intestine [172] . Using a CCR2 knockout mouse or a CCL2 antagonist, Popivanova et al [173] showed that CCL2 is a crucial mediator of colon cancer development, as mice lacking CCL2 had reduced intracolonic macrophage infiltration and COX-2 expression, attenuated neovascularization, and reduced numbers and size of colon tumors.…”

“…Plays role of sequestering several chemokines (in mouse colitis model experiment), plays suppressive role in the development and growth of vascular tumors [170,172] CCL2, CCR2 important mediator in colon tumor development [173] …”