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.
SourceAvailable from: Ryu-Ichiro Hata[Show abstract] [Hide abstract]
ABSTRACT: Cancer progression involves carcinogenesis, an increase in tumour size, and metastasis. Here, we investigated the effect of overexpressed CXC chemokine ligand 14 (CXCL14) on these processes by using CXCL14/BRAK (CXCL14) transgenic (Tg) mice. The rate of AOM/DSS-induced colorectal carcinogenesis in these mice was significantly lower compared with that for isogenic wild type C57BL/6 (Wt) mice. When tumour cells were injected into these mice, the size of the tumours that developed and the number of metastatic nodules in the lungs of the animals were always significantly lower in the Tg mice than in the Wt ones. Injection of anti-asialo-GM1 antibodies to the mice before and after injection of tumour cells attenuated the suppressing effects of CXCL14 on the tumor growth and metastasis, suggesting that NK cell activity played an important role during CXCL14-mediated suppression of tumour growth and metastasis. The importance of NK cells on the metastasis was also supported when CXCL14 was expressed in B16 melanoma cells. Further, the survival rates after tumour cell injection were significantly increased for the Tg mice. As these Tg mice showed no obvious abnormality, we propose that CXCL14 to be a promising molecular target for cancer suppression/prevention. S ide effects are the most serious obstacles in the case of cancer therapeutics 1–4. Thus, prevention of cancer remains the most promising strategy for reducing its incidence and associated mortality due to this disease 5,6. Tumour progression has been shown to be largely dependent on the expression of tumour-promoting and tumour-suppressing genes, with the balance being in favour of the former at each step 7. The protein products of these oncogenes and tumour suppressor genes function as regulatory intracellular signalling molecules during this process. Recently, it was revealed that the cancer microenvironment also influences carcinogenesis and cancer progression 8,9Scientific Reports 03/2015; 5:09083. DOI:10.1038/srep09083 · 5.08 Impact Factor
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ABSTRACT: Tumour-associated macrophages (TAMs) are enriched in glioblastoma multiformes (GBMs) that contain glioma stem cells (GSCs) at the apex of their cellular hierarchy. The correlation between TAM density and glioma grade suggests a supportive role for TAMs in tumour progression. Here we interrogated the molecular link between GSCs and TAM recruitment in GBMs and demonstrated that GSCs secrete periostin (POSTN) to recruit TAMs. TAM density correlates with POSTN levels in human GBMs. Silencing POSTN in GSCs markedly reduced TAM density, inhibited tumour growth, and increased survival of mice bearing GSC-derived xenografts. We found that TAMs in GBMs are not brain-resident microglia, but mainly monocyte-derived macrophages from peripheral blood. Disrupting POSTN specifically attenuated the tumour-supportive M2 type of TAMs in xenografts. POSTN recruits TAMs through the integrin αvβ3 as blocking this signalling by an RGD peptide inhibited TAM recruitment. Our findings highlight the possibility of improving GBM treatment by targeting POSTN-mediated TAM recruitment.Nature Cell Biology 01/2015; 17(2). DOI:10.1038/ncb3090 · 20.06 Impact Factor
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ABSTRACT: p38 mitogen-activated protein kinase (MAPK) signalling has been implicated in the regulation of processes leading to cancer development and progression. Chronic inflammation is a known risk factor for tumourigenesis, yet the precise mechanism of this association remains largely unknown. The related p38αMAPK (MAPK14) proteins p38γ (MAPK12) and p38δ (MAPK13) were recently shown to modulate the immune response, although their role in tumourigenesis remains controversial and their function in inflammation-associated cancer has not been studied. We analysed the role of p38γ and p38δ in colon cancer associated to colitis, using the azoxymethane/dextran sodium sulphate colitis-associated colon cancer model in wild type (WT), p38γ-, p38δ- and p38γ/δ-deficient (p38γ/δ-/-) mice. We found that p38γ/δ deficiency significantly decreased tumour formation, in parallel with a decrease in proinflammatory cytokine and chemokine production. Analysis of leukocyte populations in p38γ/δ-/- mouse colon showed less macrophage and neutrophil recruitment than in WT mice. Furthermore, WT chimaeric mice with transplanted p38γ/δ-/- bone marrow (BM) had less tumours than WT mice transplanted with WT BM, whereas tumour number was significantly increased in p38γ/δ-/- chimaeric mice with WT BM compared to p38γ/δ-/- mice transplanted with p38γ/δ-/- BM. Together, our results establish that p38γ and p38δ are central to colitis-associated colon cancer formation through regulation of haematopoietic cell response to injury, and validate p38γ and p38δ as potential targets for cancer therapy.Cancer Research 09/2014; 74(21). DOI:10.1158/0008-5472.CAN-14-0870 · 9.28 Impact Factor