CCL2 Promotes Colorectal Carcinogenesis by Enhancing Polymorphonuclear Myeloid-Derived Suppressor Cell Population and Function.
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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. |
Year of Publication | 2015
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Journal | Cell Rep
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Volume | 12
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Issue | 2
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Pages | 244-57
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Date Published | 2015 Jul 14
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ISSN | 2211-1247
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URL | |
DOI | 10.1016/j.celrep.2015.06.024
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PubMed ID | 26146082
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PubMed Central ID | PMC4620029
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Grant list | K08 AI078942 / AI / NIAID NIH HHS / United States
R01 CA154426 / CA / NCI NIH HHS / United States
K08AI078942 / AI / NIAID NIH HHS / United States
R01CA154426 / CA / NCI NIH HHS / United States
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