Linking tumor associated macrophages, inflammation, and intestinal tumorigenesis: Role of MCP‐1

Abstract

Monocyte chemoattractant protein 1 (MCP‐1) is thought to be the most important chemokine for the recruitment of macrophages (MΦs) to the tumor microenvironment. We examined the role of MCP‐1 on tumor associated MΦs, inflammation, and intestinal tumorigenesis in a genetic mouse model of colon cancer. Male ApcMin/+, ApcMin/+/MCP‐1−/− or wild type mice (n=10/group) were sacrificed at 18 wks of age and intestines were analyzed for polyp burden, apoptosis, β‐catenin expression, MΦ number & phenotype, and inflammation. MCP‐1−/− decreased overall polyp number by 25% and large polyp number by 45% (P<0.05). This was consistent with an increase in apoptotic cells (P<0.05). Similarly, the number of β‐catenin positive polyps was reduced in ApcMin/+/MCP‐1−/− mice (P<0.05). MCP‐1 deficient mice showed decreased F4/80 positive cells in the polyp tissue (P=0.06) and surrounding intestinal tissue (P<0.05), and there was a decrease in CD206 mRNA expression (P<0.05). Further, MCP‐1−/− offset the increased mRNA expression of IL‐1β & IL‐6 in intestinal tissue and IL‐1β & TNF‐α in polyp tissue (P<0.05) and prevented the decrease in SOCS1 expression (P<0.05). Circulating IL‐6 levels were also decreased in MCP‐1−/− mice (P<0.05). We demonstrate that MCP‐1 is an important mediator of tumor growth and cancer‐induced inflammation and may serve as an important biomarker and/or therapeutic target in colon cancer.