Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer

Abstract

Chemokines promote tumour progression by enhancing proliferation and modifying the immune response. The purpose of this study was to test the hypothesis that CCL2 monocyte chemotactic protein-1 (MCP-1) contributes to the progression of colorectal cancer by influencing the number and distribution of tumour associated macrophages (TAMs). Chemokine expression was assessed in human colorectal adenocarcinomas by ribonuclease protection assay (RPA). Colonic adenocarcinoma cell lines were used to assess chemokine production by enzyme linked immunosorbant assay (ELISA), and Boyden microchemotaxis assays were performed to determine cell line supernatant monocyte chemotactic activity. CCL2 production was assessed in paraffin embedded tumour samples by immunohistochemistry. Finally, the number of macrophages and their distribution was determined in the same colorectal adenocarcinomas and compared with CCL2 expression and tumour stage. Results showed that CCL2 produced by cell lines induced monocyte chemoattraction, the expression of this chemokine in solid cancers increased with tumour stage (P < 0.05) and immunohistochemistry localized production to tumour cells. Analysis of the macrophage infiltrate showed that the accumulation was significantly greater in tumours than controls (P < 0.005) and within tumours it was greatest in necrotic regions (median 44,600 per mm(3)). Macrophage accumulation increased with tumour stage and correlated with CCL2 expression (r(s) = 0.8). CXCL8 interleukin 8 (IL-8), a potent angiogenic factor and growth factor, was expressed in all tumours and cell lines. It is concluded that CCL2 induces the accumulation of tumour promoting TAMs in human colorectal cancer and represents a therapeutic target to modify the macrophage response and direct immune mediated therapy.

Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model

“…13,29,30 Our results are consistent with previous studies that have linked MCP-1 gene knockdown or ablation with a reduction in primary tumorigenesis in various cancer models. In a study previously conducted by our laboratory, MCP-1 deficiency resulted in a reduction of overall intestinal polyp number in a mouse model of intestinal tumorigenesis.…”

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

“…14 Furthermore, another study evaluating the prognostic role of macrophages in tumors demonstrated that accumulation of macrophages throughout human colorectal cancers, as determined by immunohistochemistry, was adversely associated with prognosis. 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.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…However, these chemokines are usually associated with pro-rather than anti-tumor activities. For example, CCL2 (MCP-1), which is overexpressed in a wide range of cancers [234], is associated with poor prognosis in breast, colorectal, cervical and thyroid cancers [235][236][237][238][239]. Tumor-derived CCL2 plays a pro-tumor role by recruiting inflammatory monocytes to pulmonary metastases [240] and MDSCs to the tumor microenvironment [241], as well as promoting angiogenesis [242], tumor cell proliferation [243] and migration [244].…”