Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer
Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer
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DOI：
10.1007/s10585-007-9060-3
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发表时间：
2007-04-01
影响因子：
4
通讯作者：
Darzi, Ara
中科院分区：
文献类型：
--
作者：
Bailey, Charles;Negus, Rupert;Darzi, Ara
趋化因子通过增强增殖和改变免疫应答来促进肿瘤进展。本研究的目的是检验CCL 2单核细胞趋化蛋白-1（MCP-1）通过影响肿瘤相关巨噬细胞（TAM）的数量和分布而促进结直肠癌进展的假设。用核糖核酸酶保护试验（RPA）检测大肠腺癌中趋化因子的表达。结肠腺癌细胞系用于通过酶联免疫吸附测定（ELISA）评估趋化因子产生，并且进行Boyden微量趋化性测定以确定细胞系上清液单核细胞趋化活性。通过免疫组织化学在石蜡包埋的肿瘤样品中评估CCL 2产生。最后，在相同的结直肠腺癌中确定巨噬细胞的数量及其分布，并与CCL 2表达和肿瘤分期进行比较。结果表明，CCL 2可诱导单核细胞趋化，其表达随肿瘤分期的增加而增加（P < 0.05），免疫组化结果显示CCL 2的表达定位于肿瘤细胞。对巨噬细胞浸润的分析表明，肿瘤中的积聚明显大于对照组（P < 0.005），肿瘤内坏死区域的积聚最大（中位数为44，600/mm（3））。巨噬细胞积聚随肿瘤分期增加，并与CCL 2表达相关（r（s）= 0.8）。CXCL 8白细胞介素8（IL-8），一种有效的血管生成因子和生长因子，在所有肿瘤和细胞系中表达。结论是CCL 2诱导肿瘤促进TAM在人结直肠癌中的积累，并且代表了修改巨噬细胞应答和直接免疫介导治疗的治疗靶点。
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.