Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages
Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages
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DOI：
10.1080/2162402x.2016.1189052
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Gold, Jason S.
中科院分区：
文献类型：
--
作者：
Nandi, Bisweswar;Shapiro, Mia;Gold, Jason S.
炎性趋化因子CCL 20及其受体CCR 6之间的相互作用与结肠癌的发生有关;然而，这种作用背后的机制尚不清楚。我们以前已经证明，在散发性肠道肿瘤发生模型中，CCR 6的缺乏与肿瘤巨噬细胞积聚减少有关。在这项研究中，我们的目的是确定间质CCR 6的表达在小鼠同基因可移植结肠癌模型中的作用。我们发现宿主CCR 6的缺乏与表达CCR 6的同基因结肠癌的生长减少有关。过继移植到CCR 6缺陷小鼠的结肠癌减少了肿瘤相关的巨噬细胞，而血液或骨髓中单核细胞的数量没有改变。CCL 20是CCR 6的独特配体，在体外促进单核细胞的迁移，并在体内促进巨噬细胞的积累。肿瘤相关巨噬细胞的消耗降低了可移植肿瘤模型中肿瘤的生长。在该模型中浸润结肠癌的巨噬细胞分泌炎性介质CCL 2、IL-1 α、IL-6和TNF α。因此，Ccl 2、IL 1 α和IL 6在CCR 6缺陷小鼠的肿瘤中下调。CCL 2、IL-1 α和IL-6也促进结肠癌细胞的增殖，将CCL 20-CCR 6相互作用介导的巨噬细胞向肿瘤中迁移的减少与CCR 6缺陷宿主中肿瘤生长的延迟联系起来。通过CCR 6表达与巨噬细胞标志物CD 163以及CCL 2、IL 1 α和TNF α表达的相关性，证实了这些发现在人类结肠癌中的相关性。我们的研究结果支持探索靶向CCL 20-CCR 6通路治疗结肠癌。
Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been implicated in promoting colon cancer; however, the mechanisms behind this effect are poorly understood. We have previously demonstrated that deficiency of CCR6 is associated with decreased tumor macrophage accumulation in a model of sporadic intestinal tumorigenesis. In this study, we aimed to determine the role of stromal CCR6 expression in a murine syngeneic transplantable colon cancer model. We show that deficiency of host CCR6 is associated with decreased growth of syngeneic CCR6-expressing colon cancers. Colon cancers adoptively transplanted into CCR6-deficient mice have decreased tumor-associated macrophages without alterations in the number of monocytes in blood or bone marrow. CCL20, the unique ligand for CCR6, promotes migration of monocytes in vitro and promotes accumulation of macrophages in vivo. Depletion of tumor-associated macrophages decreases the growth of tumors in the transplantable tumor model. Macrophages infiltrating the colon cancers in this model secrete the inflammatory mediators CCL2, IL-1 alpha, IL-6 and TNF alpha. Ccl2, Il1 alpha and Il6 are consequently downregulated in tumors from CCR6-deficient mice. CCL2, IL-1 alpha and IL-6 also promote proliferation of colon cancer cells, linking the decreased macrophage migration into tumors mediated by CCL20-CCR6 interactions to the delay in tumor growth in CCR6-deficient hosts. The relevance of these findings in human colon cancer is demonstrated through correlation of CCR6 expression with that of the macrophage marker CD163 as well as that of CCL2, IL1 alpha and TNF alpha. Our findings support the exploration of targeting the CCL20-CCR6 pathway for the treatment of colon cancer.