Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis
Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis
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间充质循环肿瘤细胞介导的结直肠癌转移需要癌细胞和肿瘤相关巨噬细胞之间的串扰
DOI：
10.1186/s12943-019-0976-4
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发表时间：
2019-03-30
期刊：
影响因子：
37.3
通讯作者：
Xiong, Bin
中科院分区：
文献类型：
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作者：
Wei, Chen;Yang, Chaogang;Xiong, Bin
肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）是肿瘤微环境的主要组成部分，与肿瘤转移密切相关。循环肿瘤细胞（CTC）是肿瘤转移的前体细胞，来源于肿瘤原发部位。方法采用免疫组织化学方法检测人结直肠癌（CRC）连续切片中巨噬细胞浸润（CD 68和CD 163）、上皮间质转化（EMT）标志物（E-cadherin和Vimentin）的表达。分析巨噬细胞浸润与临床病理特征、间充质CTC比例及患者预后的关系。采用体外共培养法研究TAM对大肠癌EMT、迁移和侵袭的影响，并采用ELISA、荧光素酶报告基因检测和CHIP等方法研究TAM对大肠癌EMT、迁移和侵袭的影响。此外，在体内模型进行了确认TAMs间充质CTC介导的transferation.ResultsClinically的效果，CD 163 +TAMs浸润浸润在侵袭性front与EMT，间充质CTC的比例，和预后不良的CRC患者。CRC条件化巨噬细胞通过分泌IL 6调节EMT程序增强CRC细胞的迁移和侵袭。TAM衍生的IL 6激活JAK 2/STAT 3通路，并且激活的STAT 3在转录上抑制CRC细胞中的肿瘤抑制因子miR-506- 3 p。miR-506- 3 p是一种调节FoxQ 1的关键miRNA，在CRC细胞中下调，导致FoxQ 1表达增加，进而导致CCL 2的产生，促进巨噬细胞的募集。抑制CCL 2或IL 6打破了这个循环，并减少巨噬细胞迁移和间充质CTC介导的metastasis，either.ConclusionsOur data indicates，TAM诱导EMT程序，通过调节JAK 2/STAT 3/miR-506- 3 p/FoxQ 1轴，进而导致产生促进巨噬细胞募集的CCL 2，揭示了CRC微环境中免疫细胞和肿瘤细胞之间的新的串扰。
BackgroundTumor-associated macrophages (TAMs) are major components of tumor microenvironment that frequently associated with tumor metastasis in human cancers. Circulating tumor cell (CTC), originating from primary tumor sites, is considered to be the precursors of tumor metastasis. However, the regulatory mechanism of TAMs in CTC-mediated tumor metastasis still remains unclear.MethodsImmunohistochemical staining was used to detect the macrophages infiltration (CD68 and CD163), epithelial–mesenchymal transition (EMT) markers (E-cadherin and Vimentin) expression in serial sections of human colorectal cancer (CRC) specimens. Then, the correlations between macrophages infiltration and clinicopathologic features, mesenchymal CTC ratio, and patients’ prognosis were analyzed. A co-culture assay in vitro was used to evaluate the role of TAMs on CRC EMT, migration and invasion, and ELISA, luciferase reporter assay and CHIP were performed to uncover the underlying mechanism. Furthermore, an in vivo model was carried out to confirm the effect of TAMs on mesenchymal CTC-mediated metastasis.ResultsClinically, CD163+TAMs infiltrated in invasive front was associated with EMT, mesenchymal CTC ratio, and poor prognosis in patients with CRC. CRC–conditioned macrophages regulated EMT program to enhance CRC cells migration and invasion by secreting IL6. TAMs-derived IL6 activated the JAK2/STAT3 pathway, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-506-3p in CRC cells. miR-506-3p, a key miRNA regulating FoxQ1, was downregulated in CRC cells, resulting in increased FoxQ1 expression, which in turn led to the production of CCL2 that promoted macrophage recruitment. Inhibition of CCL2 or IL6 broke this loop and reduced macrophage migration and mesenchymal CTC-mediated metastasis, respectively.ConclusionsOur data indicates that TAMs induce EMT program to enhance CRC migration, invasion, and CTC-mediated metastasis by regulating the JAK2/STAT3/miR-506-3p/FoxQ1 axis, which in turn leads to the production of CCL2 that promote macrophage recruitment, revealing a new cross-talk between immune cells and tumor cells in CRC microenvironment.