Wnt5a/CaMKII/ERK/CCL2 axis is required for tumor-associated macrophages to promote colorectal cancer progression
Wnt5a/CaMKII/ERK/CCL2 axis is required for tumor-associated macrophages to promote colorectal cancer progression
复制标题
Wnt5a/CaMKII/ERK/CCL2轴是肿瘤相关巨噬细胞促进结直肠癌进展所必需的
DOI：
10.7150/ijbs.40535
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发表时间：
2020-01-01
影响因子：
9.2
通讯作者：
Xiong, Bin
中科院分区：
文献类型：
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作者：
Liu, Qing;Song, Jialin;Xiong, Bin
肿瘤相关巨噬细胞（Tumor-associated macrophages，TAMs）与肿瘤的发生、侵袭和转移密切相关。然而，影响TAMs在结直肠癌（CRC）中的生物学功能的因素还不完全清楚。在此，我们发现Wnt 5a主要表达于肿瘤间质的TAM，而不表达于CRC细胞。随后，我们发现Wnt 5a（+）TAMs促进肿瘤细胞增殖和迁移，并招募巨噬细胞浸润。此外，Wnt 5a敲低损害了TAM在体内和体外的促肿瘤作用。从机制上讲，Wnt 5a在TAM中的促癌作用依赖于CaMKII-ERK途径介导的CCL 2分泌。我们的数据揭示了TAM表达的Wnt 5a通过CCL 2的旁分泌在CRC肿瘤发生中发挥的关键作用。我们首次报道了Wnt 5a/CaMKII/ERK/CCL 2轴与肿瘤微环境中TAMs生物学功能的关系，表明Wnt 5a可能是结直肠癌治疗的新靶点。
Tumor-associated macrophages (TAMs) are closely correlated with tumor occurrence, invasion, and metastasis. However, factors affecting the biological functions of TAMs in colorectal cancer (CRC) are incompletely understood. Here, we found that Wnt5a was mainly expressed on TAMs of tumor stroma but not on CRC cells. Subsequently, we found that Wnt5a(+) TAMs facilitated tumor cell proliferation and migration, and recruited macrophages infiltration. Furthermore, Wnt5a knockdown impaired the pro-tumor roles of TAMs in vivo and in vitro. Mechanistically, the cancer-promoting roles of Wnt5a in TAMs depended on CaMKII-ERK pathway-mediated CCL2 secretion. Our data reveal the crucial role played by TAM-expressed Wnt5a in CRC tumorigenesis through paracrine secretion of CCL2. We first report the connection between Wnt5a/CaMKII/ERK/CCL2 axis and biological functions of TAMs in tumor microenvironment, indicating that Wnt5a may be a novel therapeutic target for CRC.