机构：[1]Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, Guangdong, China[2]Department of Gastroenterology, Huizhou Municipal Central Hospital, Huizhou 516001, Guangdong, China[3]Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, Guangdong, China.[4]Department of General Surgery, Afliated Tumor Hospital of Zhengzhou University, Zhengzhou 450008, Henan, China河南省肿瘤医院[5]College of Pharmacy, Jinan University, Guangzhou 510632, Guangdong, China[6]Department of Oncology, The Second Afliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong, China.
M2-polarized tumor-associated macrophages (M2-TAMs) have been shown to correlate with the progression of various cancers, including intrahepatic cholangiocarcinoma (ICC). However, the interactions and mechanism between M2 macrophages and ICC are not completely clear. We aimed to clarify whether M2 macrophages promote the malignancy of ICC and its mechanism.
Two progressive murine models of ICC were used to evaluate the alterations in different macrophage populations and phenotypes. Furthermore, we assessed M2 macrophage infiltration in 48 human ICC and 15 normal liver samples. The protumor functions and the underlying molecular mechanisms of M2 macrophages in ICC were investigated in an in vitro coculture system.
We found that the number of M2 macrophages was significantly higher in ICC tissues than in normal bile ducts in the two murine models. M2 macrophage infiltration was highly increased in peritumoral compared with intratumoral regions and normal liver (p < 0.01). ICC cells induced macrophages to differentiate into the M2-TAM phenotype, and coculture with these M2 macrophages promoted ICC cell proliferation, invasion and epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, M2-TAM-derived IL-10 promoted the malignant properties of ICC cells through STAT3 signaling. Furthermore, blockade of IL-10/STAT3 signaling partly rescued the effects of M2 macrophages on ICC.
Our results indicated that M2-polarized macrophages induced by ICC promote tumor growth and invasiveness through IL-10/STAT3-induced EMT and might be a potential therapeutic target for ICC.
基金：
This work was supported by National Natural Science Foundation of China
(81672320 and 81871987 to Jian Hong; 81802423 to Chen Qu), Science and
Technology Program of Guangzhou, China (201704020128 to Jian Hong),
Yangcheng Scholar Program (1201561579 to Jian Hong).
第一作者机构：[1]Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, Guangdong, China[2]Department of Gastroenterology, Huizhou Municipal Central Hospital, Huizhou 516001, Guangdong, China[3]Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, Guangdong, China.
