Zhenyu Zhou1,2, Yaorong Peng1,3, Xiaoying Wu4, Shiyu Meng1,5, Wei Yu1,2, Jinghua Zhao1,6, Heyun Zhang1,2, Jie Wang7, Wenbin Li8. 1. Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. 2. Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 33 Yingfeng Road, Guangzhou, 510289, China. 3. Department of Pancreaticobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 33 Yingfeng Road, Guangzhou, 510289, China. 4. Department of General Surgery, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China. 5. Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510289, China. 6. Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. 7. Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 33 Yingfeng Road, Guangzhou, 510289, China. jiewsysu@163.com. 8. Department of Pancreaticobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 33 Yingfeng Road, Guangzhou, 510289, China. gzsurgeon@163.com.
Abstract
PURPOSE: The presence of M2 macrophages within primary tumors has been correlated with a poor prognosis for many types of cancer. However, little is known about the role of M2 macrophages in gallbladder cancer (GBC). METHODS: The number of M2 macrophages in 78 GBC and 16 normal gallbladder tissue samples was assessed by immunohistochemistry. The THP-1 monocyte cell line was differentiated into M2 macrophages and co-cultured with GBC-derived cell lines. The effect of M2 macrophages on promoting GBC cell migration and invasion was analyzed using migration, invasion and scratch wound healing assays. Western blotting and real-time PCR were used to assess the expression of epithelial-mesenchymal transition (EMT) markers and the activation status of the PI3K/Akt signaling pathway in GBC cells co-cultured with THP-1-derived macrophages. RESULTS: The average number of M2 macrophages was found to be significantly higher in GBC tissues than in normal gallbladder tissues. We also found that GBC patients with higher M2 macrophage counts exhibited poorer overall survival rates. Co-culture with M2 macrophages significantly promoted the migration, invasion and EMT of GBC cells. Moreover, we found that CCL18 secreted from M2 macrophages had the same effect on GBC cells as M2 macrophages. Blocking the function of CCL18 with a neutralizing antibody reversed this effect. Finally, we found that M2 macrophages could activate PI3K/Akt signaling in GBC cells, thereby leading to migration, invasion and EMT of these cells. CONCLUSIONS: Our findings contribute to our understanding of the role of chronic inflammation in GBC development and progression, and may offer potential therapeutic targets for GBC.
PURPOSE: The presence of M2 macrophages within primary tumors has been correlated with a poor prognosis for many types of cancer. However, little is known about the role of M2 macrophages in gallbladder cancer (GBC). METHODS: The number of M2 macrophages in 78 GBC and 16 normal gallbladder tissue samples was assessed by immunohistochemistry. The THP-1 monocyte cell line was differentiated into M2 macrophages and co-cultured with GBC-derived cell lines. The effect of M2 macrophages on promoting GBC cell migration and invasion was analyzed using migration, invasion and scratch wound healing assays. Western blotting and real-time PCR were used to assess the expression of epithelial-mesenchymal transition (EMT) markers and the activation status of the PI3K/Akt signaling pathway in GBC cells co-cultured with THP-1-derived macrophages. RESULTS: The average number of M2 macrophages was found to be significantly higher in GBC tissues than in normal gallbladder tissues. We also found that GBC patients with higher M2 macrophage counts exhibited poorer overall survival rates. Co-culture with M2 macrophages significantly promoted the migration, invasion and EMT of GBC cells. Moreover, we found that CCL18 secreted from M2 macrophages had the same effect on GBC cells as M2 macrophages. Blocking the function of CCL18 with a neutralizing antibody reversed this effect. Finally, we found that M2 macrophages could activate PI3K/Akt signaling in GBC cells, thereby leading to migration, invasion and EMT of these cells. CONCLUSIONS: Our findings contribute to our understanding of the role of chronic inflammation in GBC development and progression, and may offer potential therapeutic targets for GBC.
Authors: József Dudas; Andrea Ladanyi; Julia Ingruber; Teresa Bernadette Steinbichler; Herbert Riechelmann Journal: Cells Date: 2020-02-12 Impact factor: 6.600