巨噬細胞極化及尿路感染於尿路上皮癌生長進展之意義
葉信志1,2,3、吳文正1,2,3,4、黃俊農2,3、李經家1,2,3、葉碧雯2、李威明2,3,4,5、李香瑩1,2,3,4、錢祖明2
1高雄市立大同醫院 泌尿科；2高雄醫學大學附設中和紀念醫院 泌尿部；3高雄醫學大學 醫學系泌尿學科；4高雄醫學大學 醫學研究所；5衛生福利部屏東醫院 泌尿科
The implication of macrophage polarization and urinary tract infection in development and progression of urothelial carcinoma
Hsin-Chih Yeh1,2,3, Wen-Jeng Wu1,2,3,4, Chun-Nung Huang2,3, Ching-Chia Li1,2,3, Bi-Wen Yeh2, Wei-Ming Li2,3,4,5, Hsiang-Ying Lee1,2,3,4, Tsu-Ming Chien2
1Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; 2Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 3Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 5Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan
Purpose: Inflammation and infection have been shown to be implicated in carcinogenesis, and protective effects against cancer can be stimulated by activation of immune responses. Among cells of the human immunity, macrophage is a potency immune effector cell. Macrophage is driven differentiated into classically type I (M1) or alternatively type II (M2) by environmental factors to mediate immune responses. We aim to exam the impact of macrophage polarization and urinary tract infection on the development and progression of urothelial carcinoma (UC).
Materials and Methods: We detected macrophage differentiation (M1, M2a, M2b and M2c) in peripheral blood from UC patients and healthy controls by flow cytometry. Macrophage was polarized to M1 or M2 phenotype to co-culture with UC cell lines for functional evaluation. In animal study, Sprague-Dawley rats were fed with clean water (control) or 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to induce bladder UC. A portion of BBN-fed rats received intravesical E. coli instillation twice weekly either in the beginning or after tumor development. Serum obtained from blood samples was used to analyze associated chemokines and cytokines by ELISA. Organs were harvested 8 months later and submitted for further investigation.
Results: M1 macrophage was significantly decreased in UC patients than in healthy controls (p < 0.0001), but M2 macrophages, including M2a, M2b, and M2c, were significantly increased (p < 0.0001). PM2K+CD14+ and PM2K+CD14- polarized macrophages were significantly associated with the presence of muscle-invasive and high-grade UC, respectively. When intravesical instillation was initiated after tumor formation, tumor area/weight and a number of pro-inflammatory chemokines/cytokines, including monocyte chemoattractant protein 1 (MCP-1 i.e. CCL2), monocyte chemoattractant protein 3 (MCP-3), growth-regulated oncogene α (GRO-α i.e. CXCL1), and interleukin-12 (IL-12p70), of BBN plus E. coli group were significantly elevated than those of BBN only group.
Conclusion: M1 and M2 macrophages were more depressed and predominant, respectively, in patients with UC than in people without UC. However, M1 phenotype was associated to adverse pathological features of UC but M2 phenotype may indicate minor UC stage and grade. Infection after tumor formation can enhance tumor progression by increasing M1-related chemokines or factors with pro-inflammatory properties.