The function of cancer-shed gangliosides in macrophage phenotype: involvement with angiogenesis
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Tae-Wook Chung1,2,*, Hee-Jung Choi1,2,*, Mi-Ju Park1, Hee-Jin Choi1,2, Syng-Ook Lee3, Keuk-Jun Kim4, Cheorl-Ho Kim5, Changwan Hong6, Kyun-Ha Kim2, Myungsoo Joo1,2, Ki-Tae Ha1,2
1Korean Medical Research Center for Healthy Aging and Yangsan, Gyeongsangnam-do, Republic of Korea
2School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
3Department of Food Science and Technology, Keimyung University, Daegu, Republic of Korea
4Department of Clinical Pathology, TaeKyeung University, Gyeongsan, Gyeongsangbuk-do, Republic of Korea
5Department of Biological Science, Sungkyunkwan University, Suwon, Kyunggi-do, Republic of Korea
6Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea
*These authors contributed equally to this work
Ki-Tae Ha, email: [email protected]
Keywords: ganglioside, tumor-associated macrophage, macrophage mannose receptor, monocyte chemoattractant protein-1, angiogenesis
Received: March 15, 2016 Accepted: December 05, 2016 Published: December 10, 2016
Tumor-derived gangliosides in the tumor microenvironment are involved in the malignant progression of cancer. However, the molecular mechanisms underlying the effects of gangliosides shed from tumors on macrophage phenotype remain unknown. Here, we showed that ganglioside GM1 highly induced the activity and expression of arginase-1 (Arg-1), a major M2 macrophage marker, compared to various gangliosides in bone marrow-derived macrophages (BMDM), peritoneal macrophages and Raw264.7 macrophage cells. We found that GM1 bound to macrophage mannose receptor (MMR/CD206) and common gamma chain (γc). In addition, GM1 increased Arg-1 expression through CD206 and γc-mediated activation of Janus kinase 3 (JAK3) and signal transducer and activator of transcription- 6 (STAT-6). Interestingly, GM1-stimulated macrophages secreted monocyte chemoattractant protein-1 (MCP-1/CCL2) through a CD206/γc/STAT6-mediated signaling pathway and induced angiogenesis. Moreover, the angiogenic effect of GM1-treated macrophages was diminished by RS102895, an MCP-1 receptor (CCR2) antagonist. From these results we suggest that tumor-shed ganglioside is a secretory factor regulating the phenotype of macrophages and consequently enhancing angiogenesis.
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