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Mol. Cells 2013; 36(5): 432-438

Published online October 24, 2013

https://doi.org/10.1007/s10059-013-0194-7

© The Korean Society for Molecular and Cellular Biology

Proangiogenic TIE2+/CD31+ Macrophages Are the Predominant Population of Tumor-Associated Macrophages Infiltrating Metastatic Lymph Nodes

Ok-Hee Kim, Gun-Hyung Kang, Hyungjoon Noh, Ji-Young Cha, Ho-Jae Lee, Jeong-Hwan Yoon, Mizuko Mamura, Jeong-Seok Nam, Dae Ho Lee, Young A Kim, Young Joo Park, Hyeonjin Kim, and Byung-Chul Oh

Lee Gil Ya Cancer and Diabetes Institute, Gachon University Graduate School of Medicine, Incheon 406-840, Korea, 1Department of Molecular Pathology, Tokyo Medical University, Tokyo160-8402, Japan, 2Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Iksan 570-749, Korea, 3Department of Pathology, Boramae Medical Center, Seoul National University College of Medicine, Seoul 156-707, Korea, 4Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea, 5Department of Radiology, Seoul National University College of Medicine, Seoul 110-744, Korea

Received: July 3, 2013; Revised: August 1, 2013; Accepted: September 3, 2013

Abstract

Tumor-associated macrophages (TAMs) accumulate in various cancers and promote tumor angiogenesis and metastasis, and thus may be ideal targets for the clinical diagnosis of tumor metastasis with high specificity. However, there are few specific markers to distinguish between TAMs and normal or inflammatory macrophages. Here, we show that TAMs localize in green fluorescent protein-labeled tumors of metastatic lymph nodes (MLNs) from B16F1 melanoma cells but not in necrotic tumor regions, suggesting that TAMs may promote the growth of tumor cells and the progression of tumor metastasis. Furthermore, we isolated pure populations of TAMs from MLNs and characterized their gene expression signatures compared to peritoneal macrophages (PMs), and found that TAMs significantly overexpress immunosuppressive cytokines such as IL-4, IL-10, and TGF ? as well as proangiogenic factors such as VEGF, TIE2, and CD31. Notably, immunological analysis revealed that TIE2+/CD31+ macrophages constitute the predominant population of TAMs that infiltrate MLNs, distinct from tissue or inflammatory macrophages. Importantly, these TIE2+/CD31+ macropha-ges also heavily infiltrated MLNs from human breast can-cer biopsies but not reactive hyperplastic LNs. Thus, TIE2+/ CD31+ macrophages may be a unique histopathological biomarker for detecting metastasis in clinical diagnosis, and a novel and promising target for TAM-specific cancer therapy.

Keywords breast cancer, melanoma, metastasis, proangiogenic macrophages, tumor-associated macrophages

Article

Research Article

Mol. Cells 2013; 36(5): 432-438

Published online November 30, 2013 https://doi.org/10.1007/s10059-013-0194-7

Copyright © The Korean Society for Molecular and Cellular Biology.

Proangiogenic TIE2+/CD31+ Macrophages Are the Predominant Population of Tumor-Associated Macrophages Infiltrating Metastatic Lymph Nodes

Ok-Hee Kim, Gun-Hyung Kang, Hyungjoon Noh, Ji-Young Cha, Ho-Jae Lee, Jeong-Hwan Yoon, Mizuko Mamura, Jeong-Seok Nam, Dae Ho Lee, Young A Kim, Young Joo Park, Hyeonjin Kim, and Byung-Chul Oh

Lee Gil Ya Cancer and Diabetes Institute, Gachon University Graduate School of Medicine, Incheon 406-840, Korea, 1Department of Molecular Pathology, Tokyo Medical University, Tokyo160-8402, Japan, 2Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Iksan 570-749, Korea, 3Department of Pathology, Boramae Medical Center, Seoul National University College of Medicine, Seoul 156-707, Korea, 4Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea, 5Department of Radiology, Seoul National University College of Medicine, Seoul 110-744, Korea

Received: July 3, 2013; Revised: August 1, 2013; Accepted: September 3, 2013

Abstract

Tumor-associated macrophages (TAMs) accumulate in various cancers and promote tumor angiogenesis and metastasis, and thus may be ideal targets for the clinical diagnosis of tumor metastasis with high specificity. However, there are few specific markers to distinguish between TAMs and normal or inflammatory macrophages. Here, we show that TAMs localize in green fluorescent protein-labeled tumors of metastatic lymph nodes (MLNs) from B16F1 melanoma cells but not in necrotic tumor regions, suggesting that TAMs may promote the growth of tumor cells and the progression of tumor metastasis. Furthermore, we isolated pure populations of TAMs from MLNs and characterized their gene expression signatures compared to peritoneal macrophages (PMs), and found that TAMs significantly overexpress immunosuppressive cytokines such as IL-4, IL-10, and TGF ? as well as proangiogenic factors such as VEGF, TIE2, and CD31. Notably, immunological analysis revealed that TIE2+/CD31+ macrophages constitute the predominant population of TAMs that infiltrate MLNs, distinct from tissue or inflammatory macrophages. Importantly, these TIE2+/CD31+ macropha-ges also heavily infiltrated MLNs from human breast can-cer biopsies but not reactive hyperplastic LNs. Thus, TIE2+/ CD31+ macrophages may be a unique histopathological biomarker for detecting metastasis in clinical diagnosis, and a novel and promising target for TAM-specific cancer therapy.

Keywords: breast cancer, melanoma, metastasis, proangiogenic macrophages, tumor-associated macrophages

Mol. Cells
Nov 30, 2023 Vol.46 No.11, pp. 655~725
COVER PICTURE
Kim et al. (pp. 710-724) demonstrated that a pathogen-derived Ralstonia pseudosolanacearum type III effector RipL delays flowering time and enhances susceptibility to bacterial infection in Arabidopsis thaliana. Shown is the RipL-expressing Arabidopsis plant, which displays general dampening of the transcriptional program during pathogen infection, grown in long-day conditions.

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