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Cancer-Derived Transforming Growth Factor-β Modulates Tumor-Associated Macrophages in Ampullary Cancer

Authors Cheng LC, Chao YJ, Wang CY, Phan NN, Chen YL, Wang TW, Hsu HP, Lin YJ, Shan YS, Lai MD

Received 11 February 2020

Accepted for publication 14 July 2020

Published 3 August 2020 Volume 2020:13 Pages 7503—7516

DOI https://doi.org/10.2147/OTT.S246714

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Nicola Silvestris


Li-Chin Cheng,1 Ying-Jui Chao,2,3 Chih-Yang Wang,4– 7 Nam Nhut Phan,8 Yi-Ling Chen,9 Tzu-Wen Wang,2 Hui-Ping Hsu,2,10 Yih-Jyh Lin,2 Yan-Shen Shan,2,3 Ming-Derg Lai4,5

1Division of Colorectal Surgery, Department of Surgery, Chi-Mei Medical Center, Tainan 71004, Taiwan; 2Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan; 3Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; 4Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; 5Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; 6Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; 7Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; 8NTT Institute of Hi-Technology, Nguyen Tat Thanh University, Ho Chi Minh City, Vietnam; 9Senior Citizen Service Management, Chia-Nan University of Pharmacy and Science, Tainan 71710, Taiwan; 10Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA

Correspondence: Hui-Ping Hsu; Yan-Shen Shan Tel +886-6-2353535 Ext #5272
; +886-6-2353535 Ext #5272
Fax +886-6-2766676
; +886-6-2766676
Email hphsu@mail.ncku.edu.tw; ysshan@mail.ncku.edu.tw

Purpose: Tumor-associated macrophages (TAMs) originate from monocytes and differentiate into mature macrophages. The interaction between cancer cells and TAMs promotes tumor growth and suppresses immunosurveillance. However, this phenomenon has seldom been observed in ampullary cancer.
Patients and Methods: TAMs in ampullary cancer were investigated using immunohistochemical (IHC) staining of cancer tissues. Bioinformatic analysis of data from the Gene Expression Omnibus (GEO) database revealed transforming growth factor-beta (TGF-β) signaling in ampullary cancer. The complementary DNA microarray of cancer was compared with adjacent normal duodenum and enzyme-linked immunosorbent assay of serum was used to verify TGF-β signaling in patients. The THP-1 cell line was activated in vitro to imitate M2 TAMs. ClueGo and CluePedia software were operated to simulate TGF-β-related networks in ampullary cancer.
Results: The IHC study revealed that the majority of TAMs inside ampullary cancer were cluster of differentiation (CD)163+ cells and that the expression of mature CD68+ macrophages was correlated with advanced cancer stage. Bioinformatics analysis revealed that TGF-β and its downstream signaling were significantly upregulated. To verify our bioinformatics-derived predictions, we performed several experiments and demonstrated that increased TGF-β expression was detected in the cDNA microarray. Higher serum levels of TGF-β were correlated with fewer CD68+ and more inducible nitric oxide synthase macrophages in ampullary cancer. Treatment with TGF-β induced modulation of THP-1-derived macrophages.
Conclusion: The present study demonstrates that TGF-β modulates macrophage activity in ampullary cancer. Targeting TGF-β could be an approach to activating immunosurveillance.

Keywords: ampullary cancer, tumor-associated macrophages, transforming growth factor-beta, bioinformatics

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