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

Li-Chin Cheng; Ying-Jui Chao; Chih-Yang Wang; Nam Nhut Phan; Yi-Ling Chen; Tzu-Wen Wang; Hui-Ping Hsu; Yih-Jyh Lin; Yan-Shen Shan; Ming-Derg Lai

doi:10.2147/OTT.S246714

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

Onco Targets Ther. 2020 Aug 3:13:7503-7516. doi: 10.2147/OTT.S246714. eCollection 2020.

Authors

Li-Chin Cheng¹, Ying-Jui Chao^{2

3}, Chih-Yang Wang^{4

5

6

7}, Nam Nhut Phan⁸, Yi-Ling Chen⁹, Tzu-Wen Wang², Hui-Ping Hsu^{2

10}, Yih-Jyh Lin², Yan-Shen Shan^{2

3}, Ming-Derg Lai^{4

5}

Affiliations

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

Abstract

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; bioinformatics; transforming growth factor-beta; tumor-associated macrophages.

Grants and funding

The study was supported by the Ministry of Science and Technology (MOST) of Taiwan (grants MOST108-2314-B006-082 to H.P.H.), National Cheng Kung University Hospital (grant NCKUH-10902031 to H.P.H.), and Chi Mei Medical Center (grant B106-F058E and B107-F408 to L.C.C.).