Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 21, 2024; 30(47): 5032-5054
Published online Dec 21, 2024. doi: 10.3748/wjg.v30.i47.5032
Macrophage-derived cathepsin L promotes epithelial-mesenchymal transition and M2 polarization in gastric cancer
Lu-Xi Xiao, Xun-Jun Li, Hai-Yi Yu, Ren-Jie Qiu, Zhong-Ya Zhai, Wen-Fu Ding, Man-Sheng Zhu, Wu Zhong, Chuan-Fa Fang, Jia Yang, Tao Chen, Jiang Yu
Lu-Xi Xiao, Xun-Jun Li, Hai-Yi Yu, Ren-Jie Qiu, Zhong-Ya Zhai, Wen-Fu Ding, Man-Sheng Zhu, Tao Chen, Jiang Yu, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
Wu Zhong, Chuan-Fa Fang, Tao Chen, Department of Gastrointestinal and Hernia Surgery, Ganzhou Hospital-Nanfang Hospital, Ganzhou 341099, Jiangxi Province, China
Jia Yang, Department of Gastrointestinal Surgery, Central Hospital of Wuhan, Wuhan 430014, Hubei Province, China
Jia Yang, Department of General Surgery, Xiangyang Central Hospital, The Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, Hubei Province, China
Co-first authors: Lu-Xi Xiao and Xun-Jun Li.
Co-corresponding authors: Tao Chen and Jiang Yu.
Author contributions: Li XJ, Xiao LX, Yu J, and Chen T were responsible for the concept and design; Yu J, Chen T, Qiu RJ, Zhai ZY, Fang CF, and Zhong W were responsible for the acquisition of data, providing animals, acquiring and managing patients, providing facilities; Xiao LX, Li XJ, Yu HY, Ding WF, and Zhu MS were responsible for analysis and interpretation of data, statistical analysis, biostatistics, and computational analysis; Xiao LX and Li XJ were responsible for writing, review, and revision of the manuscript; all of the authors read and approved the final version of the manuscript to be published.
Supported by The National Natural Science Foundation of China, No. 82272087 and No. 82103150; The Guangdong Natural Science Foundation Outstanding Youth Project, China, No. 2021B1515020055; and The Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer, China, No. 2020B121201004.
Institutional review board statement: The study was reviewed and approved by The Nanfang Hospital Institutional Review Board, No. NFEC-2021-008.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by The Institutional Animal Care and Use Committee of the Animal Ethics Committee of Nanfang Hospital, China, IACUC protocol number: No. IACUC-LAC-20230717-008.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jiang Yu, MD, Adjunct Professor, Doctor, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1023 Shatai South Road, Baiyun District, Guangzhou 510515, Guangdong Province, China. balbc@163.com
Received: June 17, 2024
Revised: September 11, 2024
Accepted: October 13, 2024
Published online: December 21, 2024
Processing time: 161 Days and 22.3 Hours
Abstract
BACKGROUND

Advanced gastric tumors are extremely prone to metastasize the in 20%–30% of gastric cancer, and patients have a poor prognosis despite systemic chemotherapy. Peritoneal metastases from gastric cancer usually indicate the end stage of the disease without curative treatment.

AIM

To peritoneal metastasis for facilitating clinical therapy are urgently needed.

METHODS

Immunohistochemical staining and immunofluorescence staining were used to demonstrate the high expression of cathepsin L (CTSL) in human gastric cancer tissues and its localization in cells. Lentivirus transfection was used to construct stable cell lines. Transwell invasion assays, wound healing assays, and animal tests were used to determine the relationships between CTSL and epithelial-mesenchymal transition (EMT) and tumorigenic potential in vivo.

RESULTS

We observed that macrophage-derived CTSL promoted gastric cancer cell migration and metastasis via the EMT pathway in vitro and in vivo, which involved macrophage polarization. Our findings suggest that macrophages improve extracellular matrix remodeling and hence facilitate tumor metastasis. Ablation of CTSL in macrophages within the tumor microenvironment may improve tumor therapy and the prognosis of patients with gastric cancer peritoneal metastasis.

CONCLUSION

In consideration of our findings, tumor-associated macrophage-derived CTSL is an important factor that promotes the metastasis and invasion of gastric cancer cells, and the targeting of CTSL may potentially improve the prognosis of patients with gastric cancer with peritoneal metastasis.

Keywords: Gastric cancer; Invasion and metastasis; Epithelial-mesenchymal transition; Inflammation; Immunology; Tumor-associated macrophages; Cancer prevention

Core Tip: Advanced gastric tumors are extremely prone to metastasize into the peritoneum and herald a dismal prognosis with limited therapeutic options. Certain intraperitoneal chemotherapies have been examined, but their response is still underperforming. Discovering target molecules associated with the development of gastric cancer peritoneal metastasis (GCPM) is critical for improving clinical therapy. In our study, we revealed that tumor-associated macrophage-derived cathepsin L can significantly facilitate gastric cancer invasion and metastasis both in vitro and in vivo. Immune-related therapy may be a promising approach to improve the prognosis of patients with GCPM.