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World J Stem Cells. Jan 26, 2022; 14(1): 76-91
Published online Jan 26, 2022. doi: 10.4252/wjsc.v14.i1.76
Molecular mechanism of therapeutic approaches for human gastric cancer stem cells
Hsi-Lung Hsieh, Ming-Chin Yu, Li-Ching Cheng, Ta-Sen Yeh, Ming-Ming Tsai
Hsi-Lung Hsieh, Li-Ching Cheng, Ming-Ming Tsai, Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
Hsi-Lung Hsieh, Ming-Ming Tsai, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
Hsi-Lung Hsieh, Department of Neurology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
Ming-Chin Yu, Ta-Sen Yeh, Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan
Ming-Chin Yu, Ta-Sen Yeh, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
Ming-Chin Yu, Department of General Surgery, New Taipei Municipal TuCheng Hospital, New Taipei 236, Taiwan
Ming-Ming Tsai, Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
Author contributions: All authors contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version; Hsieh HL, Yu MC and Cheng LC have contributed equally to this work.
Supported by the Ministry of Science and Technology, Taiwan, No. MOST 108-2320-B-255-002-MY3; Chang Gung Medical Research Foundation, Taoyuan, Taiwan No. CMRPF1I0031, No. CMRPF1I0041, No. CMRPF1I0041-2, and No. CMRPF1L0021; and Chang Gung University of Science and Technology, Taoyuan, Taiwan, No. ZRRPF3J0081, No. ZRRPF3K0111, and No. ZRRPF3L0091.
Conflict-of-interest statement: The author has no conflict of interest to declare.
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:
Corresponding author: Ming-Ming Tsai, PhD, Associate Professor, Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, No. 261 Wen-hwa 1 Road, Taoyuan 333, Taiwan.
Received: April 18, 2021
Peer-review started: April 18, 2021
First decision: May 12, 2021
Revised: May 15, 2021
Accepted: December 21, 2021
Article in press: December 21, 2021
Published online: January 26, 2022

Gastric cancer (GC) is a primary cause of cancer-related mortality worldwide, and even after therapeutic gastrectomy, survival rates remain poor. The presence of gastric cancer stem cells (GCSCs) is thought to be the major reason for resistance to anticancer treatment (chemotherapy or radiotherapy), and for the development of tumor recurrence, epithelial–mesenchymal transition, and metastases. Additionally, GCSCs have the capacity for self-renewal, differentiation, and tumor initiation. They also synthesize antiapoptotic factors, demonstrate higher performance of drug efflux pumps, and display cell plasticity abilities. Moreover, the tumor microenvironment (TME; tumor niche) that surrounds GCSCs contains secreted growth factors and supports angiogenesis and is thus responsible for the maintenance of the growing tumor. However, the genesis of GCSCs is unclear and exploration of the source of GCSCs is essential. In this review, we provide up-to-date information about GCSC-surface/intracellular markers and GCSC-mediated pathways and their role in tumor development. This information will support improved diagnosis, novel therapeutic approaches, and better prognosis using GCSC-targeting agents as a potentially effective treatment choice following surgical resection or in combination with chemotherapy and radiotherapy. To date, most anti-GCSC blockers when used alone have been reported as unsatisfactory anticancer agents. However, when used in combination with adjuvant therapy, treatment can improve. By providing insights into the molecular mechanisms of GCSCs associated with tumors in GC, the aim is to optimize anti-GCSCs molecular approaches for GC therapy in combination with chemotherapy, radiotherapy, or other adjuvant treatment.

Keywords: Gastric cancer stem cells, Stem cell-surface markers, Tumor niche, Tumor microenvironment

Core Tip: In recent years, cancer stem cells (CSCs) have become an extremely important subject in cancer biology. CSCs are considered to be a very small component of tumor tissues, which nevertheless have the capacity for self-renewal, differentiation, and epithelial–mesenchymal transition. CSCs can also explain the clinical phenomenon of resistance to chemotherapy or radiotherapy. Many studies have also found that CSCs are important for cancer initiation and metastasis and play a key role in cancer recurrence. Here, we review GCSC (gastric cancer stem cell)-targeting therapies in GC, including information on GCSC-surface/intracellular markers and GCSC-mediated pathways. This review also provides a brief description of the GCSC niche. Understanding the molecular mechanism of GCSC-targeting agents can help optimize the accuracy of diagnosis and prognosis and the selection of the most appropriate therapy for GC patients.