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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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Shi Y, An K, ShaoX zhou, Zhang X, Kan Q, Tian X. Integration of single-cell sequencing and bulk transcriptome data develops prognostic markers based on PCLAF + stem-like tumor cells using artificial neural network in gastric cancer. Heliyon 2024; 10:e38662. [PMID: 39524750 PMCID: PMC11547969 DOI: 10.1016/j.heliyon.2024.e38662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 08/10/2024] [Accepted: 09/26/2024] [Indexed: 11/16/2024] Open
Abstract
Background Gastric cancer stem cells (GCSCs) are important tumour cells involved in tumourigenesis and gastric cancer development. However, their clinical value remains unclear due to the limitations of the available technologies. This study aims to explore the clinical significance of GCSCs, their connection to the tumour microenvironment, and their underlying molecular mechanisms. Methods Stem-like tumour cells were identified by mining single-cell transcriptomic data from multiple samples. Integrated analysis of single-cell and bulk transcriptome data was performed to analyse the role of stem-like tumour cells in predicting clinical outcomes by introducing the intermediate variable mRNA stemness degree (SD). Consensus clustering analysis was performed to develop an SD-related molecular classification strategy to assess the clinical characteristics in gastric cancer. A prognostic model was constructed using a customized approach that comprehensively considered SD-related gene signatures based on an artificial neural network. Results By analysing single-cell data and validating immunofluorescence results, we identified a PCLAF+ stem-like tumour cell population in GC. By calculating SD, we observed that PCLAF+ stem-like tumour cells were associated with poor prognosis and certain clinical features. The SD was negatively correlated with the abundance of most immune cell types. Furthermore, we proposed an SD-related classification method and prognostic model. In addition, the customised prognostic model can be used to predict whether a patient respond to PD-1/PD-L1 immunotherapy. Conclusion We identified a cluster of stem-like cells and elucidated their clinical significance, highlighting the possibility of their use as immunotherapeutic targets.
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Affiliation(s)
- Yong Shi
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Ke An
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - ShaoX zhou
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - XuR. Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - QuanC. Kan
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Xin Tian
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, Henan, 450052, China
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Becerril-Rico J, Grandvallet-Contreras J, Ruíz-León MP, Dorantes-Cano S, Ramírez-Vidal L, Tinajero-Rodríguez JM, Ortiz-Sánchez E. Circulating Gastric Cancer Stem Cells as Blood Screening and Prognosis Factor in Gastric Cancer. Stem Cells Int 2024; 2024:9999155. [PMID: 39148939 PMCID: PMC11326876 DOI: 10.1155/2024/9999155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 06/10/2024] [Accepted: 07/11/2024] [Indexed: 08/17/2024] Open
Abstract
Gastric cancer (GC) is the fourth leading cause of cancer-related death, associated with late diagnosis and treatment resistance. Currently, screening tests for GC are not cost-effective or have low accuracy. Previously, we described an extended phenotype of gastric cancer stem cells (GCSCs; CD24+CD44+CD54+EpCAM+) that is associated with metastasis and tumor stage in GC patients. The goal of the current research is to evaluate the presence of these GCSCs in the peripheral blood of GC patients and healthy volunteers. A total of 73 blood samples were collected from 32 GC patients and 41 healthy volunteers. After peripheral blood mononuclear cell (PBMC) extraction, multiparametric flow cytometry was performed looking for GCSCs. Using clustering data through artificial intelligence (AI), we defined high/low levels of circulating GCSCs (cGCSCs) and proceeded to evaluate its association with clinical and prognostic variables. Finally, a diagnostic test analysis was performed evaluating patients and healthy volunteers. We found that cGCSCs are present in most GC patients with a mean concentration of 0.48%. The AI clustering showed two groups with different cGCSC levels and clinical characteristics. Through statistical analysis, we confirmed the association between cGCSC levels and lymph node metastasis, distant metastasis, and overall survival. The diagnostic test analysis showed sensibility, specificity, and area under the curve (AUC) of 83%, 95%, and 0.911, respectively. Our results suggest that the assessment of cGCSCs CD24+CD44+CD54+EpCAM+ could be a potential noninvasive test, with prognostic value, as well as highly sensitive and specific for screening or diagnosis of GC; however, a larger scale study will be necessary to confirm this.
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Affiliation(s)
- Jared Becerril-Rico
- Subdirección de Investigación BásicaInstituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
- Posgrado en Ciencias BiológicasUniversidad Nacional Autónoma de México, Mexico City, Mexico
| | - Julian Grandvallet-Contreras
- Subdirección de Investigación BásicaInstituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
| | - M. Patricia Ruíz-León
- Subdirección de Investigación BásicaInstituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
| | - Sebastián Dorantes-Cano
- Subdirección de Investigación BásicaInstituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
| | - Lizbeth Ramírez-Vidal
- Posgrado en Ciencias BiomédicasUniversidad Nacional Autónoma de MéxicoCircuito Exterior s/n Ciudad Universitaria, Coyoacán, Mexico City 04510, Mexico
| | - José M. Tinajero-Rodríguez
- Subdirección de Investigación BásicaInstituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
- Doctorado en Ciencias BiomédicasFacultad de Ciencias Químico BiológicasUniversidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo 39090, Guerrero, Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación BásicaInstituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
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Kashani SF, Abedini Z, Darehshouri AF, Jazi K, Bereimipour A, Malekraeisi MA, Javanshir HT, Mahmoodzadeh H, Hadjilooei F. Investigation of Molecular Mechanisms of S-1, Docetaxel and Cisplatin in Gastric Cancer with a History of Helicobacter Pylori Infection. Mol Biotechnol 2024; 66:1303-1313. [PMID: 38273052 DOI: 10.1007/s12033-023-01032-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 12/12/2023] [Indexed: 01/27/2024]
Abstract
Gastric cancer rates and fatality rates have not decreased. Gastric cancer treatment has historically included surgery (both endoscopic and open), chemotherapy, targeted therapy, and immunotherapy. One of the aggravating carriers of this cancer is Helicobacter pylori infection. Various drug combinations are used to treat gastric cancer. However, examining the molecular function of these drugs, depending on whether or not there is a history of Helicobacter pylori infection, can be a better help in the treatment of these patients. This study was designed as bioinformatics. Various datasets such as patients with gastric cancer, with and without a history of H. pylori, and chemotherapy drugs cisplatin, docetaxel, and S-1 were selected. Using Venn diagrams, the similarities between gene expression profiles were assessed and isolated. Then, selected the signal pathways, ontology of candidate genes and proteins. Then, in clinical databases, we confirmed the candidate genes and proteins. The association between gastric cancer patients with and without a history of H. pylori with chemotherapy drugs was investigated. The pathways of cellular aging, apoptosis, MAPK, and TGFβ were clearly seen. After a closer look at the ontology of genes and the relationship between proteins, we nominated important biomolecules. Accordingly, NCOR1, KIT, MITF, ESF1, ARNT2, TCF7L2, and KRR1 proteins showed an important role in these connections. Finally, NCOR1, KIT, KRR1, and ESF1 proteins showed a more prominent role in the molecular mechanisms of S-1, Docetaxel, and Cisplatin in gastric cancer associated with or without H. pylori.
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Affiliation(s)
| | - Zainab Abedini
- Medical Genomics Research Center, Tehran Medical Sciences Islamic Azad University, Tehran, Iran
| | | | - Kimia Jazi
- Student Research Committee, Faculty of Medicine, Medical University of Qom, Qom, Iran
| | - Ahmad Bereimipour
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton, TX, 76203, USA.
| | | | | | | | - Farimah Hadjilooei
- Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Peng Y, Zheng W, Chen Y, Lei X, Yang Z, Yang Y, Liang W, Sun K, Li G, Yu J. POLQ inhibition attenuates the stemness and ferroptosis resistance in gastric cancer cells via downregulation of dihydroorotate dehydrogenase. Cell Death Dis 2024; 15:248. [PMID: 38575587 PMCID: PMC10995193 DOI: 10.1038/s41419-024-06618-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 03/14/2024] [Accepted: 03/18/2024] [Indexed: 04/06/2024]
Abstract
Gastric cancer (GC) contains subpopulations of cancer stem cells (CSCs), which are described as the main contributors in tumor initiation and metastasis. It is necessary to clarify the molecular mechanism underlying CSCs phenotype and develop novel biomarkers and therapeutic targets for gastric cancer. Here, we show that POLQ positively regulates stem cell-like characteristics of gastric cancer cells, knockdown of POLQ suppressed the stemness of GC cells in vitro and in vivo. Further mechanistic studies revealed that POLQ knockdown could downregulate the expression of dihydroorotate dehydrogenase (DHODH). DHODH overexpression rescued the reduced stemness resulted by POLQ knockdown. Furthermore, we found that POLQ expression correlated with resistance to ferroptosis, and POLQ inhibition renders gastric cancer cells more vulnerable to ferroptosis. Further investigation revealed that POLQ regulated DHODH expression via the transcription factors E2F4, thereby regulating ferroptosis resistance and stemness of gastric cancer cells. Given the importance of POLQ in stemness and ferroptosis resistance of GC, we further evaluated the therapeutic potential of POLQ inhibitor novobiocin, the results show that novobiocin attenuates the stemness of GC cells and increased ferroptosis sensitivity. Moreover, the combination of POLQ inhibitor and ferroptosis inducer synergistically suppressed MGC-803 xenograft tumor growth and diminished metastasis. Our results identify a POLQ-mediated stemness and ferroptosis defense mechanism and provide a new therapeutic strategy for gastric cancer.
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Affiliation(s)
- Yanmei Peng
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Wenbo Zheng
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Yuehong Chen
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Xuetao Lei
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Zhijing Yang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Yuxuan Yang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Weiqi Liang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Kai Sun
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
| | - Guoxin Li
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
- Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China.
| | - Jiang Yu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
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Li P, Zhang Z, Sun P. DOT1L promotes expression of CD44 through the Wnt/β-catenin signaling pathway in early gastric carcinoma. J Cancer 2024; 15:2276-2291. [PMID: 38495505 PMCID: PMC10937288 DOI: 10.7150/jca.90170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 02/14/2024] [Indexed: 03/19/2024] Open
Abstract
To assess telomere silencing 1-like (DOTIL) gene expression within gastric cancer (GC) tissues as well as its function of promoting cancer stem cell (CSC)-mediated epithelial-mesenchymal switching, tissue samples from 8 patients each in 3 stages (normal, low-grade intraepithelial neoplasia (LGIN), as well as early gastric carcinoma (EGC)) were collected for whole-exome sequencing, which revealed differentially expressed genes (DEGs). The DEGs and their prognostic value were verified through TCGA and GTEx analyses. We also verified the role of DOT1L in EGC development. We collected samples from three patients each with LGIN and EGC for single-cell sequencing. We conducted single-cell transcriptomic analysis, DEG analysis, cell‒cell interaction analysis, and pseudotime analysis using R language. Sites and levels of DOT1L, CD44 and DOT1L expression were verified by IF. We found 703 deleterious mutation sites in the LGIN group and 389 deleterious mutation sites in the EGC group. The LGIN as well as EGC categories exhibited increased levels of DOT1L expression compared to the standard category (P<0.05) in TCGA and GTEx. DOT1L also correlated significantly with TMB (P=8.45E-06), MSI (P=0.001), and tumor proliferation index (P=7.17E-09) in the TCGA and GTEx datasets. In single cells, we found that DOT1L promotes CD44 expression via the Wnt/β-catenin signaling pathway and the development for stemness properties within GC. In addition, we found that DOT1L, CD44 and CTNNB1 colocalize and correlate positively. In conclusion, one important CSC regulator in GC, DOT1L may be crucial in coordinating the expression of genes specific to a certain lineage during MSC development.
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Affiliation(s)
- Ping Li
- Department of Pathology, Jiangnan University Medical Center, Wuxi, Jiangsu Province 214002, PR China
- Department of Pathology, Wuxi No.2 People's Hospital, Wuxi, Jiangsu Province 214002, PR China
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province 214002, PR China
| | - Zhou Zhang
- Department of Clinical Laboratory, Affiliated Huishan Hospital of Xinglin College, Nantong University, Wuxi Huishan District People's Hospital, Wuxi, Jiangsu Province 214000, PR China
| | - Ping Sun
- Department of Pathology, Jiangnan University Medical Center, Wuxi, Jiangsu Province 214002, PR China
- Department of Pathology, Wuxi No.2 People's Hospital, Wuxi, Jiangsu Province 214002, PR China
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province 214002, PR China
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Sinha S, Hembram KC, Chatterjee S. Targeting signaling pathways in cancer stem cells: A potential approach for developing novel anti-cancer therapeutics. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 385:157-209. [PMID: 38663959 DOI: 10.1016/bs.ircmb.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
Cancer stem cells (CSCs) have emerged as prime players in the intricate landscape of cancer development, progression, and resistance to traditional treatments. These unique cellular subpopulations own the remarkable capability of self-renewal and differentiation, giving rise to the diverse cellular makeup of tumors and fostering their recurrence following conventional therapies. In the quest for developing more effective cancer therapeutics, the focus has now shifted toward targeting the signaling pathways that govern CSCs behavior. This chapter underscores the significance of these signaling pathways in CSC biology and their potential as pivotal targets for the development of novel chemotherapy approaches. We delve into several key signaling pathways essential for maintaining the defining characteristics of CSCs, including the Wnt, Hedgehog, Notch, JAK-STAT, NF-κB pathways, among others, shedding light on their potential crosstalk. Furthermore, we highlight the latest advancements in CSC-targeted therapies, spanning from promising preclinical models to ongoing clinical trials. A comprehensive understanding of the intricate molecular aspects of CSC signaling pathways and their manipulation holds the prospective to revolutionize cancer treatment paradigms. This, in turn, could lead to more efficacious and personalized therapies with the ultimate goal of eradicating CSCs and enhancing overall patient outcomes. The exploration of CSC signaling pathways represents a key step towards a brighter future in the battle against cancer.
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Affiliation(s)
- Saptarshi Sinha
- National Institute of Biomedical Genomics, Kalyani, West Bengal, India
| | | | - Subhajit Chatterjee
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, United States.
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Xiong JX, Li YT, Tan XY, Chen T, Liu BH, Fu L. Targeting PRSS23 with tipranavir induces gastric cancer stem cell apoptosis and inhibits growth of gastric cancer via the MKK3/p38 MAPK-IL24 pathway. Acta Pharmacol Sin 2024; 45:405-421. [PMID: 37814123 PMCID: PMC10789761 DOI: 10.1038/s41401-023-01165-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 09/04/2023] [Indexed: 10/11/2023]
Abstract
Gastric cancer stem cells (GCSCs) contribute to the refractory features of gastric cancer (GC) and are responsible for metastasis, relapse, and drug resistance. The key factors drive GCSC function and affect the clinical outcome of GC patients remain poorly understood. PRSS23 is a novel serine protease that is significantly up-regulated in several types of cancers and cancer stem cells, and related to tumor progression and drug resistance. In this study, we investigated the role of PRSS23 in GCSCs as well as the mechanism by which PRSS23 regulated the GCSC functions. We demonstrated that PRSS23 was critical for sustaining GCSC survival. By screening a collection of human immunodeficiency virus (HIV) protease inhibitors (PIs), we identified tipranavir as a PRSS23-targeting drug, which effectively killed both GCSC and GC cell lines (its IC50 values were 4.7 and 6.4 μM in GCSC1 cells and GCSC2 cells, respectively). Administration of tipranavir (25 mg·kg-1·d-1, i.p., for 8 days) in GCSC-derived xenograft mice markedly inhibited the growth of subcutaneous GCSC tumors without apparent toxicity. In contrast, combined treatment with 5-FU plus cisplatin did not affect the tumor growth but causing significant weight loss. Furthermore, we revealed that tipranavir induced GCSC cell apoptosis by suppressing PRSS23 expression, releasing MKK3 from the PRSS23/MKK3 complex to activate p38 MAPK, and thereby activating the IL24-mediated Bax/Bak mitochondrial apoptotic pathway. In addition, tipranavir was found to kill other types of cancer cell lines and drug-resistant cell lines. Collectively, this study demonstrates that by targeting both GCSCs and GC cells, tipranavir is a promising anti-cancer drug, and the clinical development of tipranavir or other drugs specifically targeting the PRSS23/MKK3/p38MAPK-IL24 mitochondrial apoptotic pathway may offer an effective approach to combat gastric and other cancers.
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Affiliation(s)
- Ji-Xian Xiong
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China.
| | - Yu-Ting Li
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China
| | - Xiang-Yu Tan
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China
| | - Tie Chen
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China
| | - Bao-Hua Liu
- Department of Biochemistry, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China
| | - Li Fu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China.
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Wu Z, Huang D, Wang J, Zhao Y, Sun W, Shen X. Engineering Heterogeneous Tumor Models for Biomedical Applications. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2304160. [PMID: 37946674 PMCID: PMC10767453 DOI: 10.1002/advs.202304160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 09/16/2023] [Indexed: 11/12/2023]
Abstract
Tumor tissue engineering holds great promise for replicating the physiological and behavioral characteristics of tumors in vitro. Advances in this field have led to new opportunities for studying the tumor microenvironment and exploring potential anti-cancer therapeutics. However, the main obstacle to the widespread adoption of tumor models is the poor understanding and insufficient reconstruction of tumor heterogeneity. In this review, the current progress of engineering heterogeneous tumor models is discussed. First, the major components of tumor heterogeneity are summarized, which encompasses various signaling pathways, cell proliferations, and spatial configurations. Then, contemporary approaches are elucidated in tumor engineering that are guided by fundamental principles of tumor biology, and the potential of a bottom-up approach in tumor engineering is highlighted. Additionally, the characterization approaches and biomedical applications of tumor models are discussed, emphasizing the significant role of engineered tumor models in scientific research and clinical trials. Lastly, the challenges of heterogeneous tumor models in promoting oncology research and tumor therapy are described and key directions for future research are provided.
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Affiliation(s)
- Zhuhao Wu
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing210096China
| | - Danqing Huang
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing210096China
| | - Jinglin Wang
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing210096China
| | - Yuanjin Zhao
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing210096China
- Department of Gastrointestinal SurgeryThe First Affiliated HospitalWenzhou Medical UniversityWenzhou325035China
| | - Weijian Sun
- Department of Gastrointestinal SurgeryThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou325027China
| | - Xian Shen
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing210096China
- Department of Gastrointestinal SurgeryThe First Affiliated HospitalWenzhou Medical UniversityWenzhou325035China
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Soundararajan L, Warrier S, Dharmarajan A, Bhaskaran N. Predominant factors influencing reactive oxygen species in cancer stem cells. J Cell Biochem 2024; 125:3-21. [PMID: 37997702 DOI: 10.1002/jcb.30506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 10/17/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023]
Abstract
Reactive oxygen species (ROS) and its related signaling pathways and regulating molecules play a major role in the growth and development of cancer stem cells. The concept of ROS and cancer stem cells (CSCs) has been gaining much attention since the past decade and the evidence show that these CSCs possess robust self-renewal and tumorigenic potential and are resistant to conventional chemo- and radiotherapy and believed to be responsible for tumor progression, metastasis, and recurrence. It seems reasonable to say that cancer can be cured only if the CSCs are eradicated. ROS are Janus-faced molecules that can regulate cellular physiology as well as induce cytotoxicity, depending on the magnitude, duration, and site of generation. Unlike normal cancer cells, CSCs expel ROS efficiently by upregulating ROS scavengers. This unique redox regulation in CSCs protects them from ROS-mediated cell death and nullifies the effect of radiation, leading to chemoresistance and radioresistance. However, how these CSCs control ROS production by scavenging free radicals and how they maintain low levels of ROS is a challenging to understand and these attributes make CSCs as prime therapeutic targets. Here, we summarize the mechanisms of redox regulation in CSCs, with a focus on therapy resistance, its various pathways and microRNAs regulation, and the potential therapeutic implications of manipulating the ROS levels to eradicate CSCs. A better understanding of these molecules, their interactions in the CSCs may help us to adopt proper control and treatment measures.
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Affiliation(s)
- Loshini Soundararajan
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India
| | - Sudha Warrier
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka, India
- Cuor Stem Cellutions Pvt Ltd., Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Bangalore, Karnataka, India
- Department of Biotechnology, Sri Ramachandra Institute of Higher Education and Research, Faculty of Biomedical Sciences and Technology, Chennai, Tamil Nādu, India
| | - Arun Dharmarajan
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Faculty of Biomedical Sciences and Technology, Chennai, Tamil Nādu, India
- Stem Cell and Cancer Biology laboratory, Curtin University, Perth, Western Australia, Australia
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Western Australia, Australia
- Curtin Health and Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
- School of Human Sciences, University of Western Australia, Perth, Western Australia, Australia
| | - Natarajan Bhaskaran
- Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Faculty of Biomedical Sciences and Technology, Chennai, Tamil Nādu, India
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11
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Wang WD, Guo YY, Yang ZL, Su GL, Sun ZJ. Sniping Cancer Stem Cells with Nanomaterials. ACS NANO 2023; 17:23262-23298. [PMID: 38010076 DOI: 10.1021/acsnano.3c07828] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Cancer stem cells (CSCs) drive tumor initiation, progression, and therapeutic resistance due to their self-renewal and differentiation capabilities. Despite encouraging progress in cancer treatment, conventional approaches often fail to eliminate CSCs, necessitating the development of precise targeted strategies. Recent advances in materials science and nanotechnology have enabled promising CSC-targeted approaches, harnessing the power of tailoring nanomaterials in diverse therapeutic applications. This review provides an update on the current landscape of nanobased precision targeting approaches against CSCs. We elucidate the nuanced application of organic, inorganic, and bioinspired nanomaterials across a spectrum of therapeutic paradigms, encompassing targeted therapy, immunotherapy, and multimodal synergistic therapies. By examining the accomplishments and challenges in this potential field, we aim to inform future efforts to advance nanomaterial-based therapies toward more effective "sniping" of CSCs and tumor clearance.
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Affiliation(s)
- Wen-Da Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Yan-Yu Guo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Zhong-Lu Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Guang-Liang Su
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Zhi-Jun Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
- Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
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12
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Novikova SE, Tolstova TV, Soloveva NA, Farafonova TE, Tikhonova OV, Kurbatov LK, Rusanov AL, Zgoda VG. System analysis of surface CD markers during the process of granulocytic differentiation. BIOMEDITSINSKAIA KHIMIIA 2023; 69:383-393. [PMID: 38153053 DOI: 10.18097/pbmc20236906383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]
Abstract
Plasma membrane proteins with extracellular-exposed domains are responsible for transduction of extracellular signals into intracellular responses, and their accessibility to therapeutic molecules makes them attractive targets for drug development. In this work, using omics technologies and immunochemical methods, we have studied changes in the content of markers of clusters of differentiation (CD markers) of neutrophils (CD33, CD97, CD54, CD38, CD18, CD11b, CD44, and CD71) at the level of transcripts and proteins in NB4, HL-60 and K562 cell lines, induced by the treatment with all-trans-retinoic acid (ATRA). Transcriptomic analysis revealed the induction of CD38, CD54, CD11b, and CD18 markers as early as 3 h after the addition of the inducer in the ATRA-responsive cell lines HL-60 and NB4. After 24 h, a line-specific expression pattern of CD markers could be observed in all cell lines. Studies of changes in the content of CD antigens by means of flow cytometry and targeted mass spectrometry (MS) gave similar results. The proteomic profile of the surface markers (CD38, CD54, CD11b, and CD18), characteristic of the NB4 and HL-60 lines, reflects different molecular pathways for the implementation of ATRA-induced differentiation of leukemic cells into mature neutrophils.
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Affiliation(s)
- S E Novikova
- Institute of Biomedical Chemistry, Moscow, Russia
| | - T V Tolstova
- Institute of Biomedical Chemistry, Moscow, Russia
| | - N A Soloveva
- Institute of Biomedical Chemistry, Moscow, Russia
| | | | | | - L K Kurbatov
- Institute of Biomedical Chemistry, Moscow, Russia
| | - A L Rusanov
- Institute of Biomedical Chemistry, Moscow, Russia
| | - V G Zgoda
- Institute of Biomedical Chemistry, Moscow, Russia
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13
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Tan XY, Li YT, Li HH, Ma LX, Zeng CM, Zhang TT, Huang TX, Zhao XD, Fu L. WNT2-SOX4 positive feedback loop promotes chemoresistance and tumorigenesis by inducing stem-cell like properties in gastric cancer. Oncogene 2023; 42:3062-3074. [PMID: 37634009 DOI: 10.1038/s41388-023-02816-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 08/14/2023] [Accepted: 08/18/2023] [Indexed: 08/28/2023]
Abstract
Gastric cancer (GC) is characterized by its vigorous chemoresistance to current therapies, which is attributed to the highly heterogeneous and immature phenotype of cancer stem cells (CSCs) during tumor initiation and progression. The secretory WNT2 ligand regulates multiple cancer pathways and has been demonstrated to be a potential therapeutic target for gastrointestinal tumors; however, its role involved in gastric CSCs (GCSCs) remains unclear. Here, we found that overexpression of WNT2 enhanced stemness properties to promote chemoresistance and tumorigenicity in GCSCs. Mechanistically, WNT2 was positively regulated by its transcription factor SOX4, and in turn, SOX4 was upregulated by the canonical WNT2/FZD8/β-catenin signaling pathway to form an auto-regulatory positive feedback loop, resulting in the maintenance of GCSCs self-renewal and tumorigenicity. Furthermore, simultaneous overexpression of both WNT2 and SOX4 was correlated with poor survival and reduced responsiveness to chemotherapy in clinical GC specimens. Blocking WNT2 using a specific monoclonal antibody significantly disrupted the WNT2-SOX4 positive feedback loop in GCSCs and enhanced the chemotherapeutic efficacy when synergized with the chemo-drugs 5-fluorouracil and oxaliplatin in a GCSC-derived mouse xenograft model. Overall, this study identified a novel WNT2-SOX4 positive feedback loop as a mechanism for GCSCs-induced chemo-drugs resistance and suggested that the WNT2-SOX4 axis may be a potential therapeutic target for gastric cancer treatment.
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Affiliation(s)
- Xiang-Yu Tan
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Yu-Ting Li
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China
- Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Hua-Hui Li
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China
- Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Li-Xiang Ma
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Chui-Mian Zeng
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Tian-Tian Zhang
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Tu-Xiong Huang
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Xiao-Di Zhao
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Li Fu
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China.
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14
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Li YT, Tan XY, Ma LX, Li HH, Zhang SH, Zeng CM, Huang LN, Xiong JX, Fu L. Targeting LGSN restores sensitivity to chemotherapy in gastric cancer stem cells by triggering pyroptosis. Cell Death Dis 2023; 14:545. [PMID: 37612301 PMCID: PMC10447538 DOI: 10.1038/s41419-023-06081-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/25/2023]
Abstract
Gastric cancer (GC) is notoriously resistant to current therapies due to tumor heterogeneity. Cancer stem cells (CSCs) possess infinite self-renewal potential and contribute to the inherent heterogeneity of GC. Despite its crucial role in chemoresistance, the mechanism of stemness maintenance of gastric cancer stem cells (GCSCs) remains largely unknown. Here, we present evidence that lengsin, lens protein with glutamine synthetase domain (LGSN), a vital cell fate determinant, is overexpressed in GCSCs and is highly correlated with malignant progression and poor survival in GC patients. Ectopic overexpression of LGSN in GCSC-derived differentiated cells facilitated their dedifferentiation and treatment resistance by interacting with vimentin and inducing an epithelial-to-mesenchymal transition. Notably, genetic interference of LGSN effectively suppressed tumor formation by inhibiting GCSC stemness maintenance and provoking gasdermin-D-mediated pyroptosis through vimentin degradation/NLRP3 signaling. Depletion of LGSN combined with the chemo-drugs 5-fluorouracil and oxaliplatin could offer a unique and promising approach to synergistically rendering this deadly cancer eradicable in vivo. Our data place focus on the role of LGSN in GCSC regeneration and emphasize the critical importance of pyroptosis in battling GCSC.
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Affiliation(s)
- Yu-Ting Li
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518055, China
- Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University Medical School, Shenzhen, Guangdong, 518055, China
| | - Xiang-Yu Tan
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Li-Xiang Ma
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Hua-Hui Li
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518055, China
- Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University Medical School, Shenzhen, Guangdong, 518055, China
| | - Shu-Hong Zhang
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Chui-Mian Zeng
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Liu-Na Huang
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Ji-Xian Xiong
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518055, China.
| | - Li Fu
- Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518055, China.
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15
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Reisenauer KN, Aroujo J, Tao Y, Ranganathan S, Romo D, Taube JH. Therapeutic vulnerabilities of cancer stem cells and effects of natural products. Nat Prod Rep 2023; 40:1432-1456. [PMID: 37103550 PMCID: PMC10524555 DOI: 10.1039/d3np00002h] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Abstract
Covering: 1995 to 2022Tumors possess both genetic and phenotypic heterogeneity leading to the survival of subpopulations post-treatment. The term cancer stem cells (CSCs) describes a subpopulation that is resistant to many types of chemotherapy and which also possess enhanced migratory and anchorage-independent growth capabilities. These cells are enriched in residual tumor material post-treatment and can serve as the seed for future tumor re-growth, at both primary and metastatic sites. Elimination of CSCs is a key goal in enhancing cancer treatment and may be aided by application of natural products in conjunction with conventional treatments. In this review, we highlight molecular features of CSCs and discuss synthesis, structure-activity relationships, derivatization, and effects of six natural products with anti-CSC activity.
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Affiliation(s)
| | - Jaquelin Aroujo
- Department of Chemistry and Biochemistry, Baylor Univesrity, Waco, TX, USA
| | - Yongfeng Tao
- Department of Chemistry and Biochemistry, Baylor Univesrity, Waco, TX, USA
| | | | - Daniel Romo
- Department of Chemistry and Biochemistry, Baylor Univesrity, Waco, TX, USA
| | - Joseph H Taube
- Department of Biology, Baylor University, Waco, TX, USA.
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
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16
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Sravani A, Chandrasekaran N, Thomas J, Mukherjee A. Formulation and characterization of cisplatin-loaded hydroxyl functionalized single-walled carbon nanotubes for targeting gastric cancer stem cells. Heliyon 2023; 9:e18798. [PMID: 37593603 PMCID: PMC10432176 DOI: 10.1016/j.heliyon.2023.e18798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 07/27/2023] [Accepted: 07/27/2023] [Indexed: 08/19/2023] Open
Abstract
Chemotherapy is the most commonly used therapeutic method for treating many malignancies including gastric cancer. Due to their non-specific and non-targeted drug delivery, it causes resistance leading to cancer progression, relapse, and metastasis of cancer. To overcome this problem we carried out a study aimed to develop a new cisplatin (Cisp) loaded hydroxyl functionalized single-walled carbon nanotube (OH-SWCNT) nanocarrier system to selectively eliminate gastric cancer stem cells. To our understanding, this is the first study of the non-covalent interaction of cisplatin loaded on the surface of hydroxyl-functionalized single-walled carbon nanotubes by ultrasonication. The physical and morphological characterization was carried out by UV-Vis, FTIR spectroscopy, and TEM. A sustained and controlled release of cisp from OH-SWCNT at all three pHs 3.5, 5.5, and 7.4 was observed. Gastric cancer stem cells were isolated from primary cells and were identified by using CD133+ and CD44+ specific markers. Cisplatin-loaded OH-SWCNT nanocarrier was capable of limiting the self-renewal capacity of both CD133+ and CD44+ populations and also decreasing the number of tumorspheres in gastric CSCs. The cell viability percent of AGS cells was 20% at 250 μg/ml concentration. The IC50 value was less than 50% mol/L at both 200 μg/ml and 250 μg/ml of cisplatin-loaded OH-SWCNT. Our findings suggest that cisplatin-loaded OH-SWCNT nanocarrier complexes could target gastric CSCs and also could provide a potential strategy for selectively targeting and efficiently eliminating gastric CSCs. This could be a promising approach to prevent gastric cancer recurrence and metastasis and also improve gastric cancer therapy.
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Affiliation(s)
- A.N.K.V. Sravani
- Centre for Nanobiotechnology, Vellore Institute of Technology (VIT), Vellore, 632014, Tamil Nadu, India
| | - Natarajan Chandrasekaran
- Centre for Nanobiotechnology, Vellore Institute of Technology (VIT), Vellore, 632014, Tamil Nadu, India
| | - John Thomas
- Centre for Nanobiotechnology, Vellore Institute of Technology (VIT), Vellore, 632014, Tamil Nadu, India
| | - Amitava Mukherjee
- Centre for Nanobiotechnology, Vellore Institute of Technology (VIT), Vellore, 632014, Tamil Nadu, India
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17
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Biao L, Liu J, Hu X, Xiang W, Hou W, Li C, Wang J, Yao K, Tang J, Long Z, Long W, Liu J. Recent advances in aptamer-based therapeutic strategies for targeting cancer stem cells. Mater Today Bio 2023; 19:100605. [PMID: 36969696 PMCID: PMC10034522 DOI: 10.1016/j.mtbio.2023.100605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 03/04/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Cancer stem cells (CSCs) are believed to be the main cause of chemotherapy resistance and tumor relapse. Various therapeutic strategies to eliminate CSCs have been developed recently. Aptamers, also called "chemical antibodies", can specifically bind with their molecular targets through special tertiary structures. The advantages of aptamers, such as lower immunogenicity and smaller size, make them superior to conventional antibodies. Therefore, aptamers have been used widely as targeting ligands for CSC-targeted therapeutic strategies in different tumor types. To date, various therapeutic cargoes have been conjugated to aptamers to kill CSCs, such as chemotherapy drugs, small interfering RNAs, and microRNAs. Aptamer-based targeted therapies for CSCs have made great progress in recent years, especially the development of multifunctional aptamer-based therapeutic strategies. Besides, cell-systematic evolution of ligands by exponential enrichment has been applied to screen new aptamers that might have a higher binding ability for CSCs. In this review, we focus on recent advances and introduce some new modalities of aptamer-drug conjugates against CSCs. Some considerations of the advantages and limitations of different aptamer-based targeted therapies for CSCs are also discussed.
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18
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Gómez-Gallegos AA, Ramírez-Vidal L, Becerril-Rico J, Pérez-Islas E, Hernandez-Peralta ZJ, Toledo-Guzmán ME, García-Carrancá A, Langley E, Hernández-Guerrero A, López-Casillas F, Herrera-Goepfert R, Oñate-Ocaña LF, Ortiz-Sánchez E. CD24+CD44+CD54+EpCAM+ gastric cancer stem cells predict tumor progression and metastasis: clinical and experimental evidence. Stem Cell Res Ther 2023; 14:16. [PMID: 36737794 PMCID: PMC9898964 DOI: 10.1186/s13287-023-03241-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 01/17/2023] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. Specific and thorough identification of cancer cell subsets with higher tumorigenicity and chemoresistance, such as cancer stem cells (CSCs), could lead to the development of new and promising therapeutic targets. For better CSC identification, a complete or extended surface marker phenotype is needed to provide increased specificity for new cell targeting approaches. Our goal is to identify and characterize a putative extended phenotype for CSCs derived from patients with GC before treatment, as well as to evaluate its clinical value. In addition, we aim to ensure that cells with this phenotype have stemness and self-renewal capabilities. METHODS This is a cohort study including 127 treatment-naïve patients with GC who attended the Instituto Nacional de Cancerología. Multiparametric flow cytometry analysis was performed to determine the extended phenotype of cells derived from gastric biopsies. The tumorigenic capability of cells identified in patients was assessed in a zebrafish model. RESULTS CD24+CD44+CD54+EpCAM+ cells were present in all treatment-naïve patients included, with a median abundance of 1.16% (0.57-1.89%). The percentage of CD24+CD44+CD54+EpCAM+ cells was categorized as high or low using 1.19% as the cutoff for the CD24+CD44+CD54+EpCAM+ cell subset. Additionally, a higher TNM stage correlated with a higher percentage of CD24+CD44+CD54+EpCAM+ cells (Rho coefficient 0.369; p < 0.0001). We also demonstrated that a higher percentage of CD24+CD44+CD54+EpCAM+ cells was positively associated with metastasis. The metastatic potential of these cells was confirmed in a zebrafish model. Ultimately, under our conditions, we conclude that CD24+CD44+CD54+EpCAM+ cells are true gastric cancer stem cells (GCSCs). CONCLUSION The CD24+CD44+CD54+EpCAM+ cells present in tissue samples from patients are true GCSCs. This extended phenotype results in better and more specific characterization of these highly tumorigenic cells. The relative quantification of CD24+CD44+CD54+EpCAM+ cells has potential clinical value, as these cells are associated with metastatic disease, making their presence an additional prognostic marker and possibly a target for the design of new antineoplastic treatments in the era of precision oncology. Overall, the extended CD24+CD44+CD54+EpCAM+ phenotype of GCSCs could support their isolation for the study of their stemness mechanisms, leading to the identification of better molecular targets for the development of both new therapeutic approaches such as oncoimmunotherapy and new diagnostic and clinical prognostic strategies for GC.
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Affiliation(s)
- Angel A Gómez-Gallegos
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Edificio A, 1° Piso, Circuito de Posgrados, Ciudad Universitaria, C.P. 04510, Coyoacán, Distrito Federal, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Lizbeth Ramírez-Vidal
- Posgrado de Ciencias Biomédicas. Facultad de Medicina, Universidad Nacional Autónoma de México, Circuito Exterior s/n Ciudad Universitaria, Coyoacán, 04510, Mexico City, Mexico
| | - Jared Becerril-Rico
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Edificio A, 1° Piso, Circuito de Posgrados, Ciudad Universitaria, C.P. 04510, Coyoacán, Distrito Federal, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Elizabeth Pérez-Islas
- Departamento de Patología, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Zuly J Hernandez-Peralta
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Mariel E Toledo-Guzmán
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Alejandro García-Carrancá
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
- Unidad de Investigación en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Elizabeth Langley
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Angélica Hernández-Guerrero
- Unidad de Endoscopia, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Fernando López-Casillas
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Circuito Exterior s/n Ciudad Universitaria, Coyoacán, 04510, Mexico City, Mexico
| | - Roberto Herrera-Goepfert
- Departamento de Patología, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Luis F Oñate-Ocaña
- Subdirección de Investigación Clínica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico.
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Chang MR, Rusanov DA, Arakelyan J, Alshehri M, Asaturova AV, Kireeva GS, Babak MV, Ang WH. Targeting emerging cancer hallmarks by transition metal complexes: Cancer stem cells and tumor microbiome. Part I. Coord Chem Rev 2023. [DOI: 10.1016/j.ccr.2022.214923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
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20
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Martin J, Islam F. Detection and Isolation of Cancer Stem Cells. CANCER STEM CELLS: BASIC CONCEPT AND THERAPEUTIC IMPLICATIONS 2023:45-69. [DOI: 10.1007/978-981-99-3185-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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21
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D’Accardo C, Porcelli G, Mangiapane LR, Modica C, Pantina VD, Roozafzay N, Di Franco S, Gaggianesi M, Veschi V, Lo Iacono M, Todaro M, Turdo A, Stassi G. Cancer cell targeting by CAR-T cells: A matter of stemness. FRONTIERS IN MOLECULAR MEDICINE 2022; 2:1055028. [PMID: 39086964 PMCID: PMC11285689 DOI: 10.3389/fmmed.2022.1055028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/01/2022] [Indexed: 08/02/2024]
Abstract
Chimeric antigen receptor (CAR)-T cell therapy represents one of the most innovative immunotherapy approaches. The encouraging results achieved by CAR-T cell therapy in hematological disorders paved the way for the employment of CAR engineered T cells in different types of solid tumors. This adoptive cell therapy represents a selective and efficacious approach to eradicate tumors through the recognition of tumor-associated antigens (TAAs). Binding of engineered CAR-T cells to TAAs provokes the release of several cytokines, granzyme, and perforin that ultimately lead to cancer cells elimination and patient's immune system boosting. Within the tumor mass a subpopulation of cancer cells, known as cancer stem cells (CSCs), plays a crucial role in drug resistance, tumor progression, and metastasis. CAR-T cell therapy has indeed been exploited to target CSCs specific antigens as an effective strategy for tumor heterogeneity disruption. Nevertheless, a barrier to the efficacy of CAR-T cell-based therapy is represented by the poor persistence of CAR-T cells into the hostile milieu of the CSCs niche, the development of resistance to single targeting antigen, changes in tumor and T cell metabolism, and the onset of severe adverse effects. CSCs resistance is corroborated by the presence of an immunosuppressive tumor microenvironment (TME), which includes stromal cells, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and immune cells. The relationship between TME components and CSCs dampens the efficacy of CAR-T cell therapy. To overcome this challenge, the double strategy based on the use of CAR-T cell therapy in combination with chemotherapy could be crucial to evade immunosuppressive TME. Here, we summarize challenges and limitations of CAR-T cell therapy targeting CSCs, with particular emphasis on the role of TME and T cell metabolic demands.
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Affiliation(s)
- Caterina D’Accardo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Gaetana Porcelli
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Laura Rosa Mangiapane
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Chiara Modica
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Vincenzo Davide Pantina
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Narges Roozafzay
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Simone Di Franco
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Miriam Gaggianesi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Veronica Veschi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Melania Lo Iacono
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Matilde Todaro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Alice Turdo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Giorgio Stassi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
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22
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Mayani H, Chávez-González A, Vázquez-Santillan K, Contreras J, Guzman ML. Cancer Stem Cells: Biology and Therapeutic Implications. Arch Med Res 2022; 53:770-784. [PMID: 36462951 DOI: 10.1016/j.arcmed.2022.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/14/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022]
Abstract
It is well recognized that most cancers derive and progress from transformation and clonal expansion of a single cell that possesses stem cell properties, i.e., self-renewal and multilineage differentiation capacities. Such cancer stem cells (CSCs) are usually present at very low frequencies and possess properties that make them key players in tumor development. Indeed, besides having the ability to initiate tumor growth, CSCs drive tumor progression and metastatic dissemination, are resistant to most cancer drugs, and are responsible for cancer relapse. All of these features make CSCs attractive targets for the development of more effective oncologic treatments. In the present review article, we have summarized recent advances in the biology of CSCs, including their identification through their immunophenotype, and their physiology, both in vivo and in vitro. We have also analyzed some molecular markers that might become targets for developing new therapies aiming at hampering CSCs regeneration and cancer relapse.
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Affiliation(s)
- Hector Mayani
- Unidad de Investigaci..n en Enfermedades Oncol..gicas, Hospital de Oncolog.ía, Centro M..dico Nacional SXXI, Instituto Mexicano del Seguro Social. Ciudad de M..xico, M..xico.
| | - Antonieta Chávez-González
- Unidad de Investigaci..n en Enfermedades Oncol..gicas, Hospital de Oncolog.ía, Centro M..dico Nacional SXXI, Instituto Mexicano del Seguro Social. Ciudad de M..xico, M..xico
| | | | - Jorge Contreras
- Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Monica L Guzman
- Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, USA
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23
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Hou W, Kong L, Hou Z, Ji H. CD44 is a prognostic biomarker and correlated with immune infiltrates in gastric cancer. BMC Med Genomics 2022; 15:225. [PMCID: PMC9620622 DOI: 10.1186/s12920-022-01383-w] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 10/25/2022] [Indexed: 11/10/2022] Open
Abstract
Objective Gastric carcinoma is the most common malignant tumour of the human digestive system worldwide. CD44 serves as a marker for several tumour stem cells, including gastric cancer. However, the prognostic value of CD44 and its correlation with immune infiltration in gastric cancer remain unclear. Methods The relative expression level of CD44 RNA in gastric cancer was analysed in the TCGA and GEPIA2 databases and validated in the GEO database. Differences in CD44 between gastric cancer cell lines and normal cells were detected by real-time PCR, and the HPA database was used to analyse the differential expression of CD44 protein in gastric cancer and normal tissues. The effect of CD44 on the proliferation and migration of gastric cancer cells was detected by CCK8 and transwell assays. UALCAN was used to analyse the relationship between CD44 expression and clinical parameters, and the Kaplan‒Meier Plotter was used to evaluate the prognostic value, including overall survival (OS), progression-free survival (PFS) and post-progression survival (PPS). The CD44 gene and protein interaction network was constructed by using the Linked Omics, GeneMANIA, STRING and DisGeNET databases. GO and KEGG analyses and GSEA of CD44 were performed by using R language. The correlation between CD44 and immune infiltration was explored by using the TIMER, CIBERSORT and GEPIA databases. Results CD44 is highly expressed in gastric cancer compared with normal tissues. Inhibition of proliferation and migration of gastric cancer cells after CD44 knockdown was observed. The UALCAN database showed that CD44 was independent of sex in gastric cancer but correlated with cancer stage and lymph node metastasis. Kaplan‒Meier Plotter online analysis showed that OS, PFS and PPS were prolonged in the CD44 low-expression group. GO and KEGG analyses and GSEA results showed that CD44 was mainly located in the endoplasmic reticulum and the extracellular matrix containing collagen, which was mainly involved in protein digestion and absorption. TIMER, CIBERSORT and GEPIA showed that CD44 was associated with infiltrating immune cells and thereby affected survival prognosis. Conclusion CD44 is highly expressed in gastric cancer and is an independent prognostic factor associated with immune invasion, which can be used as a candidate prognostic biomarker to determine the prognosis associated with gastric immune invasion.
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Affiliation(s)
- Weiyan Hou
- grid.413851.a0000 0000 8977 8425College of Basic Medicine, Chengde Medical University, Chengde, China
| | - Lingwei Kong
- grid.413851.a0000 0000 8977 8425Department of Orthopaedics, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Zhiping Hou
- grid.413851.a0000 0000 8977 8425Department of Pathology, Chengde Medical University, Shangerdaohezi Avenue, Chengde, 067000 Hebei China
| | - Hairu Ji
- grid.413851.a0000 0000 8977 8425Department of Pathology, Chengde Medical University, Shangerdaohezi Avenue, Chengde, 067000 Hebei China
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24
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Sukri A, Hanafiah A, Kosai NR, Mohammed Taher M, Mohamed R. New insight on the role of Helicobacter pylori cagA in the expression of cell surface antigens with important biological functions in gastric carcinogenesis. Helicobacter 2022; 27:e12913. [PMID: 35848223 DOI: 10.1111/hel.12913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 06/17/2022] [Accepted: 06/28/2022] [Indexed: 12/20/2022]
Abstract
BACKGROUND Expression of cluster of differentiation (CD) antigens changes according to disease status and inflammation. Profiles of CD antigens expression in gastric cancer patients are different based on the status of H. pylori infection. AIMS We conducted this study to profile CD antigen markers in gastric adenocarcinoma cells (AGS cell line) infected with distinct cytotoxin-associated gene A (cagA) genotypes of H. pylori clinical isolates. METHODS The AGS cells were infected with H. pylori isolates with different cagA genotypes, and CD antigens expression was determined using DotScan™ antibody microarray. Formation of "hummingbird" phenotype was determined, and the percentage was calculated. RESULTS H. pylori strains harboring cagA upregulated the expression of CD antigen involved in cancer stem cell formation (CD55), but downregulated CD antigens involved in immune regulation (CD40 and CD186) and cell adhesion (CD44). CD54 (neutrophil adhesion) and CD71 (iron transfer) were highly downregulated in the gastric cells infected with Western cagA isolates compared with East Asian isolates. CD antigen expression was different in the cells infected with H. pylori harboring different CagA EPIYA (Glu-Pro-Ile-Tyr-Ala) numbers, in which higher repression of CD54 and CD15 (Lewis x antigen) were observed in the isolate with the highest number of EPIYA motif. Furthermore, higher downregulation of CD15 was observed in the infected gastric cells with high percentage of "hummingbird" phenotype than that of low percentage of "hummingbird" phenotype. CONCLUSION Our study demonstrated the critical roles of CD antigens in the CagA pathogenesis and should be investigated further.
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Affiliation(s)
- Asif Sukri
- Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA, Bandar Puncak Alam, Malaysia
| | - Alfizah Hanafiah
- Department of Medical Microbiology & Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nik Ritza Kosai
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Mustafa Mohammed Taher
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Ramelah Mohamed
- Department of Medical Microbiology & Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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25
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Establishment and characterization of chemotherapy-enriched sphere-forming cells with stemness phenotypes as a new cell line (BAG 50) of gastric carcinoma. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:201. [PMID: 36175578 DOI: 10.1007/s12032-022-01742-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/26/2022] [Indexed: 10/14/2022]
Abstract
Gastric cancer is a malignancy with a high mortality rate worldwide. Cancer stem cells (CSCs) are a small subpopulation of tumor cells that possess the tumor-initiating ability, self-renewal capacity, and high resistance to conventional therapies. Due to the diversity and complexity of human tumors, new cell lines are urgently needed to supply clinically and physiologically relevant cancer models. Here, we report establishing a novel cell line (BAG50) with stemness properties. Chemotherapy-enriched sphere-forming cells with CSC properties isolated from a patient with GC were cultured in a serum-containing medium and passaged for up to 51 passages. The colony-forming ability and tumor-forming capacity of BAG50 cells were evaluated in vitro and in vivo. mRNA upregulation of stemness-related transcriptional factors using real-time PCR as well as expression of CSC markers using flow cytometry was investigated. Finally, STR profiling and chromosome studies were performed. BAG50 cells formed floating spheroid colonies in a serum-free medium. Subcutaneous injection of these cells generated xenograft tumors in nude mice. Pluripotency markers (SOX-2, OCT4, and Cripto-1) in them were upregulated compared with normal gastric cells. The majority of them expressed CSC markers of CD44, CD54, and EpCAM, and stemness marker of oct-4. STR profiling showed a unique DNA fingerprint. Karyotype also demonstrated multiple aneuploidies and chromosomal translocations. We suggested that the highly tumorigenic BAG50 cell line with stem cell-like phenotypes may provide a valuable in vitro tool to support new diagnostic, prognostic, and predictive biomarkers as well as the development of more effective treatment strategies.
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26
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Yang Y, Meng WJ, Wang ZQ. The origin of gastric cancer stem cells and their effects on gastric cancer: Novel therapeutic targets for gastric cancer. Front Oncol 2022; 12:960539. [PMID: 36185219 PMCID: PMC9520244 DOI: 10.3389/fonc.2022.960539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/30/2022] [Indexed: 11/25/2022] Open
Abstract
Gastric cancer (GC) is one of the most prevalent malignancies and the most common causes of cancer-related mortality worldwide. Furthermore, the prognosis of advanced GC remains poor even after surgery combined with chemoradiotherapy. As a small group of cells with unlimited differentiation and self-renewal ability in GC, accumulating evidence shows that GC stem cells (GCSCs) are closely associated with the refractory characteristics of GC, such as drug resistance, recurrence, and metastasis. With the extensive development of research on GCSCs, GCSCs seem to be promising therapeutic targets for GC. However, the relationship between GCSCs and GC is profound and intricate, and its mechanism of action is still under exploration. In this review, we elaborate on the source and key concepts of GCSCs, systematically summarize the role of GCSCs in GC and their underlying mechanisms. Finally, we review the latest information available on the treatment of GC by targeting GCSCs. Thus, this article may provide a theoretical basis for the future development of the novel targets based on GCSCs for the treatment of GC.
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27
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Lu Z, Zhang Z, Yang M, Xiao M. Ubiquitin-specific protease 1 inhibition sensitizes hepatocellular carcinoma cells to doxorubicin by ubiquitinated proliferating cell nuclear antigen-mediated attenuation of stemness. Anticancer Drugs 2022; 33:622-631. [PMID: 35324534 DOI: 10.1097/cad.0000000000001311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Currently, resistance to the chemotherapeutic agent doxorubicin (Dox) in hepatocellular carcinoma (HCC) cells is an obstacle in developing effective Dox-targeted clinical therapies. Ubiquitin-specific protease 1 (USP1) plays a crucial role in the progression of multiple cancers. In this study, the purpose was to investigate the effect of USP1 depletion with chemotherapeutant Dox on the HCC cells. Flow cytometry was used to detect the ratio of apoptosis. The expression levels of selected proteins were evaluated by western blotting. In addition, the expression of genes was quantitated by quantitative real-time PCR assay. Coimmunoprecipitation was performed to confirm the interaction between USP1 and proliferating cell nuclear antigen (PCNA). Sphere formation assay was carried out to investigate the cancer stemness. Subcutaneous xenograft and orthotopic liver tumor models were established to examine the growth of tumor. Knockdown of USP1 increased the rate of Dox-induced apoptosis in stem-like and nonstem-like HCC cells. The combination of Dox and the USP1 inhibitor SJB3-019A (SJB3) markedly enhanced apoptosis in the primary liver carcinoma/PRF/5 and MHCC-97H cell lines. Notably, Dox/SJB3-induced tumor inhibition was further determined in vivo using a xenograft and orthotopic liver tumor model. Mechanically, USP1 inhibition via SJB3 or short hairpin RNA significantly decreased cancer stemness, including sphere formation ability and the expression of Nanog, Sox2, and c-Myc. The sensitization of HCC to Dox by SJB3 is attributed to the upregulation of PCNA ubiquitylation. Thus, genetic or pharmacological inhibition of USP1 restored the sensitivity of HCC cells to Dox in vitro and in vivo , representing a new potential therapeutic strategy for HCC.
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Affiliation(s)
- Zhe Lu
- Clinical Laboratory, Women and Children's Health Care Center of Hainan Province and Departments of
| | | | - Min Yang
- Medical Oncology, Hainan Cancer Hospital, Haikou, P.R. China
| | - Meifang Xiao
- Clinical Laboratory, Women and Children's Health Care Center of Hainan Province and Departments of
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28
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Endometrial stem/progenitor cells: Properties, origins, and functions. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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29
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Izadpanah A, Delirezh N, Mahmodlou R. Ex vivo Optimization of Glucose-Regulated Protein 94/Glycoprotein 96 Expressions in Mammospheres; Implication for Breast Cancer Immunotherapy. CELL JOURNAL 2022; 24:261-266. [PMID: 35717566 PMCID: PMC9445520 DOI: 10.22074/cellj.2022.7908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 06/22/2021] [Indexed: 12/03/2022]
Abstract
OBJECTIVE The induction of immunity against cancer stem cells (CSCs) can boost the efficiency of cancer vaccines. Heat shock proteins (HSPs) are required for the successful activation of anti-tumor immune responses. Glycoprotein 96 (gp96) is a well-known HSP that promotes the cross-presentation of tumor antigens. The aim of the present study was to optimize the temperature for induction of gp96 in grade 3 breast cancer spheres. MATERIALS AND METHODS In the experimental study, CSCs were enriched from breast tumor tissue samples and cultured in DMEM-F12 with epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), B27, and bovine serum albumin (BSA) for 22 days. The expression level of CD24 and CD44 as CSC markers was measured by flow cytometry in secondary mammospheres, and the expression of NANOG, SOX2, and OCT4 genes in CSCs was also analyzed using the real-time polymerase chain reaction (PCR). To find the optimal temperature regulation of gp96, the mammosphere was incubated at different temperatures for 1 hour, and gp96 expression was measured using the western blotting assay. RESULTS Primary mammospheres were obtained after seven days of culture, and secondary spheres formed 22 days after passage. Flow cytometry analysis showed that cells with CD24- CD44+ phenotype were enriched in the culture period (from 2.6% on day 1 to 32.6% on day 22). Real-time PCR indicated that OCT4, NANOG, and SOX2 expression in mammospheres were increased by 3.8 ± 0.6, 17.8 ± 0.6, and 7.7 ± 0.8 fold respectively in comparison to the MCF-7 cell line. Western blot analysis showed that gp96 production was significantly upregulated when mammospheres were incubated at both 42°C and 43°C in comparison to the control group. CONCLUSION Altogether, we found that heat-induced upregulated expression of gp96 in CSCs enriched mammospheres from breast tumor tissue might be used as a complementary procedure to generate more immunogenic antigens in immunotherapy settings.
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Affiliation(s)
- Amirhossein Izadpanah
- Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran,Department of Stem cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and
Technology, Tehran, Iran
| | - Nowruz Delirezh
- Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran,P.O.Box: 165Department of MicrobiologyFaculty of Veterinary MedicineUrmia UniversityUrmiaIran
| | - Rahim Mahmodlou
- Department of Surgery, Emam Khomeini General Hospital, Urmia, Iran
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30
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Saito S, Ku CC, Wuputra K, Pan JB, Lin CS, Lin YC, Wu DC, Yokoyama KK. Biomarkers of Cancer Stem Cells for Experimental Research and Clinical Application. J Pers Med 2022; 12:715. [PMID: 35629138 PMCID: PMC9147761 DOI: 10.3390/jpm12050715] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/22/2022] [Accepted: 04/27/2022] [Indexed: 12/12/2022] Open
Abstract
The use of biomarkers in cancer diagnosis, therapy, and prognosis has been highly effective over several decades. Studies of biomarkers in cancer patients pre- and post-treatment and during cancer progression have helped identify cancer stem cells (CSCs) and their related microenvironments. These analyses are critical for the therapeutic application of drugs and the efficient targeting and prevention of cancer progression, as well as the investigation of the mechanism of the cancer development. Biomarkers that characterize CSCs have thus been identified and correlated to diagnosis, therapy, and prognosis. However, CSCs demonstrate elevated levels of plasticity, which alters their functional phenotype and appearance by interacting with their microenvironments, in response to chemotherapy and radiotherapeutics. In turn, these changes induce different metabolic adaptations of CSCs. This article provides a review of the most frequently used CSCs and stem cell markers.
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Affiliation(s)
- Shigeo Saito
- Saito Laboratory of Cell Technology, Yaita 329-1571, Japan
- Horus Co., Ltd., Nakano, Tokyo 164-0001, Japan
| | - Chia-Chen Ku
- Graduate Institute of Medicine, Department of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.K.); (K.W.); (J.-B.P.); (C.-S.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Kenly Wuputra
- Graduate Institute of Medicine, Department of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.K.); (K.W.); (J.-B.P.); (C.-S.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Jia-Bin Pan
- Graduate Institute of Medicine, Department of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.K.); (K.W.); (J.-B.P.); (C.-S.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Chang-Shen Lin
- Graduate Institute of Medicine, Department of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.K.); (K.W.); (J.-B.P.); (C.-S.L.)
| | - Ying-Chu Lin
- School of Dentistry, Department of Dentistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Deng-Chyang Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Kazunari K. Yokoyama
- Graduate Institute of Medicine, Department of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.K.); (K.W.); (J.-B.P.); (C.-S.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
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31
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Bagheri V, Esmaeili SA, Gholamin M, Abbaszadegan MR. Rapid Isolation of Gastric Adenocarcinoma Cancer Stem Cells as a Target for Autologous Dendritic Cell-Based Immunotherapy. IRANIAN JOURNAL OF BIOTECHNOLOGY 2022; 20:e3045. [PMID: 36337066 PMCID: PMC9583826 DOI: 10.30498/ijb.2021.284841.3045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Gastric cancer (GC) is a malignancy cause associated with a high death rate in the world. Cancer stem cells (CSCs) are a rare immortal subpopulation of cells within tumors with characteristics of the ability to self-renew, initiate tumor, and differentiate into defined progenies as well as and high resistance to conventional therapies. OBJECTIVES Despite the use of surgery and chemotherapy for GC therapy, there are no efficient therapeutic protocols for it to date. Therefore, rapid isolation of CSCs in order to therapeutic targets, especially immunotherapy is very important. MATERIALS AND METHODS Cancerous cell suspension isolated from patients with GC was cultured in the serum-free medium containing EGF, bFGF, LIF, and heparin under non-adherent culture conditions to generate spheres. Expression of mRNA level stemness transcription factors (OCT4, SOX2, SALL4, and Cripto-1), CD44 variable isoforms (CD44s, CD44v3, CD44v6, CD44V8-10) of spheroid-forming single cells compared with gastric normal tissue cells using real time PCR and molecules of CD44, CD54, and EpCAM as gastric CSC markers, and stemness factor Oct4 using flow cytometry, as well as tumorgenicity using subcutaneous injection of sphere-forming cells to nude mice were investigated. RESULTS Few cancerous cells isolated from patients with GC were able to generate three-dimensional spheroid colonies in the serum-free medium containing EGF, bFGF, LIF, and heparin under non-adherent culture conditions, and form xenograft tumors in immunodeficient nude mice after subcutaneous injection. Spheroid-forming single cells upregulated stemness transcription factors OCT4, SOX2, SALL4, and Cripto-1 that are associated with pluripotency and self-renewal and CD44 isoforms (CD44s, CD44v3, CD44v6, CD44V8-10) compared with gastric normal tissue cells. Finally, molecules of CD44, CD54, and EpCAM as gastric CSC markers and stemness factor Oct4 were expressed in sphere-forming cells. CONCLUSION We suggested that the sphere formation and tumorigenicity assays are two procedures, leading to the rapid isolation of cancer cells with certain stem-like properties in order to target CSCs using autologous dendritic cell therapy, especially in patients with advanced disease.
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Affiliation(s)
- Vahid Bagheri
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehran Gholamin
- Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Abbaszadegan
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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32
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Evaluation of hydroalcoholic extract effects of Ferula assa-foetida on expression change of EMT and CD44-related genes in gastric cancer stem cell. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Hsieh HL, Yu MC, Cheng LC, Yeh TS, Tsai MM. Molecular mechanism of therapeutic approaches for human gastric cancer stem cells. World J Stem Cells 2022; 14:76-91. [PMID: 35126829 PMCID: PMC8788185 DOI: 10.4252/wjsc.v14.i1.76] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/15/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
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.
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Affiliation(s)
- Hsi-Lung Hsieh
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Chin Yu
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of General Surgery, New Taipei Municipal TuCheng Hospital, New Taipei 236, Taiwan
| | - Li-Ching Cheng
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
| | - Ta-Sen Yeh
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Ming-Ming Tsai
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
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34
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Yang Y, Meng WJ, Wang ZQ. Cancer Stem Cells and the Tumor Microenvironment in Gastric Cancer. Front Oncol 2022; 11:803974. [PMID: 35047411 PMCID: PMC8761735 DOI: 10.3389/fonc.2021.803974] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/08/2021] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) remains one of the leading causes of cancer-related death worldwide. Cancer stem cells (CSCs) might be responsible for tumor initiation, relapse, metastasis and treatment resistance of GC. The tumor microenvironment (TME) comprises tumor cells, immune cells, stromal cells and other extracellular components, which plays a pivotal role in tumor progression and therapy resistance. The properties of CSCs are regulated by cells and extracellular matrix components of the TME in some unique manners. This review will summarize current literature regarding the effects of CSCs and TME on the progression and therapy resistance of GC, while emphasizing the potential for developing successful anti-tumor therapy based on targeting the TME and CSCs.
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Affiliation(s)
| | - Wen-Jian Meng
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
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35
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Becerril-Rico J, Alvarado-Ortiz E, Toledo-Guzmán ME, Pelayo R, Ortiz-Sánchez E. The cross talk between gastric cancer stem cells and the immune microenvironment: a tumor-promoting factor. Stem Cell Res Ther 2021; 12:498. [PMID: 34503571 PMCID: PMC8428093 DOI: 10.1186/s13287-021-02562-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/16/2021] [Indexed: 02/07/2023] Open
Abstract
Cross talk between cancer cells and the immune system is determinant for cancer progression. Emerging evidence demonstrates that GC characteristics such as metastasis, treatment resistance, and disease recurrence are associated with a tumor subpopulation called gastric cancer stem cells (GCSCs). However, the specific interaction between GCSCs and the immune microenvironment is still under investigation. Although immune evasion has been well described for cancer stem cells (CSCs), recent studies show that GCSCs can also regulate the immune system and even benefit from it. This review will provide an overview of bidirectional interactions between CSCs and immune cells in GC, compiling relevant data about how CSCs can induce leukocyte reprogramming, resulting in pro-tumoral immune cells that orchestrate promotion of metastasis, chemoresistance, tumorigenicity, and even increase in number of cancer cells with stem properties. Some immune cells studied are tumor-associated macrophages (TAMs), neutrophils, Th17 and T regulatory (Treg) cells, mesenchymal stem cells (MSCs), and cancer-associated fibroblasts (CAFs), as well as the signaling pathways involved in these pro-tumoral activities. Conversely, although there are cytotoxic leukocytes that can potentially eliminate GCSCs, we describe mechanisms for immune evasion in GCSCs and their clinical implications. Furthermore, we describe current available immunotherapy targeting GCSC-related markers as possible treatment for GC, discussing how the CSC-modified immune microenvironment can mitigate or inactivate these immunotherapies, limiting their effectiveness. Finally, we summarize key concepts and relevant evidence to understand the cross talk between GCSCs and the immune microenvironment as an important process for effective design of therapies against GCSCs that improve the outcome of patients with GC.
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Affiliation(s)
- Jared Becerril-Rico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, Mexico
| | - Eduardo Alvarado-Ortiz
- Programa de Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
| | - Mariel E Toledo-Guzmán
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, Mexico
| | - Rosana Pelayo
- Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Delegación Puebla, Puebla, Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, Mexico.
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36
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Chang Y, Roy S, Pan Z. Store-Operated Calcium Channels as Drug Target in Gastroesophageal Cancers. Front Pharmacol 2021; 12:668730. [PMID: 34012400 PMCID: PMC8126661 DOI: 10.3389/fphar.2021.668730] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/12/2021] [Indexed: 12/24/2022] Open
Abstract
Gastroesophageal cancers, including tumors occurring in esophagus and stomach, usually have poor prognosis and lack effective chemotherapeutic drugs for treatment. The association between dysregulated store-operated calcium entry (SOCE), a key intracellular Ca2+ signaling pathway and gastroesophageal cancers are emerging. This review summarizes the recent advances in understanding the contribution of SOCE-mediated intracellular Ca2+ signaling to gastroesophageal cancers. It assesses the pathophysiological role of each component in SOCE machinery, such as Orais and STIMs in the cancer cell proliferation, migration, and invasion as well as stemness maintenance. Lastly, it discusses efforts towards development of more specific and potent SOCE inhibitors, which may be a new set of chemotherapeutic drugs appearing at the horizon, to provide either targeted therapy or adjuvant treatment to overcome drug resistance for gastroesophageal cancers.
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Affiliation(s)
- Yan Chang
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, United States
| | - Souvik Roy
- Department of Mathematics, The University of Texas at Arlington, Arlington, TX, United States
| | - Zui Pan
- College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX, United States
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Zhang M, Chen T, Fang S, Wu W, Wang X, Wu H, Xiong Y, Song J, Li C, He Z, Lee CS. Peroxide- and transition metal-free electrochemical synthesis of α,β-epoxy ketones. Org Biomol Chem 2021; 19:2481-2486. [PMID: 33656035 DOI: 10.1039/d0ob02444a] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A novel electrochemical method for the synthesis of α,β-epoxy ketones is reported. With KI as the redox mediator, methyl ketones reacted with aldehydes under peroxide- and transition metal-free electrolytic conditions and afforded α,β-epoxy ketones in one pot (36 examples, 52-90% yield). This safe and environmental-friendly method has a broad substrate scope and can readily provide a variety of α,β-epoxy ketones in gram-scales for evaluation of their anti-cancer activities.
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Affiliation(s)
- Mengxun Zhang
- Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen 518060, China. and College of physics and optoelectronic engineering, Shenzhen University, Shenzhen 518060, China
| | - Tie Chen
- Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen 518060, China.
| | - Shisong Fang
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518100, China
| | - Weihua Wu
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518100, China
| | - Xin Wang
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518100, China
| | - Haiqiang Wu
- Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen 518060, China.
| | - Yongai Xiong
- Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen 518060, China.
| | - Jun Song
- College of physics and optoelectronic engineering, Shenzhen University, Shenzhen 518060, China
| | - Chenyang Li
- Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen 518060, China.
| | - Zhendan He
- Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen 518060, China. and College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China
| | - Chi-Sing Lee
- Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
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Xia Y, Lv J, Jiang T, Li B, Li Y, He Z, Xuan Z, Sun G, Wang S, Li Z, Wang W, Wang L, Xu Z. CircFAM73A promotes the cancer stem cell-like properties of gastric cancer through the miR-490-3p/HMGA2 positive feedback loop and HNRNPK-mediated β-catenin stabilization. J Exp Clin Cancer Res 2021; 40:103. [PMID: 33731207 PMCID: PMC7972245 DOI: 10.1186/s13046-021-01896-9] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 02/26/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) have emerged as a new subclass of regulatory RNAs that play critical roles in various cancers. Cancer stem cells (CSCs), a small subset of cancer cells, are believed to possess the capacities to initiate tumorigenesis and promote progression. Although accumulating evidence has suggested that cells with CSC-like properties are crucial for the malignancy of gastric cancer (GC), it remains unclear whether circRNAs are related to the acquisition of CSC-like properties in GC. METHODS CircFAM73A expression was analyzed by GEO datasets and verified in GC samples. The roles of circFAM73A in GC cell proliferation, migration, cisplatin resistance, and CSC-like properties were determined by a series of functional experiments both in vitro and in vivo. RNA pulldown was used to explore the miRNAs and proteins binding to circFAM73A. Bioinformatic analysis and experimental verification confirmed the downstream targets of circFAM73A. The regulation of circFAM73A by HMGA2 was verified by ChIP and RIP assays. RESULTS Elevated circFAM73A expression was confirmed in GC tissues, and higher circFAM73A predicted poor prognosis in GC patients. The upregulation of circFAM73A enhanced CSC-like properties in GC, thus facilitating cell proliferation, migration, and cisplatin resistance. Mechanistically, circFAM73A promoted GC malignancy by regulating miR-490-3p/HMGA2 in a positive feedback loop and recruiting HNRNPK to facilitate β-catenin stabilization. Moreover, HMGA2 further enhanced E2F1 and HNRNPL activity, which in turn promoted circFAM73A expression. CONCLUSIONS Our work demonstrates the crucial role of circFAM73A in the CSC-like properties of GC and uncovers a positive feedback loop in circFAM73A regulation that leads to the progression of gastric cancer, which may provide new insights into circRNA-based diagnostic and therapeutic strategies.
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Affiliation(s)
- Yiwen Xia
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Jialun Lv
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Tianlu Jiang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Bowen Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Ying Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Zhongyuan He
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Zhe Xuan
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Guangli Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Sen Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Zheng Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Weizhi Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Linjun Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China.
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu Province, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.
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Mao D, Zhou Z, Song S, Li D, He Y, Wei Z, Zhang C. Identification of Stemness Characteristics Associated With the Immune Microenvironment and Prognosis in Gastric Cancer. Front Oncol 2021; 11:626961. [PMID: 33747944 PMCID: PMC7966731 DOI: 10.3389/fonc.2021.626961] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 01/25/2021] [Indexed: 12/24/2022] Open
Abstract
Background Gastric cancer (GC) is a highly heterogeneous disease. In recent years, the prognostic value of the mRNA expression-based stemness index (mRNAsi) across cancers has been reported. We intended to identify stemness index-associated genes (SI-genes) for clinical characteristic, gene mutation status, immune response, and tumor microenvironment evaluation as well as risk stratification and survival prediction. Methods The correlations between the mRNAsi and GC prognosis, clinical characteristics, gene mutation status, immune cell infiltration and tumor microenvironment were evaluated. Weighted gene correlation network analysis (WGCNA) was performed to identify SI-genes from differentially expressed genes (DEGs) in The Cancer Genome Atlas (TCGA). Single-sample gene set enrichment analysis (ssGSEA) was employed to calculate the sample SI-gene-based ssGSEA score according to the SI-genes. Then, the correlations between the ssGSEA score and GC prognosis, clinical characteristics, gene mutation status, immune cell infiltration and tumor microenvironment were analyzed. Finally, the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to construct a prognostic signature with prognostic SI-genes. The ssGSEA score and prognostic signature were validated using the Gene Expression Omnibus (GEO) database. Results The mRNAsi could predict overall survival (OS), clinical characteristics, the gene mutation status, immune cell infiltration, and the tumor microenvironment composition. Fourteen positive SI-genes and 178 negative SI-genes were screened out using WGCNA. The ssGSEA score, similar to the mRNAsi, was found to be closely related to OS, clinical characteristics, the gene mutation status, immune cell infiltration, and the tumor microenvironment composition. Finally, a prognostic signature based on 18 prognostic SI-genes was verified to more accurately predict GC 1-year, 3-year, and 5-year OS than traditional clinical prediction models. Conclusion The ssGSEA score and prognostic signature based on 18 prognostic SI-genes are of great value for immune response evaluation, risk stratification and survival prediction in GC and suggest that stemness features are crucial drivers of GC progression.
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Affiliation(s)
- Deli Mao
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Zhijun Zhou
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Shenglei Song
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Dongsheng Li
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yulong He
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Zhewei Wei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
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40
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Prieto EI, Mojares EBA, Cortez JJM, Vasquez MR. Electrospun nanofiber scaffolds for the propagation and analysis of breast cancer stem cells in vitro. Biomed Mater 2021; 16:035004. [PMID: 33634797 DOI: 10.1088/1748-605x/abc3dd] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Despite advances in cancer treatment, breast cancer remains the second foremost cause of cancer mortality among women, with a high rate of relapse after initial treatment success. A subpopulation of highly malignant cancer cells, known as cancer stem cells (CSCs), is suspected to be linked to metastasis and relapse. Targeting of CSCs may therefore provide a means of addressing cancer-related mortality. However, due to their low population in vivo and a lack of proper culture platform for their propagation, much of the CSC biology remains unknown. Since maintenance of CSCs is heavily influenced by the tumor microenvironment, this study developed a 3D culture platform that mimics the metastatic tumor extracellular matrix (ECM) to effectively increase CSC population in vitro and allow CSC analysis. Through electrospinning, nanofibers that were aligned, porous, and collagen-coated were fabricated from polycaprolactone to recreate the metastatic tumor ECM assemblage. Breast cancer cells seeded onto the nanofiber scaffolds exhibited gross morphology and cytoskeletal phenotype similar to invasive cancer cells. Moreover, the population of breast cancer stem cells increased in nanofiber scaffolds. Analysis of breast cancer cells grown on the nanofiber scaffolds demonstrated an upregulation of mesenchymal markers and an increase in cell invasiveness suggesting the cells have undergone epithelial-mesenchymal transition. These results indicate that the fabricated nanofiber scaffolds effectively mimicked the tumor microenvironment that maintains the cancer stem cell population, offering a platform to enrich and analyze CSCs in vitro.
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Affiliation(s)
- E I Prieto
- National Institute of Molecular Biology and Biotechnology, College of Science, National Science Complex, University of the Philippines, Diliman, Quezon City 1101, Philippines
| | - E B A Mojares
- National Institute of Molecular Biology and Biotechnology, College of Science, National Science Complex, University of the Philippines, Diliman, Quezon City 1101, Philippines
| | - J J M Cortez
- National Institute of Molecular Biology and Biotechnology, College of Science, National Science Complex, University of the Philippines, Diliman, Quezon City 1101, Philippines
| | - M R Vasquez
- Department of Mining, Metallurgical, and Materials Engineering, College of Engineering, University of the Philippines, Diliman, Quezon City 1101, Philippines
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Mamun MA, Mannoor K, Cao J, Qadri F, Song X. SOX2 in cancer stemness: tumor malignancy and therapeutic potentials. J Mol Cell Biol 2021; 12:85-98. [PMID: 30517668 PMCID: PMC7109607 DOI: 10.1093/jmcb/mjy080] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 11/18/2018] [Accepted: 12/04/2018] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs), a minor subpopulation of tumor bulks with self-renewal and seeding capacity to generate new tumors, posit a significant challenge to develop effective and long-lasting anti-cancer therapies. The emergence of drug resistance appears upon failure of chemo-/radiation therapy to eradicate the CSCs, thereby leading to CSC-mediated clinical relapse. Accumulating evidence suggests that transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells, drives cancer stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug resistance mechanisms like epithelial-to-mesenchymal transition, ATP-binding cassette drug transporters, anti-apoptotic and/or pro-survival signaling, lineage plasticity, and evasion of immune surveillance. Gaining a better insight and comprehensive interrogation into the mechanistic basis of SOX2-mediated generation of CSCs and treatment failure might therefore lead to new therapeutic targets involving CSC-specific anti-cancer strategies.
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Affiliation(s)
- Mahfuz Al Mamun
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Kaiissar Mannoor
- Oncology Laboratory, Institute for Developing Science & Health Initiatives (ideSHi), Dhaka, Bangladesh
| | - Jun Cao
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Firdausi Qadri
- Oncology Laboratory, Institute for Developing Science & Health Initiatives (ideSHi), Dhaka, Bangladesh
| | - Xiaoyuan Song
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.,CAS Key Laboratory of Brain Function and Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences, University of Science and Technology of China, Hefei, China
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Aramini B, Masciale V, Grisendi G, Banchelli F, D'Amico R, Maiorana A, Morandi U, Dominici M, Haider KH. Cancer stem cells and macrophages: molecular connections and future perspectives against cancer. Oncotarget 2021; 12:230-250. [PMID: 33613850 PMCID: PMC7869576 DOI: 10.18632/oncotarget.27870] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) have been considered the key drivers of cancer initiation and progression due to their unlimited self-renewal capacity and their ability to induce tumor formation. Macrophages, particularly tumor-associated macrophages (TAMs), establish a tumor microenvironment to protect and induce CSCs development and dissemination. Many studies in the past decade have been performed to understand the molecular mediators of CSCs and TAMs, and several studies have elucidated the complex crosstalk that occurs between these two cell types. The aim of this review is to define the complex crosstalk between these two cell types and to highlight potential future anti-cancer strategies.
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Affiliation(s)
- Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Valentina Masciale
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Federico Banchelli
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto D'Amico
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonino Maiorana
- Institute of Pathology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Uliano Morandi
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
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Kim HS, Song HJ, Kim HU, Jeong IH, Koh HM, Shin JH, Jang BG. Expression profile of intestinal stem cell and cancer stem cell markers in gastric cancers with submucosal invasion. Pathol Res Pract 2021; 218:153336. [PMID: 33450435 DOI: 10.1016/j.prp.2020.153336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/29/2020] [Accepted: 12/30/2020] [Indexed: 11/16/2022]
Abstract
Cancer stem cells (CSCs) are believed to be responsible for tumor growth, invasion, and metastasis. Submucosal invasion, which greatly enhances metastasis risk, is a critical step in gastric cancer (GC) progression. To identify stem cell-related markers associated with submucosal invasion and lymph node (LN) metastasis in GCs, we investigated the expression of candidate CSC markers (CD133, CD44, and ALDH1A) and intestinal stem cell (ISC) markers (EPHB2, OLFM4, and LGR5) in early GCs that manifested submucosal invasion. We discovered that EPHB2 and LGR5 expression was frequently confined to the basal area of the lamina propria (basal pattern) in mucosal cancer, and the proportion of stem cell marker-positive cells substantially increased during submucosal invasion. CD44 expression showed a focal pattern, ALDH1A was predominantly expressed diffusely, and there was no expansion of CD44 or ALDH1A expression in the submucosal cancer cells. Unexpectedly, no CSC markers showed any associations with LN metastasis, and only loss of EPHB2 expression was associated with increased LN metastasis. Treatment of RSPO2, a niche factor, along with Wnt 3a, to GC cells led to increased EPHB2 and LGR5 mRNA levels. RNA in situ hybridization confirmed specific RSPO2 expression in the smooth muscle cells of the muscularis mucosa, suggesting that RSPO2 is responsible for the increased expression of ISC markers in GC cells at the basal areas. In summary, no stem cell markers were associated with increased LN metastasis in early GCs. Conversely, isolated EPHB2 expression was associated with lower LN metastasis. EPHB2 and LGR5 showed a basal distribution pattern along with enhanced expression in submucosal invading cells in early GCs, which was induced by a niche factor, RSPO2, from the muscularis mucosa.
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Affiliation(s)
- Hye Sung Kim
- Department of Pathology, Jeju National University School of Medicine and Jeju National University Hospital, South Korea
| | - Hyun Joo Song
- Department of Internal Medicine, Jeju National University School of Medicine and Jeju National University Hospital, South Korea
| | - Heung Up Kim
- Department of Internal Medicine, Jeju National University School of Medicine and Jeju National University Hospital, South Korea
| | - In Ho Jeong
- Department of Surgery, Jeju National University School of Medicine and Jeju National University Hospital, South Korea
| | - Hyun Min Koh
- Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, South Korea
| | - Jung Hyub Shin
- Department of Pathology, Jeju National University School of Medicine and Jeju National University Hospital, South Korea
| | - Bo Gun Jang
- Department of Pathology, Jeju National University School of Medicine and Jeju National University Hospital, South Korea.
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Basati G, Mohammadpour H, Emami Razavi A. Association of High Expression Levels of SOX2, NANOG, and OCT4 in Gastric Cancer Tumor Tissues with Progression and Poor Prognosis. J Gastrointest Cancer 2020; 51:41-47. [PMID: 30628031 DOI: 10.1007/s12029-018-00200-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Expression of the essential regulator genes, SOX2, NANOG, and OCT4, so-called as stemness factors, is prerequisite for the tumorigenic capability of cancer stem cells (CSCs) and their potential role in the formation and progression of various human cancers. METHODS In this study, the expression levels of SOX2, NANOG, and OCT4 were quantified by a qRT-PCR method in 100 gastric cancer tumor tissues vs the paired adjacent normal tissues. Then, the relationship between the expression of the three genes in gastric cancer tumor tissues and the clinicopathological characteristics and overall survival of patients was investigated. RESULTS Higher expression levels of SOX2, NANOG, and OCT4 were found in gastric cancer tumor tissues compared with those in paired adjacent normal tissues (P = 0.0001). Overexpression of the mentioned genes in gastric cancer tumor tissues was resolved to be significantly associated with tumor size (P < 0.05), TNM stage (P = 0.001), tumor grade (P < 0.01), and shortened overall survival time (P = 0.0001). CONCLUSIONS These findings indicted that the stemness factors SOX2, NANOG, and OCT4 are significantly overexpressed in gastric cancer and may serve as potential biomarkers of gastric cancer progression and prognosis.
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Affiliation(s)
- Gholam Basati
- Biotechnology and Medicinal Plants Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Hadiseh Mohammadpour
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirnader Emami Razavi
- Iran National Tumor Bank, Cancer Biology Research Center, Cancer Institute of Iran., Tehran University of Medical Sciences, Keshavarz Boulevard, Tehran, Iran.
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Yang T, Shu X, Zhang HW, Sun LX, Yu L, Liu J, Sun LC, Yang ZH, Ran YL. Enolase 1 regulates stem cell-like properties in gastric cancer cells by stimulating glycolysis. Cell Death Dis 2020; 11:870. [PMID: 33067426 PMCID: PMC7567818 DOI: 10.1038/s41419-020-03087-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 12/18/2022]
Abstract
Recent studies have demonstrated that gastric cancer stem cells (CSCs) are a rare sub-group of gastric cancer (GC) cells and have an important role in promoting the tumor growth and progression of GC. In the present study, we demonstrated that the glycolytic enzyme Enolase 1 (ENO1) was involved in the regulation of the stem cell-like characteristics of GC cells, as compared to the parental cell lines PAMC-82 and SNU16, the expression of ENO1 in spheroids markedly increased. We then observed that ENO1 could enhance stem cell-like characteristics, including self-renewal capacity, cell invasion and migration, chemoresistance, and even the tumorigenicity of GC cells. ENO1 is known as an enzyme that is involved in glycolysis, but our results showed that ENO1 could markedly promote the glycolytic activity of cells. Furthermore, inhibiting glycolysis activity using 2-deoxy-D-glucose treatment significantly reduced the stemness of GC cells. Therefore, ENO1 could improve the stemness of CSCs by enhancing the cells' glycolysis. Subsequently, to further confirm our results, we found that the inhibition of ENO1 using AP-III-a4 (ENOblock) could reduce the stemness of GC cells to a similar extent as the knockdown of ENO1 by shRNA. Finally, increased expression of ENO1 was related to poor prognosis in GC patients. Taken together, our results demonstrated that ENO1 is a significant biomarker associated with the stemness of GC cells.
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Affiliation(s)
- Ting Yang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiong Shu
- Laboratory of Molecular orthopaedics, Beijing Research Institute of Orthopaedics and Traumatology, Beijing Ji Shui Tan Hospital, Beijing, 100035, China
| | - Hui-Wen Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Li-Xin Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Long Yu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jun Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Li-Chao Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhi-Hua Yang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yu-Liang Ran
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Yao H, Sun L, Li J, Zhou X, Li R, Shao R, Zhang Y, Li L. A Novel Therapeutic siRNA Nanoparticle Designed for Dual-Targeting CD44 and Gli1 of Gastric Cancer Stem Cells. Int J Nanomedicine 2020; 15:7013-7034. [PMID: 33061365 PMCID: PMC7522319 DOI: 10.2147/ijn.s260163] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 08/07/2020] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Gastric cancer stem cells (CSCs) are important for the initiation, growth, recurrence, and metastasis of gastric cancer, due to their chemo-resistance and indefinite proliferation. Herein, to eliminate gastric CSCs, we developed novel CSC-targeting glioma-associated oncogene homolog 1 (Gli1) small interfering RNA (siRNA) nanoparticles that are specifically guided by a di-stearoyl-phosphatidyl-ethanolamine- hyaluronic-acid (DSPE-HA) single-point conjugate, as an intrinsic ligand of the CD44 receptor. We refer to these as targeting Gli1 siRNA nanoparticles. METHODS We used the reductive amination reaction method for attaching amine groups of DSPE to aldehydic group of hyaluronic acid (HA) at the reducing end, to synthesize the DSPE-HA single-point conjugate. Next, targeting Gli1 siRNA nanoparticles were prepared using the layer-by-layer assembly method. We characterized the stem cellular features of targeting Gli1 siRNA nanoparticles, including their targeting efficiency, self-renewal capacity, the migration and invasion capacity of gastric CSCs, and the penetration ability of 3D tumor spheroids. Next, we evaluated the therapeutic efficacy of the targeting Gli1 siRNA nanoparticles by using in vivo relapsed tumor models of gastric CSCs. RESULTS Compared with the multipoint conjugates, DSPE-HA single-point conjugates on the surface of nanoparticles showed significantly higher binding affinities with CD44. The targeting Gli1 siRNA nanoparticles significantly decreased Gli1 protein expression, inhibited CSC tumor spheroid and colony formation, and suppressed cell migration and invasion. Furthermore, in vivo imaging demonstrated that targeting Gli1 siRNA nanoparticles accumulated in tumor tissues, showing significant antitumor recurrence efficacy in vivo. CONCLUSION In summary, our targeting Gli1 siRNA nanoparticles significantly inhibited CSC malignancy features by specifically blocking Hedgehog (Hh) signaling both in vitro and in vivo, suggesting that this novel siRNA delivery system that specifically eliminates gastric CSCs provides a promising targeted therapeutic strategy for gastric cancer treatment.
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Affiliation(s)
- Hongjuan Yao
- Key Laboratory of Antibiotic Bioengineering of National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology (IMB), Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing100050, People’s Republic of China
| | - Lan Sun
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing100850, People’s Republic of China
| | - Jingcao Li
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing100850, People’s Republic of China
| | - Xiaofei Zhou
- Key Laboratory of Antibiotic Bioengineering of National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology (IMB), Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing100050, People’s Republic of China
| | - Rui Li
- Key Laboratory of Antibiotic Bioengineering of National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology (IMB), Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing100050, People’s Republic of China
| | - Rongguang Shao
- Key Laboratory of Antibiotic Bioengineering of National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology (IMB), Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing100050, People’s Republic of China
| | - Yingge Zhang
- Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing100850, People’s Republic of China
| | - Liang Li
- Key Laboratory of Antibiotic Bioengineering of National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology (IMB), Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing100050, People’s Republic of China
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Sun LF, Yang K, Wang YG, Liu YX, Hou PX, Lu ZH, Chen XL, Zhang WH, Zhou ZG, Mo XM, Hu JK. The Role of HER2 in Self-Renewal, Invasion, and Tumorigenicity of Gastric Cancer Stem Cells. Front Oncol 2020; 10:1608. [PMID: 32974199 PMCID: PMC7472958 DOI: 10.3389/fonc.2020.01608] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 07/24/2020] [Indexed: 02/05/2023] Open
Abstract
Background Deregulation of HER2 expression could affect the biological characteristics of gastric cancer cells and treatment option for gastric cancer patients. This research aims to investigate the impact of HER2 on biological characteristics of gastric cancer stem cells (GCSCs) and prognosis of gastric cancer patients. Methods HER2 knockdown in GCSCs were constructed by lentivirus transfection. Alterations of proliferation, self-renewal, invasion, migration, colony formation, and tumorigenicity of GCSCs were examined. The changes of gene expressions after HER2 interference in GCSCs were detected by gene microarray. The impact of concentration of serum HER2 and expression of HER2 in tumor tissues on survival of 213 gastric cancer patients was also analyzed. Results Down-regulation of HER2 decreased the self-renewal, colony formation, migration, invasion, proliferation, and chemotherapy resistance of GCSCs. However, the tumorigenicity of GCSCs in vivo was increased after down-regulation of HER2. The results of gene microarray showed that HER2 gene might regulate the signal transduction of mTOR, Jak-STAT, and other signal pathways and affect the biological characteristics of GCSCs. Furthermore, survival analyses indicated that patients with high concentration of HER2 in serum had a favorable overall survival. However, there was no significant correlation between expression of HER2 in tumor tissue and overall survival. Conclusion Interference of HER2 in GCSCs decreased the capacity of self-renewal, proliferation, colony formation, chemotherapy resistance, invasion, and migration but might increase the tumorigenicity in vivo. Patients with high concentration of HER2 in serum seemed to have a favorable prognosis.
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Affiliation(s)
- Li-Fei Sun
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Kun Yang
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Yi-Gao Wang
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yu-Xin Liu
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Pei-Xian Hou
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Zheng-Hao Lu
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Xiao-Long Chen
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Wei-Han Zhang
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Zong-Guang Zhou
- Department of Gastrointestinal Surgery and Laboratory of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Xian-Ming Mo
- Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Jian-Kun Hu
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
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Song XH, Chen XZ, Chen XL, Liu K, Zhang WH, Mo XM, Hu JK. Peritoneal Metastatic Cancer Stem Cells of Gastric Cancer with Partial Mesenchymal-Epithelial Transition and Enhanced Invasiveness in an Intraperitoneal Transplantation Model. Gastroenterol Res Pract 2020; 2020:3256538. [PMID: 32831823 PMCID: PMC7426763 DOI: 10.1155/2020/3256538] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 05/29/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES This preliminary study is aimed at enriching and isolating peritoneal metastatic cancer stem cells (pMCSCs) of gastric cancer and assessing their epithelial-mesenchymal transition (EMT) phenotype and invasiveness. METHODS Cancer stem cells of human gastric cancer (CSC-hGC) were previously isolated and transfected with green fluorescent protein and luciferase genes to validate the mouse model of peritoneal metastasis established via transplantation. The first and second generations ([G1] and [G2], respectively) of pMCSCs were isolated from intraperitoneally transplanted CSC-hGC (pMCSC-tGC) by spherical culture. CSC and EMT-related markers and regulators in the two generations of intraperitoneally transplanted tumors were examined by immunohistochemistry, immunofluorescence staining, and quantitative PCR. Cell mobility was examined by a transwell assay. RESULTS The nude mouse model of intraperitoneally transplanted CSC-hGC was successful in establishing sequential formation of peritoneal tumors and enrichment of pMCSCs. CD44 and CD54 were consistently expressed in the two generations of transplanted tumors. In vitro cell (migration) assays and immunocytofluorescence assays showed that in pMCSC-tGC[G2], E-cad, Survivin, and Vimentin expression was stable; α-SMA expression was decreased; and OVOL2, GRHL2, and ZEB1 expression was increased. PCR analysis indicated that in pMCSC-tGC[G2], the mRNA expression of E-cad, α-SMA, MMP9, MMP2, and Vimentin was downregulated, while that of ZEB1, OVOL2, and GRHL2 was upregulated. In vivo tumor (homing) assays and immunohistochemical assays demonstrated that in pMCSC-tGC[G2], E-cad and Snail were upregulated, while α-SMA was downregulated. The numbers of migrated and invaded pMCSC-tGC[G1] and pMCSC-tGC[G2] were significantly higher than those of CSC-hGC in migration and invasion assays. CONCLUSIONS pMCSCs might be a specific subpopulation that can be sequentially enriched by intraperitoneal transplantation. pMCSCs exhibited a tendency towards partial mesenchymal-epithelial transition, enhancing their invasiveness during homing and the formation of peritoneal tumors. However, these preliminary findings require validation in further experiments.
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Affiliation(s)
- Xiao-Hai Song
- Department of Gastrointestinal Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xin-Zu Chen
- Department of Gastrointestinal Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao-Long Chen
- Department of Gastrointestinal Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Kai Liu
- Department of Gastrointestinal Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Han Zhang
- Department of Gastrointestinal Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xian-Ming Mo
- Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, China
| | - Jian-Kun Hu
- Department of Gastrointestinal Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
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Pádua D, Figueira P, Ribeiro I, Almeida R, Mesquita P. The Relevance of Transcription Factors in Gastric and Colorectal Cancer Stem Cells Identification and Eradication. Front Cell Dev Biol 2020; 8:442. [PMID: 32626705 PMCID: PMC7314965 DOI: 10.3389/fcell.2020.00442] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 05/11/2020] [Indexed: 12/12/2022] Open
Abstract
Gastric and colorectal cancers have a high incidence and mortality worldwide. The presence of cancer stem cells (CSCs) within the tumor mass has been indicated as the main reason for tumor relapse, metastasis and therapy resistance, leading to poor overall survival. Thus, the elimination of CSCs became a crucial goal for cancer treatment. The identification of these cells has been performed by using cell-surface markers, a reliable approach, however it lacks specificity and usually differs among tumor type and in some cases even within the same type. In theory, the ideal CSC markers are those that are required to maintain their stemness features. The knowledge that CSCs exhibit characteristics comparable to normal stem cells that could be associated with the expression of similar transcription factors (TFs) including SOX2, OCT4, NANOG, KLF4 and c-Myc, and signaling pathways such as the Wnt/β-catenin, Hedgehog (Hh), Notch and PI3K/AKT/mTOR directed the attention to the use of these similarities to identify and target CSCs in different tumor types. Several studies have demonstrated that the abnormal expression of some TFs and the dysregulation of signaling pathways are associated with tumorigenesis and CSC phenotype. The disclosure of common and appropriate biomarkers for CSCs will provide an incredible tool for cancer prognosis and treatment. Therefore, this review aims to gather the new insights in gastric and colorectal CSC identification specially by using TFs as biomarkers and divulge promising drugs that have been found and tested for targeting these cells.
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Affiliation(s)
- Diana Pádua
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Paula Figueira
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Inês Ribeiro
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Raquel Almeida
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Patrícia Mesquita
- i3S – Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
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El-Gowily AH, Abosheasha MA. Differential mechanisms of autophagy in cancer stem cells: Emphasizing gastrointestinal cancers. Cell Biochem Funct 2020; 39:162-173. [PMID: 32468609 DOI: 10.1002/cbf.3552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/17/2020] [Accepted: 05/03/2020] [Indexed: 12/15/2022]
Abstract
Gastrointestinal (GI) cancers are one of the most common forms of malignancies and still are the most important cause of cancer-related mortality worldwide. Autophagy is a conserved catabolic pathway involving lysosomal degradation and recycling of whole cellular components, which is essential for cellular homeostasis. For instance, it acts as a pivotal intracellular quality control and repair mechanism but also implicated in cell reformation during cell differentiation and development. Indeed, GI cancer stem cells (CSCs) are thought to be responsible for tumour initiation, traditional therapies resistance, metastasis and tumour recurrence. Molecular mechanisms of autophagy in normal vs CSCs gain great interest worldwide. Here, we shed light on the role of autophagy in normal stem cells differentiation for embryonic progression and its role in maintaining the activity and self-renewal capacity of CSCs which offer novel viewpoints on promising cancer therapeutic strategies based on the differential roles of autophagy in CSCs.
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Affiliation(s)
- Afnan H El-Gowily
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, Egypt.,Organ and Cell physiology Department, Juntendo University, Tokyo, Japan
| | - Mohammed A Abosheasha
- Cellular Genetics Laboratory, Graduate School of Science, Tokyo Metropolitan University, Tokyo, Japan
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