|
1
|
Chen D, Wang W, Chen X, Liang N, Li J, Ding W, Zhang H, Yang Z, Zhao H, Liu Z. Plant-derived extracts or compounds for Helicobacter-associated gastritis: a systematic review of their anti-Helicobacter activity and anti-inflammatory effect in animal experiments. Chin Med 2025; 20:53. [PMID: 40264171 PMCID: PMC12013188 DOI: 10.1186/s13020-025-01093-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 03/10/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Helicobacter infection, which is the leading cause of gastritis and stomach cancer, has become common worldwide. Almost all Helicobacter-infected patients have chronic active gastritis, also known as Helicobacter-associated gastritis (HAG). However, the eradication rate of Helicobacter is decreasing due to the poor efficacy of current medications, which causes infection to recur, inflammation to persist, and stomach cancer to develop. Natural components have robust antibacterial activity and anti-inflammatory capacity, as confirmed by many studies of alternative natural medicines. PURPOSE This article aimed to conduct a comprehensive search and meta-analysis to evaluate the efficacy of anti-Helicobacter and anti-inflammatory activities of plant-derived extracts or compounds that can treat HAG in animal experiments. We intended to provide detailed preclinical-research foundation including plant and compound information, as well as the mechanisms by which these plant-derived substances inhibit the progression of Helicobacter infection, gastritis and neoplasms for future study. METHODS The systematic review is aligned with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the protocol was registered in PROSPERO (CRD42024527889). An extensive search was performed across multiple databases, including PubMed, Scopus, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal database (VIP), the Wanfang database, and the China biomedical literature service system (SinoMed), up until November 2023. Meta-analysis on Review Manager software (RevMan 5.4) estimating anti-Helicobacter and anti-inflammatory activity was performed. We used the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk of bias tool to evaluate the risk of bias of each study included. RESULTS Our study encompassed 61 researches, comprised 36 extracts and 37 compounds improving HAG by inhibiting Helicobacter infection, the inflammatory response, oxidative stress, and regulating apoptosis and proliferation. Sixteen families especially Asteraceae, Fabaceae and Rosaceae and nine classes including Terpenoids, Alkaloids, Phenols, and Flavonoids may be promising directions for valuable new drugs. The Meta-analyse demonstrated the plant-base substance treatments possess significant anti-Helicobacter and anti-inflammation activity comparing to control groups. The included plants and compounds confirmed that signaling pathways NF-κB, JAK2/STAT3, MAPK, TLR4/MyD88, PI3K/AKT, NLRP3/Caspase-1 and NRF2/HO-1 play a key role in the progression of HAG. CONCLUSION Plant-derived extracts or compounds actively improve HAG by modulating relevant mechanisms and signaling pathways, particularly through the anti-Helicobacter and inflammatory regulation ways. Further researches to apply these treatments in humans are needed, which will provide direction for the future development of therapeutic drugs to increase eradication rate and alleviate gastritis.
Collapse
Affiliation(s)
- Danni Chen
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Wenlai Wang
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei, Dongcheng District, Beijing, 100700, China
| | - Xiangyun Chen
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Ning Liang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Jiawang Li
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Wei Ding
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Hongrui Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing, 100700, China
- Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Zhen Yang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China.
| | - Hongxia Zhao
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei, Dongcheng District, Beijing, 100700, China.
| | - Zhenhong Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing, 100700, China.
- Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, 100700, China.
| |
Collapse
|
|
2
|
Lospinoso Severini F, Falco G, Notarangelo T. Role of Soluble Cytokine Receptors in Gastric Cancer Development and Chemoresistance. Int J Mol Sci 2025; 26:2534. [PMID: 40141175 PMCID: PMC11942508 DOI: 10.3390/ijms26062534] [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: 01/27/2025] [Revised: 02/28/2025] [Accepted: 03/08/2025] [Indexed: 03/28/2025] Open
Abstract
Gastric cancer is among the top five most important malignancies in the world due to the high burden of the disease and its lethality. Indeed, it is the fourth most common cause of death worldwide, characterized by a poor prognosis and low responsiveness to chemotherapy. Multidrug resistance limits the clinical management of the patient. Among these, the role of chronic activation of inflammatory pathways underlying gastric tumorigenesis should be highlighted. Furthermore, the gastric immunosuppressive TME influences the response to therapy. This review discusses the role of soluble cytokine receptors in the development and chemoresistance of gastric cancer, considered as a molecular marker and target of strategies to overcome resistance.
Collapse
Affiliation(s)
- Francesca Lospinoso Severini
- Laboratory of Preclinical and Translational Research, IRCCS CROB Centro di Riferimento Oncologico della Basilicata, 85028 Rionero in Vulture, PZ, Italy
| | - Geppino Falco
- Department of Biology, University of Naples Federico II, 80138 Napoli, NA, Italy
- Biogem, Istituto di Biologia e Genetica Molecolare, 83031 Ariano Irpino, AV, Italy
| | - Tiziana Notarangelo
- Laboratory of Preclinical and Translational Research, IRCCS CROB Centro di Riferimento Oncologico della Basilicata, 85028 Rionero in Vulture, PZ, Italy
| |
Collapse
|
|
3
|
Liu Q, Shaibu Z, Xu A, Yang F, Cao R, Yang F. Predictive value of serum cytokines in patients with non-small-cell lung cancer receiving anti-PD-1 blockade therapy: a meta-analysis. Clin Exp Med 2025; 25:59. [PMID: 39955679 PMCID: PMC11830645 DOI: 10.1007/s10238-025-01587-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 02/03/2025] [Indexed: 02/17/2025]
Abstract
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Immunotherapy, particularly PD-1 inhibitors, has revolutionized the treatment landscape for NSCLC. However, the predictive biomarkers for PD-1 inhibitor therapy are still limited. Serum cytokines have emerged as potential biomarkers for predicting treatment outcomes. This meta-analysis aims to investigate the predictive value of serum cytokines in PD-1 inhibitor therapy for NSCLC. We conducted a comprehensive literature search in major databases, including PubMed, Google scholar, Embase, and Cochrane database, with a focus on literature published up until October 22, 2024. Studies investigating the association between serum cytokine levels and treatment outcomes in NSCLC patients receiving PD-1 inhibitor therapy were included. The primary outcomes were progression-free survival (PFS) and overall survival (OS). The meta-analysis revealed that elevated IL-6 levels were significantly associated with poorer PFS in NSCLC patients (HR = 2.30, 95% CI [1.39-3.80], P = 0.001). Additionally, high IL-10 expression was related to poorer PFS in NSCLC after therapy (HR = 2.45, 95% CI [1.26-4.76], P = 0.009). In contrast, no significant associations were found between OS and the expression of various cytokines, including IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, IL-1β, TNF-α, and IL-12p70. This meta-analysis demonstrates that elevated IL-6 and IL-10 levels are significantly associated with poorer PFS in NSCLC patients receiving PD-1 inhibitor therapy. These findings suggest that serum cytokine levels may serve as predictive biomarkers for treatment outcomes. Further studies are needed to validate these results and explore the underlying mechanisms.
Collapse
Affiliation(s)
- Qian Liu
- Department of Laboratory Medicine, Lianyungang Clinical College Jiangsu University & the Second People'S Hospital of Lianyungang, 41 East Hailian Road, Lianyungang, 222006, Jiangsu, China
- Department of Laboratory Medicine, Lianyungang Clinical College Xuzhou Medical University & the Second People'S Hospital of Lianyungang, Lianyungang, 222006, Jiangsu, China
- Department of Laboratory Medicine, The Second People'S Hospital of Lianyungang Affiliated with Kangda College of Nanjing Medical University, Lianyungang, 222006, Jiangsu, China
- Department of Laboratory Medicine, Lianyungang Clinical College, Bengbu Medical University & the Second People'S Hospital of Lianyungang, Lianyungang, 222006, Jiangsu, China
| | - Zakari Shaibu
- School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Aiguo Xu
- Department of Oncology, The Second People'S Hospital of Lianyungang, Lianyungang, 222006, Jiangsu, China
| | - Fang Yang
- Department of Laboratory Medicine, Lianyungang Clinical College Jiangsu University & the Second People'S Hospital of Lianyungang, 41 East Hailian Road, Lianyungang, 222006, Jiangsu, China
- Department of Laboratory Medicine, Lianyungang Clinical College Xuzhou Medical University & the Second People'S Hospital of Lianyungang, Lianyungang, 222006, Jiangsu, China
- Department of Laboratory Medicine, The Second People'S Hospital of Lianyungang Affiliated with Kangda College of Nanjing Medical University, Lianyungang, 222006, Jiangsu, China
- Department of Laboratory Medicine, Lianyungang Clinical College, Bengbu Medical University & the Second People'S Hospital of Lianyungang, Lianyungang, 222006, Jiangsu, China
| | - Ruoxue Cao
- Department of Laboratory Medicine, Lianyungang Clinical College Jiangsu University & the Second People'S Hospital of Lianyungang, 41 East Hailian Road, Lianyungang, 222006, Jiangsu, China
- Department of Laboratory Medicine, Lianyungang Clinical College Xuzhou Medical University & the Second People'S Hospital of Lianyungang, Lianyungang, 222006, Jiangsu, China
- Department of Laboratory Medicine, The Second People'S Hospital of Lianyungang Affiliated with Kangda College of Nanjing Medical University, Lianyungang, 222006, Jiangsu, China
- Department of Laboratory Medicine, Lianyungang Clinical College, Bengbu Medical University & the Second People'S Hospital of Lianyungang, Lianyungang, 222006, Jiangsu, China
| | - Fumeng Yang
- Department of Laboratory Medicine, Lianyungang Clinical College Jiangsu University & the Second People'S Hospital of Lianyungang, 41 East Hailian Road, Lianyungang, 222006, Jiangsu, China.
- Department of Laboratory Medicine, Lianyungang Clinical College Xuzhou Medical University & the Second People'S Hospital of Lianyungang, Lianyungang, 222006, Jiangsu, China.
- Department of Laboratory Medicine, The Second People'S Hospital of Lianyungang Affiliated with Kangda College of Nanjing Medical University, Lianyungang, 222006, Jiangsu, China.
- Department of Laboratory Medicine, Lianyungang Clinical College, Bengbu Medical University & the Second People'S Hospital of Lianyungang, Lianyungang, 222006, Jiangsu, China.
| |
Collapse
|
|
4
|
Zhang L, Guo X, Sun X, Liao J, Liu Q, Ye Y, Yang Z, Cressey R, He Q, Yuan Q. Analysis of tumor-infiltrating exhausted T cells highlights IL-6 and PD1 blockade as a combined immunotherapy strategy for non-small cell lung cancer. Front Immunol 2025; 16:1486329. [PMID: 40040705 PMCID: PMC11876966 DOI: 10.3389/fimmu.2025.1486329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 01/20/2025] [Indexed: 03/06/2025] Open
Abstract
Objective Given the limitations of immunotherapy for treating non-small cell lung cancer (NSCLC), we investigated the phenotype and function of exhausted CD8+T cells and analyzed a novel combination immunotherapy to restore the effector killing function of tumor-infiltrating CD8+T lymphocyte (TIL). Methods We examined the expression and function of immunosuppressive molecules on CD8+T cells of peripheral blood mononuclear cells (PBMCs) and TILs by using prospectively collected peripheral blood, pleural effusions, and tumor tissues from patients with NSCLC and correlated the results with clinical data. We then evaluated the effect of interleukin 6 (IL-6) stimulation on CD8+T cells. Finally, we assessed the effects of combined blockade of PD1 and IL-6 on macrophage recruitment in a zebrafish macrophage model and CD8+ T cell function and tumor growth in PBMC humanized mouse model. Results The expression of exhaustion markers on CD8+ T cells was found to be notably higher in both tumor and paraneoplastic tissues compared to peripheral blood. Furthermore, the degree of CD8+ T cell exhaustion exhibited a progressive increase with proximity to the tumor. When CD8+ T cells from peripheral blood and tumor tissues of NSCLC patients were stimulated with IL-6, the expression level of exhaustion markers, especially PD1, was further elevated. In the in vitro experiment, the combined inhibition of IL-6 and PD1 substantially enhanced the effector killing function of CD8+ T cells in NSCLC pleural effusion samples. In a macrophage-labeled zebrafish model, combined blockade of IL-6 and PD1 enhanced the recruitment of macrophages. In PBMC humanized mouse model, combined blockade of IL-6 and PD1 enhanced the inhibition of tumor growth. Conclusion Our data suggest that CD8+ T cells in NSCLC patients were in a state of exhaustion and combined blockade of IL-6 and PD1 to restore CD8+ T cell function to inhibit tumor growth may be an effective clinical strategy for the treatment of NSCLC.
Collapse
Affiliation(s)
- Lulu Zhang
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
- Blood Distribution Department Nanjing Red Cross Blood Center, Nanjing, Jiangsu, China
| | - Xiyuan Guo
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
- Division of Clinical Chemistry, Department of Medical Technology, Faculty of Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Xiaoke Sun
- Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Jue Liao
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
| | - Qin Liu
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
| | - Yingchun Ye
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
| | - Zhihui Yang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Ratchada Cressey
- Division of Clinical Chemistry, Department of Medical Technology, Faculty of Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Qing He
- Department of Head and Neck Oncology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Qing Yuan
- Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
- Institute of Nuclear Medicine, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, China
| |
Collapse
|
|
5
|
Soto D, Serafín V, Pedrero M, Pingarrón JM, Campuzano S, Orozco J. Hierarchical Au@Pt nanoparticle/amino benzoic acid polymer-based hybrid material for labeled and label-free detection of interleukin-6: a comparative assessment. Mikrochim Acta 2024; 191:683. [PMID: 39432122 PMCID: PMC11493819 DOI: 10.1007/s00604-024-06745-y] [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: 08/14/2024] [Accepted: 10/02/2024] [Indexed: 10/22/2024]
Abstract
Interleukin-6 (IL6) is a cytokine mainly involved in inflammatory processes associated with various diseases, from rheumatoid arthritis and pathogen-caused infections to cancer, where malignant cells exhibit high proliferation and overexpression of cytokines, including IL6. Furthermore, IL6 plays a fundamental role in detecting and differentiating tumor cells, including colorectal cancer (CRC) cells. Therefore, given its range of biological activities and pathological role, IL6 determination has been claimed for the diagnosis/prognosis of immune-mediated diseases. Herein, a comparative study is presented of labeled and label-free electrochemical immunosensors involving a hierarchical Au@Pt nanoparticle/polymer hybrid material for detecting IL6. The electrochemical immunosensors were independently coupled to the surface of screen-printed carbon electrodes (SPCEs) previously modified with polymeric layers. While in the label-free immunosensor, an anti-IL6 antibody (IL6-Ab) was covalently bound to the modified SPCE surface, in the sandwich-like amperometric immunosensor, an anti-biotinylated-IL6 antibody (B-IL6-Ab) was attached to the electrode through biotin-avidin affinity interactions. The label-free format employed a straightforward detection of IL6 by differential pulse voltammetry (DPV). The resulting electrochemical immunosensors exhibited a linear dynamic range from 50 to 750 pg/mL IL6, with detection limits (LOD) of 14.4 and 6.0 pg/mL for label-free and sandwich-like immunosensors, respectively. This outstanding performance makes them versatile platforms for clinical analysis of a panel of biomarkers for early diagnosis/prognosis of inflammatory processes associated with oncological diseases, among other pathologies.
Collapse
Affiliation(s)
- Dayana Soto
- Max Planck Tandem Group in Nanobioengieneering, University of Antioquia, Complejo Ruta N, Calle 67 Nº 52-20, 050010, Medellín, Colombia
- CECOLTEC Group, Cecoltec Services S.A.S Company, Universidad EAFIT, Edificio Ingenierías, Bloque 19, 050022, Medellín, Colombia
| | - Verónica Serafín
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Pza. de Las Ciencias 2, 28040, Madrid, Spain
| | - María Pedrero
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Pza. de Las Ciencias 2, 28040, Madrid, Spain
| | - José M Pingarrón
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Pza. de Las Ciencias 2, 28040, Madrid, Spain
| | - Susana Campuzano
- Departamento de Química Analítica, Facultad de CC. Químicas, Universidad Complutense de Madrid, Pza. de Las Ciencias 2, 28040, Madrid, Spain
| | - Jahir Orozco
- Max Planck Tandem Group in Nanobioengieneering, University of Antioquia, Complejo Ruta N, Calle 67 Nº 52-20, 050010, Medellín, Colombia.
| |
Collapse
|
|
6
|
Zhang Y, Li J, Li J, Wang J. Dysregulation of systemic immunity and its clinical application in gastric cancer. Front Immunol 2024; 15:1450128. [PMID: 39301031 PMCID: PMC11410619 DOI: 10.3389/fimmu.2024.1450128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 08/22/2024] [Indexed: 09/22/2024] Open
Abstract
Immunotherapy has profoundly changed the treatment of gastric cancer, but only a minority of patients benefit from immunotherapy. Therefore, numerous studies have been devoted to clarifying the mechanisms underlying resistance to immunotherapy or developing biomarkers for patient stratification. However, previous studies have focused mainly on the tumor microenvironment. Systemic immune perturbations have long been observed in patients with gastric cancer, and the involvement of the peripheral immune system in effective anticancer responses has attracted much attention in recent years. Therefore, understanding the distinct types of systemic immune organization in gastric cancer will aid personalized treatment designed to pair with traditional therapies to alleviate their detrimental effects on systemic immunity or to directly activate the anticancer response of systemic immunity. Herein, this review aims to comprehensively summarize systemic immunity in gastric cancer, including perturbations in systemic immunity induced by cancer and traditional therapies, and the potential clinical applications of systemic immunity in the detection, prediction, prognosis and therapy of gastric cancer.
Collapse
Affiliation(s)
- Yao Zhang
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Junfeng Li
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Department of Pharmacy, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Jian Li
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Jisheng Wang
- School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Department of Pharmacy, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| |
Collapse
|
|
7
|
Yang Z, Guo L, Sun Y, Huang Y, Li J, Lin Y, Zhang X, Wu D, Luo Y. Investigation of the causal relationship between Interleukin-6 signaling and gastrointestinal tract cancers: A Mendelian randomization study. Dig Liver Dis 2024; 56:679-686. [PMID: 37612215 DOI: 10.1016/j.dld.2023.08.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/28/2023] [Accepted: 08/11/2023] [Indexed: 08/25/2023]
Abstract
BACKGROUND Observational studies indicate that interleukin-6(IL-6) has been associated with gastrointestinal tract cancers. However, the causal association is still confusing. Thus, we aimed to putative the causality between IL-6 signaling and gastrointestinal tract cancers. METHODS We conducted a two-sample Mendelian randomization analysis to assess the causal effects. Two groups of IL-6 signaling-related single nucleotide polymorphisms were chosen from two Genome-wide association studies. Summary-level data for gastrointestinal tract cancers including esophageal, gastric, and colorectal cancer, were obtained from the FinnGen consortium and UK Biobank study. We also performed survival analysis to explore the prognostic value of IL-6 in gastrointestinal tract cancers. RESULTS Genetically predicted plasma sIL6R level, which inhibits IL-6 Signaling, was associated with a reduced risk of gastric cancer in FinnGen. In the combined analysis of the two sources, genetically predicted sIL6R was associated with a decreased risk of gastric cancer (OR = 0.943, 95%CI: 0.904,0.983, p = 0.006). Survival analysis results indicated the prognostic value of IL-6 in gastric cancer. CONCLUSIONS These results present evidence indicating that genetically-determined reduced IL-6 signaling lowers the risk of gastric cancer, which may provide potential prevention and therapeutic strategies for gastric cancer. Additionally, IL-6 may be a prognostic biomarker for gastric cancer.
Collapse
Affiliation(s)
- Ze Yang
- Department of Biochemistry & Cancer Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhejiang 310058, China
| | - Lingyun Guo
- Department of Biochemistry & Cancer Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhejiang 310058, China
| | - Yandi Sun
- Department of Biochemistry & Cancer Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhejiang 310058, China
| | - Yingfei Huang
- Department of Biochemistry & Cancer Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhejiang 310058, China
| | - Jingjia Li
- Department of Biochemistry & Cancer Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhejiang 310058, China
| | - Yindan Lin
- Department of Biochemistry & Cancer Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhejiang 310058, China
| | - Xueyun Zhang
- Department of Biochemistry & Cancer Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhejiang 310058, China
| | - Di Wu
- Department of Biochemistry & Cancer Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhejiang 310058, China
| | - Yan Luo
- Department of Biochemistry & Cancer Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, Zhejiang 310058, China.
| |
Collapse
|
|
8
|
Pu K, Feng Y, Tang Q, Yang G, Xu C. Review of dietary patterns and gastric cancer risk: epidemiology and biological evidence. Front Oncol 2024; 14:1333623. [PMID: 38444674 PMCID: PMC10912593 DOI: 10.3389/fonc.2024.1333623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 02/02/2024] [Indexed: 03/07/2024] Open
Abstract
Due to rapid research expansion on dietary factors and development of cancer prevention guidelines, the field of dietary pattern and its relationship to cancer risk has gained more focus. Numerous epidemiology studies have reported associations between Gastric Cancer (GC) and both data-driven posteriori dietary pattern and priori dietary pattern defined by predetermined dietary indexes. As dietary patterns have evolved, a series of patterns based on biological markers has advanced, offering deeper insights into the relationship between diet and the risk of cancer. Although researches on dietary patterns and cancer risk are booming, there is limited body of literature focusing specifically on GC. In this study, we compare the similarities and differences among the specific components of dietary patterns and indices, summarize current state of knowledge regarding dietary patterns related to GC and illustrate their potential mechanisms for GC prevention. In conclusion, we offer suggestions for future research based on the emerging themes within this rapidly evolving field.
Collapse
Affiliation(s)
- Ke Pu
- Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Yang Feng
- Department of Neurosurgery, Xi’an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi’an, Shaanxi, China
| | - Qian Tang
- Statesboro Office, Southeast Medical Group, Atlanta, GA, United States
| | - Guodong Yang
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Chuan Xu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| |
Collapse
|
|
9
|
Marcisz-Grzanka K, Kotowicz B, Nowak A, Winiarek M, Fuksiewicz M, Kowalska M, Tysarowski A, Olesinski T, Palucki J, Sulkowska U, Kolasinska-Cwikla A, Wyrwicz LS. Interleukin-6 as a Predictive Factor of Pathological Response to FLOT Regimen Systemic Treatment in Locally Advanced Gastroesophageal Junction or Gastric Cancer Patients. Cancers (Basel) 2024; 16:757. [PMID: 38398148 PMCID: PMC10887209 DOI: 10.3390/cancers16040757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/06/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND Perioperative treatment is a gold standard in locally advanced gastric cancer or GEJ cancer in the Western population. Unfortunately, the response rate after neoadjuvant chemotherapy (NAC) remains limited. Moreover, there are currently no biomarkers enabling an individual prediction of therapeutic efficacy. The aim of this study was the identification of serum biomarkers of early response to NAC. METHODS We conducted this prospective study in the MSCNRIO in Warsaw, Poland. A total of 71 patients and 15 healthy volunteers gave informed consent. Complete blood count, carcinoembryonic antigen (CEA), carcinoma antigen 125 (CA125), carcinoma antigen 19.9 (CA19.9), and fibrinogen (F) were measured at baseline and before every cycle. Circulating tumour cells (CTCs) and interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10) were measured in a pilot group of 40 patients at baseline and before cycle two (C2) and cycle three (C3). RESULTS Of all the measured parameters, only the IL-6 serum level was statistically significant. The IL-6 level before C2 of chemotherapy was significantly decreased in the complete pathological response (pCR) vs. the non-pCR group (3.71 pg/mL vs. 7.63 pg/mL, p = 0.004). In all patients with an IL-6 level below 5.0 pg/mL in C2, tumour regression TRG1a/1b according to the Becker classification and ypN0 were detected in postoperative histopathological specimens. The IL-6 level before C1 of chemotherapy was significantly elevated in ypN+ vs. ypN0 (7.69 pg/mL vs. 2.89 pg/mL, p = 0.022). CONCLUSIONS The trial showed that an elevated level of IL-6 prior to treatment and C2 might be a predictor of pathological response to NAC.
Collapse
Affiliation(s)
- Katarzyna Marcisz-Grzanka
- Department of Clinical Oncology and Radiotherapy, Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), Wawelska 15, 02-034 Warsaw, Poland; (M.W.); (A.K.-C.)
| | - Beata Kotowicz
- Cancer Biomarker and Cytokines Laboratory Unit, Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), W.K. Roentgena 5, 02-781 Warsaw, Poland; (B.K.); (M.F.); (M.K.)
| | - Aleksandra Nowak
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), W.K. Roentgena 5, 02-781 Warsaw, Poland; (A.N.); (A.T.)
| | - Mariola Winiarek
- Department of Clinical Oncology and Radiotherapy, Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), Wawelska 15, 02-034 Warsaw, Poland; (M.W.); (A.K.-C.)
| | - Malgorzata Fuksiewicz
- Cancer Biomarker and Cytokines Laboratory Unit, Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), W.K. Roentgena 5, 02-781 Warsaw, Poland; (B.K.); (M.F.); (M.K.)
| | - Maria Kowalska
- Cancer Biomarker and Cytokines Laboratory Unit, Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), W.K. Roentgena 5, 02-781 Warsaw, Poland; (B.K.); (M.F.); (M.K.)
| | - Andrzej Tysarowski
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), W.K. Roentgena 5, 02-781 Warsaw, Poland; (A.N.); (A.T.)
| | - Tomasz Olesinski
- Department of Oncological Surgery and Neuroendocrine Tumors, Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), W.K. Roentgena 5, 02-781 Warsaw, Poland;
| | - Jakub Palucki
- Department of Radiology, Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), W.K. Roentgena 5, 02-781 Warsaw, Poland;
| | - Urszula Sulkowska
- National Cancer Registry, Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), Wawelska 15B, 02-034 Warsaw, Poland;
| | - Agnieszka Kolasinska-Cwikla
- Department of Clinical Oncology and Radiotherapy, Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), Wawelska 15, 02-034 Warsaw, Poland; (M.W.); (A.K.-C.)
| | - Lucjan Stanislaw Wyrwicz
- Department of Clinical Oncology and Radiotherapy, Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), Wawelska 15, 02-034 Warsaw, Poland; (M.W.); (A.K.-C.)
| |
Collapse
|
|
10
|
Fang KT, Hung H, Lau NYS, Chi JH, Wu DC, Cheng KH. Development of a Genetically Engineered Mouse Model Recapitulating LKB1 and PTEN Deficiency in Gastric Cancer Pathogenesis. Cancers (Basel) 2023; 15:5893. [PMID: 38136437 PMCID: PMC10741874 DOI: 10.3390/cancers15245893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/12/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023] Open
Abstract
The LKB1 and PTEN genes are critical in gastric cancer (G.C.) development. LKB1, a robust tumor suppressor gene, encodes a serine/threonine kinase that directly triggers the activation of AMPK-an integral cellular metabolic kinase. The role of the LKB1 pathway extends to maintaining the stability of epithelial junctions by regulating E-cadherin expression. Conversely, PTEN, a frequently mutated tumor suppressor gene in various human cancers, emerges as a pivotal negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. This study is set to leverage the H+/K+ ATPase Cre transgene strain to precisely target Cre recombinase expression at parietal cells within the stomach. This strategic maneuver seeks to selectively nullify the functions of both LKB1 and PTEN in a manner specific to the stomach, thereby instigating the development of G.C. in a fashion akin to human gastric adenocarcinoma. Moreover, this study endeavors to dissect the intricate ways in which these alterations contribute to the histopathologic advancement of gastric tumors, their potential for invasiveness and metastasis, their angiogenesis, and the evolving tumor stromal microenvironment. Our results show that conditional deletion of PTEN and LKB1 provides an ideal cancer microenvironment for G.C. tumorigenesis by promoting cancer cell proliferation, angiogenesis, and metastasis.
Collapse
Affiliation(s)
- Kuan-Te Fang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
| | - Hsin Hung
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
| | - Nga Yin Sadonna Lau
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Jou-Hsi Chi
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Deng-Chyang Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Kuang-Hung Cheng
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan
| |
Collapse
|
|
11
|
Kaviani E, Hajibabaie F, Abedpoor N, Safavi K, Ahmadi Z, Karimy A. System biology analysis to develop diagnostic biomarkers, monitoring pathological indexes, and novel therapeutic approaches for immune targeting based on maggot bioactive compounds and polyphenolic cocktails in mice with gastric cancer. ENVIRONMENTAL RESEARCH 2023; 238:117168. [PMID: 37742751 DOI: 10.1016/j.envres.2023.117168] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/26/2023] [Accepted: 09/15/2023] [Indexed: 09/26/2023]
Abstract
Early diagnosis and prognosis are prerequisites for mitigating mortality in gastric cancer (GaCa). Identifying some causative or sensitive elements (coding RNA (cRNA)-non-cRNAs (ncRNAs)) can be very helpful in the early diagnosis of GaCa. Notably, despite significant development in the GaCa treatment, the outcome of patients does not remain satisfactory due to limitations such as multi-drug resistance and tumor relapse. Therefore, more attention has been drawn to complementary therapies and the use of supplements. In this regard, Polyphenol natural compounds (PNC) and maggot larvae (MaLa) alone or in combination were administered along with chemotherapy (paclitaxel) to N-methyl-N-nitrosourea (MNU)- induced murine tumor model. In addition, in order to identify potential diagnostic or prognostic biomarkers, transcriptomics analysis was performed through a bioinformatics approach. Then transcription profile of ncRNAs with their target hub genes was assessed through qPCR Real-Time, Western blot, and ELISA. According to the bioinformatics results, 17 hub genes (e.g., IL-6, CXCL8, MKI67, IL-2, IL-4, IL-10, IL-1β, SPP1, LOX, COL1A1, and IFN-γ) were explored that contribute towards inflammation and oxidative stress and ultimately GaCa development. Upstream of the mentioned hub genes, regulatory factors (lncRNA XIST and NEAT1) were also identified and introduced as prognosis and diagnosis biomarkers for GaCa. Our results showed that PNC alone and in combination with MaLa was able to reduce the size and number of tumors, which is related to the reduction of genes expression levels (including IL-6, CXCL8, MKI67, IL-2, IL-4, IL-10, IL-1β, SPP1, LOX, COL1A1, IFN-γ, NEAT1, and XIST). In conclusion, PNC and MaLa have the potential to be considered as complementary and improving chemotherapy due to their effective compounds. Also, the introduced hub gene and lncRNA in addition to diagnostic and prognostic biomarkers can be used as druggable proteins for novel therapeutic targeting of GaCa.
Collapse
Affiliation(s)
- Elina Kaviani
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Fatemeh Hajibabaie
- Department of Physiology, Medicinal Plants Research Center, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran; Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Navid Abedpoor
- Department of Physiology, Medicinal Plants Research Center, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran; Department of Sports Physiology, Faculty of Sports Sciences, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran.
| | - Kamran Safavi
- Department of Plant Biotechnology, Medicinal Plants Research Centre, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran.
| | - Zahra Ahmadi
- Department of Physiology, Medicinal Plants Research Center, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran; Department of Sports Physiology, Faculty of Sports Sciences, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran.
| | - Azadeh Karimy
- Department of Plant Biotechnology, Medicinal Plants Research Centre, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran.
| |
Collapse
|
|
12
|
Yadav M, Uikey BN, Rathore SS, Gupta P, Kashyap D, Kumar C, Shukla D, Vijayamahantesh, Chandel AS, Ahirwar B, Singh AK, Suman SS, Priyadarshi A, Amit A. Role of cytokine in malignant T-cell metabolism and subsequent alternation in T-cell tumor microenvironment. Front Oncol 2023; 13:1235711. [PMID: 37746258 PMCID: PMC10513393 DOI: 10.3389/fonc.2023.1235711] [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: 06/06/2023] [Accepted: 08/14/2023] [Indexed: 09/26/2023] Open
Abstract
T cells are an important component of adaptive immunity and T-cell-derived lymphomas are very complex due to many functional sub-types and functional elasticity of T-cells. As with other tumors, tissues specific factors are crucial in the development of T-cell lymphomas. In addition to neoplastic cells, T- cell lymphomas consist of a tumor micro-environment composed of normal cells and stroma. Numerous studies established the qualitative and quantitative differences between the tumor microenvironment and normal cell surroundings. Interaction between the various component of the tumor microenvironment is crucial since tumor cells can change the microenvironment and vice versa. In normal T-cell development, T-cells must respond to various stimulants deferentially and during these courses of adaptation. T-cells undergo various metabolic alterations. From the stage of quiescence to attention of fully active form T-cells undergoes various stage in terms of metabolic activity. Predominantly quiescent T-cells have ATP-generating metabolism while during the proliferative stage, their metabolism tilted towards the growth-promoting pathways. In addition to this, a functionally different subset of T-cells requires to activate the different metabolic pathways, and consequently, this regulation of the metabolic pathway control activation and function of T-cells. So, it is obvious that dynamic, and well-regulated metabolic pathways are important for the normal functioning of T-cells and their interaction with the microenvironment. There are various cell signaling mechanisms of metabolism are involved in this regulation and more and more studies have suggested the involvement of additional signaling in the development of the overall metabolic phenotype of T cells. These important signaling mediators include cytokines and hormones. The impact and role of these mediators especially the cytokines on the interplay between T-cell metabolism and the interaction of T-cells with their micro-environments in the context of T-cells lymphomas are discussed in this review article.
Collapse
Affiliation(s)
- Megha Yadav
- Department of Forensic Science, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
| | - Blessi N. Uikey
- Department of Forensic Science, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
| | | | - Priyanka Gupta
- Department of Forensic Science, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
| | - Diksha Kashyap
- Department of Forensic Science, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
| | - Chanchal Kumar
- Department of Forensic Science, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
| | - Dhananjay Shukla
- Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
| | - Vijayamahantesh
- Department of Immunology and Microbiology, University of Missouri, Columbia, SC, United States
| | - Arvind Singh Chandel
- Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Bunkyo, Japan
| | - Bharti Ahirwar
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
| | | | - Shashi Shekhar Suman
- Department of Zoology, Udayana Charya (UR) College, Lalit Narayan Mithila University, Darbhanga, India
| | - Amit Priyadarshi
- Department of Zoology, Veer Kunwar Singh University, Arrah, India
| | - Ajay Amit
- Department of Forensic Science, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
| |
Collapse
|
|
13
|
Tobi M, Weinstein D, Kim M, Hatfield J, Sochacki P, Levi E, An T, Hamre M, Tolia V, Fligiel S, Marepally R, Hallman J, Bapat B, Yuan M, McVicker B, Gallinger S. Helicobacter pylori Status May Differentiate Two Distinct Pathways of Gastric Adenocarcinoma Carcinogenesis. Curr Oncol 2023; 30:7950-7963. [PMID: 37754493 PMCID: PMC10527591 DOI: 10.3390/curroncol30090578] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/09/2023] [Accepted: 08/02/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND We evaluated the phenotype of sporadic gastric cancer based on HP status and binding of a tumor risk marker monoclonal, Adnab-9. METHODS We compared a familial GC kindred with an extremely aggressive phenotype to HP-positive (HP+) and -negative (HP-) sporadic gastric adenocarcinoma (GC) patients in the same community to determine if similar phenotypes exist. This might facilitate gene discovery to understand the pathogenesis of aggressive GC phenotypes, particularly with publications implicating immune-related gene-based signatures, and the development of techniques to gauge the stance of the innate immune system (InImS), such as the FERAD ratio (blood ferritin:fecal Adnab-9 binding OD-background binding). Resection specimens for the sporadic and familial group were stained for HP and examined for intestinal metaplasia (IM) and immunostaining for Adnab-9. Familial kindred specimens were also tested for the E-cadherin mutation and APC (adenomatous polyposis coli). Survival was evaluated. RESULTS Of 40 GC patients, 25% were HP+ with a greater proportion of intestinal metaplasia (IM) and gastric atrophy than the HP- group. The proband of the familial GC kindred, a 32-year-old mother with fatal GC, was survived by 13-year-old identical twins. Twin #1 was HP- with IM and Twin #2 was HP+. Both twins subsequently died of GC within two years. The twins did not have APC or E-cadherin mutations. The mean overall survival in the HP+ sporadic GC group was 2.47 ± 2.58 years and was 0.57 ± 0.60 years in the HP- group (p = 0.01). Survival in the kindred was 0.22 ± 0.24 years. Adnab-9 labeling was positive in fixed tissues of 50% of non-familial GC patients and in gastric tissue extract from Twin #2. The FERAD ratio was determined separately in six prospectively followed patient groups (n = 458) and was significantly lower in the gastric cancer patients (n = 10) and patients with stomach conditions predisposing them to GC (n = 214), compared to controls (n = 234 patients at increased risk for colorectal cancer but without cancer), suggesting a failure of the InImS. CONCLUSION The HP+ sporadic GC group appears to proceed through a sequence of HP infection, IM and atrophy before cancer supervenes, and the HP- phenotype appear to omit this sequence. The familial cases may represent a subset with both features, but the natural history strongly resembles that of the HP- group. Two different paths of carcinogenesis may exist locally for sporadic GC. The InImS may also be implicated in prognosis. Identifying these patients will allow for treatment stratification and early diagnosis to improve GC survival.
Collapse
Affiliation(s)
- Martin Tobi
- Department of Research and Development, John D. Dingell VAMC, Detroit, MI 48201, USA
| | - Douglas Weinstein
- Capital Health Medical Group, 2 Capital Way, Pennington, NJ 08534, USA
| | - Mijin Kim
- Gastroenterology Division, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - James Hatfield
- Department of Pathology, John D. Dingell VAMC, Detroit, MI 48201, USA (S.F.)
| | - Paula Sochacki
- Department of Pathology, John D. Dingell VAMC, Detroit, MI 48201, USA (S.F.)
| | - Edi Levi
- Gastroenterology Division, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Teisa An
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Merlin Hamre
- Department Pediatrics, Children’s Hospital, Detroit, MI 48201, USA
| | - Vasundhara Tolia
- Department Pediatrics, Children’s Hospital, Detroit, MI 48201, USA
| | - Suzanne Fligiel
- Department of Pathology, John D. Dingell VAMC, Detroit, MI 48201, USA (S.F.)
| | - Rama Marepally
- Department of Research and Development, John D. Dingell VAMC, Detroit, MI 48201, USA
| | - Jason Hallman
- Department of Research and Development, John D. Dingell VAMC, Detroit, MI 48201, USA
| | - Bharati Bapat
- Department of Medicine, Mt Sinai Hospital, Toronto, ON N5T 3H7, Canada
| | - Mei Yuan
- Division of General Surgery, Institute of Basic Medical Science of PLA Hospital, Beijing 100853, China
| | | | - Steven Gallinger
- Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON M5G 2M9, Canada
| |
Collapse
|
|
14
|
Inoue Y, Inui N, Karayama M, Asada K, Fujii M, Matsuura S, Uto T, Hashimoto D, Matsui T, Ikeda M, Yasui H, Hozumi H, Suzuki Y, Furuhashi K, Enomoto N, Fujisawa T, Suda T. Cytokine profiling identifies circulating IL-6 and IL-15 as prognostic stratifiers in patients with non-small cell lung cancer receiving anti-PD-1/PD-L1 blockade therapy. Cancer Immunol Immunother 2023:10.1007/s00262-023-03453-z. [PMID: 37099186 DOI: 10.1007/s00262-023-03453-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 04/16/2023] [Indexed: 04/27/2023]
Abstract
Whether circulating levels of specific cytokines at baseline link with treatment efficacy of immune checkpoint blockade (ICB) therapy in patients with non-small cell lung cancer remains unknown. In this study, serum samples were collected in two independent, prospective, multicenter cohorts before the initiation of ICB. Twenty cytokines were quantified, and cutoff values were determined by receiver operating characteristic analyses to predict non-durable benefit. The associations of each dichotomized cytokine status with survival outcomes were assessed. In the discovery cohort (atezolizumab cohort; N = 81), there were significant differences in progression-free survival (PFS) in accordance with the levels of IL-6 (log-rank test, P = 0.0014), IL-15 (P = 0.00011), MCP-1 (P = 0.013), MIP-1β (P = 0.0035), and PDGF-AB/BB (P = 0.016). Of these, levels of IL-6 and IL-15 were also significantly prognostic in the validation cohort (nivolumab cohort, N = 139) for PFS (log-rank test, P = 0.011 for IL-6 and P = 0.00065 for IL-15) and overall survival (OS; P = 3.3E-6 for IL-6 and P = 0.0022 for IL-15). In the merged cohort, IL-6high and IL-15high were identified as independent unfavorable prognostic factors for PFS and OS. The combined IL-6 and IL-15 status stratified patient survival outcomes into three distinct groups for both PFS and OS. In conclusion, combined assessment of circulating IL-6 and IL-15 levels at baseline provides valuable information to stratify the clinical outcome of patients with non-small cell lung cancer treated with ICB. Further studies are required to decipher the mechanistic basis of this finding.
Collapse
Affiliation(s)
- Yusuke Inoue
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan.
| | - Naoki Inui
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
- Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Masato Karayama
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
- Department of Chemotherapy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Kazuhiro Asada
- Department of Respiratory Medicine, Shizuoka General Hospital, 4-27-1 Kita-Ando, Shizuoka, 420-8527, Japan
| | - Masato Fujii
- Department of Respiratory Medicine, Shizuoka City Shizuoka Hospital, 10-93 Otemachi, Shizuoka, 420-8630, Japan
| | - Shun Matsuura
- Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda, 426-8677, Japan
| | - Tomohiro Uto
- Department of Respiratory Medicine, Iwata City Hospital, 512-3 Ohkubo, Iwata, 438-8550, Japan
| | - Dai Hashimoto
- Department of Pulmonary Medicine, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Naka-Ku, Hamamatsu, 430-8558, Japan
| | - Takashi Matsui
- Department of Respiratory Medicine, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita-Ku, Hamamatsu, 433-8558, Japan
| | - Masaki Ikeda
- Department of Respiratory Medicine, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Shizuoka, 422-8527, Japan
| | - Hideki Yasui
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Hironao Hozumi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Yuzo Suzuki
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Kazuki Furuhashi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Noriyuki Enomoto
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Tomoyuki Fujisawa
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Takafumi Suda
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| |
Collapse
|
|
15
|
Role of IL-6/STAT3 Axis in Resistance to Cisplatin in Gastric Cancers. Biomedicines 2023; 11:biomedicines11030694. [PMID: 36979673 PMCID: PMC10044743 DOI: 10.3390/biomedicines11030694] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/14/2023] [Accepted: 02/21/2023] [Indexed: 03/03/2023] Open
Abstract
Gastric cancer, the second most common cause of death worldwide, is characterized by poor prognosis and low responsiveness to chemotherapy. Indeed, multidrug resistance, based mainly on cellular and molecular factors, remains one of the most limiting factors of the current approach to gastric cancer (GC) therapy. We employed a comprehensive gene expression analysis through data mining of publicly available databases to assess the role of the signal transducer and activator of transcription 3 (STAT3) in gastric cancer drug efficiency. It has been proposed that gastric cancer cells are less sensitive to these drugs because they develop resistance to these agents through activating alternative signalling pathways responsible for overcoming pharmacological inhibition. Our study evaluated the hypothesis that activating STAT3 signalling in response to cisplatin reduces the reaction to the drug. Consistent with this hypothesis, inhibition of interleukin 6 (IL-6)/STAT3 in combination therapy with cisplatin prevented both STAT3 activation and more lethality than induction by a single agent. The data suggest that the IL-6/STAT3 axis block associated with cisplatin treatment may represent a strategy to overcome resistance.
Collapse
|
|
16
|
Li XN, Peng YH, Yue W, Tao L, Zhang WJ. A cohort study using IL-6/Stat3 activity and PD-1/PD-L1 expression to predict five-year survival for patients after gastric cancer resection. PLoS One 2022; 17:e0277908. [PMID: 36454780 PMCID: PMC9714712 DOI: 10.1371/journal.pone.0277908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 11/05/2022] [Indexed: 12/03/2022] Open
Abstract
OBJECTIVES The expression/activation of IL-6, p-Stat3, PD-1 and PD-L1 in gastric cancer (GC) tissues were examined to evaluate their abilities in predicting the survival prognosis in postoperative patients with GC. METHODS The clinicopathological data and paraffin-embedded tissues of 205 patients who underwent gastric cancer resection were collected at the First Affiliated Hospital of Shihezi University School of Medicine, and the patients were followed-up annually after surgery. Immunohistochemistry (IHC) was used to detect the expression of IL-6, p-Stat3, PD-1 and PD-L1 proteins using tissue microarrays derived from these patients. Statistical analyses were performed using non-parametric tests, Spearman's correlation, ROC curves, Kaplan-Meier survival analysis, Cox single-factor and multifactor regression models. In comparison, the analyses were also performed for GC patients from public databases (407 patients from TCGA and 433 patients from GEO, respectively). RESULTS (1) The expression levels of IL-6, p-Stat3, PD-1 and PD-L1 in GC tissues were significantly higher than adjacent normal tissues (ANT) (81.01% vs. 52.78%, P<0.001; 100% vs. 93.41%, P<0.001; 58.58% vs. 40.12%, P<0.001; 38.20% vs. 26.90%, P = 0.025, respectively). The mean optical density (MOD) values of IL-6, p-Stat3, PD-1 and PD-L1 were significantly higher in GC tissues. (2) The higher the levels of IL-6 (P<0.001), p-Stat3 (P<0.001), and PD-L1 (P = 0.003) were, the worse the survival prognoses were observed, respectively, among GC patients. The expression of PD-1 was not correlated with the prognosis of GC patients (P>0.05). The lower the degree of cell differentiation (P<0.001) was, the worse the survival prognoses were observed among GC patients. (3) Independent risk factors for postoperative prognosis in GC patients included age (≥60 years old), poor cell differentiation, invasion depth (T3/T4), lymph node metastasis (N1-3), distant metastasis (M1), and high levels of IL-6 (2+/3+). (4) A multi-factor combination (cell differentiation+IL-6+p-Stat3+PD-1+PD-L1) appeared to be the best survival predictor for GC patients as indicated by AUC (AUC 0.782, 95% CI = 0.709, 0.856, P<0.001). This combination may be the optimal predictor for postoperative survival of GC patients. (5) The levels of IL-6, p-Stat3, PD-1 and PD-L1 correlated with the infiltration levels of various tumor-infiltrating immune cells. (6) The analyses of ROC curves, calibration, DCA and Kaplan-Meier (KM) survival curves in TCGA dataset confirmed that the nomogram model could accurately predict the prognosis in GC patients. CONCLUSIONS (1) The expressed levels of IL-6, p-Stat3, PD-1 and PD-L1 are higher in GC tissues than in adjacent normal tissues. (2) The high levels of IL-6, p-Stat3 and PD-L1 are correlated with poor survival in GC patients. (3) The high levels of IL-6, p-Stat3, PD-1 and PD-L1 have influences in GC tumor microenvironment. (4) The multi-predictor combination of "IL-6+p-Stat3+PD-1+cell differentiation" serves as an optimal survival predictor for postoperative GC patients and better than the TNM staging system. As these molecules can be examined in preoperative biopsies, these observations may provide a useful guide for clinicians to strategize individualized surgical plans for GC patients before surgery.
Collapse
Affiliation(s)
- Xiao Ning Li
- Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Yun Hong Peng
- Department of Physical Examination, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Wen Yue
- Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Department of Pathology, the Affiliated Oncology Hospital, Fudan University School of Medicine, Shanghai, China
| | - Lin Tao
- Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Wen Jie Zhang
- Department of Pathology, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- * E-mail: ,
| |
Collapse
|
|
17
|
Electrochemical microfluidic paper-based analytical devices for tumor marker detection. Trends Analyt Chem 2022. [DOI: 10.1016/j.trac.2022.116816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
|
|
18
|
Ahn H, Song GJ, Jang SH, Son MW, Lee HJ, Lee MS, Lee JH, Oh MH, Jeong GC, Yun JH, Lee SM, Lee JW. Predicting the Recurrence of Gastric Cancer Using the Textural Features of Perigastric Adipose Tissue on [ 18F]FDG PET/CT. Int J Mol Sci 2022; 23:ijms231911985. [PMID: 36233285 PMCID: PMC9569486 DOI: 10.3390/ijms231911985] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/01/2022] [Accepted: 10/08/2022] [Indexed: 12/05/2022] Open
Abstract
This study aimed to assess the relationship between the histopathological and textural features of perigastric adipose tissue (AT) on 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) and to evaluate the prognostic significance of perigastric AT textural features in predicting recurrence-free survival (RFS) in patients with gastric cancer. Sixty-nine patients with gastric cancer who underwent staging [18F]FDG PET/CT and subsequent curative surgery were retrospectively reviewed. Textural features of perigastric AT were extracted from PET images. On histopathological analysis, CD4, CD8, and CD163 cell infiltration and matrix metalloproteinase-11 and interleukin-6 (IL-6) expression in perigastric AT were graded. The degree of CD163 cell infiltration in perigastric AT was significantly correlated with the mean standardized uptake value (SUV), SUV histogram entropy, grey-level co-occurrence matrix (GLCM) energy, and GLCM entropy of perigastric AT. The degree of IL-6 expression in the perigastric AT was significantly correlated with the mean and median SUVs of perigastric AT. In multivariate survival analysis, GLCM entropy, GLCM dissimilarity, and GLCM homogeneity of perigastric AT were significant predictors of RFS. The textural features of perigastric AT on [18F]FDG PET/CT significantly correlated with inflammatory response in perigastric AT and were significant prognostic factors for predicting RFS in patients with gastric cancer.
Collapse
Affiliation(s)
- Hyein Ahn
- Department of Pathology, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
| | - Geum Jong Song
- Department of Surgery, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
| | - Si-Hyong Jang
- Department of Pathology, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
| | - Myoung Won Son
- Department of Surgery, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
| | - Hyun Ju Lee
- Department of Pathology, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
| | - Moon-Soo Lee
- Department of Surgery, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
| | - Ji-Hye Lee
- Department of Pathology, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
| | - Mee-Hye Oh
- Department of Pathology, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
| | - Geum Cheol Jeong
- Department of Nuclear Medicine, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
| | - Jong Hyuk Yun
- Department of Surgery, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
| | - Sang Mi Lee
- Department of Nuclear Medicine, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
- Correspondence: (S.M.L.); (J.W.L.); Tel.: +82-41-570-3540 (S.M.L.); +82-32-290-2975 (J.W.L.)
| | - Jeong Won Lee
- Department of Nuclear Medicine, College of Medicine, Catholic Kwandong University, International St. Mary’s Hospital, 25 Simgok-ro 100-gil, Seo-gu, Incheon 22711, Korea
- Correspondence: (S.M.L.); (J.W.L.); Tel.: +82-41-570-3540 (S.M.L.); +82-32-290-2975 (J.W.L.)
| |
Collapse
|
|
19
|
Anti-Inflammatory and Antioxidant Effects of Carvacrol on N-Methyl-N′-Nitro-N-Nitrosoguanidine (MNNG) Induced Gastric Carcinogenesis in Wistar Rats. Nutrients 2022; 14:nu14142848. [PMID: 35889805 PMCID: PMC9323991 DOI: 10.3390/nu14142848] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 07/06/2022] [Accepted: 07/08/2022] [Indexed: 11/19/2022] Open
Abstract
Carvacrol is a dietary polyphenol from Lamiaceae plants that has been shown to possess a wide range of biological activities including antioxidant and antitumor effects. This study aimed to investigate its anti-inflammatory and antioxidant effects on N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) induced gastric carcinogenesis in Wistar rats. Forty-nine rats were randomly assigned to four treatment and three control groups. Over 60 days, MNNG (200 mg/kg BW) was orally applied to animals of groups 1–5 while the rats in groups 2–5 also received different doses of carvacrol (10, 25, 50, and 100 mg/kg BW, respectively) until the end of the experiment. Group 6 rats were treated with 100 mg/kg BW carvacrol and no MNNG whereas group 7 was the control group without any treatment. After the euthanasia of all rats, the inflammatory cytokines and oxidative stress parameters were assessed in the blood and tissues. The expression of caspase 9, Bax, and Bcl-2 proteins in the stomach tissues were investigated through histopathological examinations. Statistically significant differences were observed in the body weight, oxidative stress, and inflammation parameters of groups 1 to 6 compared to group 7 (p ≤ 0.001). Animals in MNNG groups 2 and 3 treated with the low dose carvacrol (10 and 25 mg/kg BW) showed significantly reduced oxidative stress, inflammation, and apoptotic effect compared to animals of the MNNG groups receiving increased doses of carvacrol (50 and 100 mg/kg BW) or no carvacrol. Rats exposed to MNNG exhibited gastric cancer cells in several areas. In the MNNG group receiving 100 mg/kg BW carvacrol, the inflammatory cell infiltration was observed in gastric mucosal and submucosal areas whereas MNNG rats supplemented with 10 and 25 mg/kg BW carvacrol showed no pathological alterations of the gastric cells. The results of this study indicate that significant antioxidant and anti-inflammatory effects induced by carvacrol at doses of 10 and 25 mg/kg BW interfered with gastric carcinogenesis induced by MNNG in Wistar rats as well as provide hepatoprotection. However, high doses of carvacrol (50 and 100 mg/kg BW) increased oxidative stress, inflammation, and apoptosis.
Collapse
|
|
20
|
Zhang Z, Weng B, Qiu Y, Feng H, Zhang R, Zhang J, Hu Y, Yu J, Li G, Liu H. Effect of Perioperative Interleukin-6 and Tumor Necrosis Factor- α on Long-Term Outcomes in Locally Advanced Gastric Cancer: Results from the CLASS-01 Trial. J Immunol Res 2022; 2022:7863480. [PMID: 35859928 PMCID: PMC9289757 DOI: 10.1155/2022/7863480] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/20/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Little is known about the relation between perioperative inflammatory changes and long-term survival in cancer patients. The aim of the study was to assess the association of perioperative serum interleukin-6 (IL6) and tumor necrosis factor-α (TNFα) levels with the 5-year overall survival in locally advanced gastric cancer. METHODS The 135 eligible patients in one center of Nanfang Hospital were retrieved from CLASS-01 trial (NCT01609309), an open-label, multicenter, randomized clinical noninferiority trial conducted at 14 centers in China. Serum IL6 and TNFα levels were tested before surgery, and on postoperative day (POD) 1, POD3, and POD5, respectively, referring to IL6_0, IL6_1, IL6_3, and IL6_5 and TNFα_0, TNFα_1, TNFα_3, and TNFα_5. Kaplan-Meier methods and COX models were used for survival analysis. RESULTS High levels of IL6_0 (≥3.67 pg/mL) and TNFα_0 (≥14.8 pg/mL) presented worse disease-free survival (DFS) (P = 0.0057 for IL6_0 and P = 0.0014 for TNFα_0) and overall survival (OS) (P = 0.0021 for IL6_0 and P = 0.0019 for TNFα_0). Both high IL6_0 and high IL6_5 levels indicated worse prognosis than other combinations (P = 0.0045 for DFS and P = 0.0022 for OS). In multivariate analysis, both high IL6_0 and high IL6_5 levels were significantly associated with poor DFS (HR = 4.29, 95% CI: 1.42-12.95, P = 0.01) and OS (HR = 4.11, 95% CI: 1.35-12.49, P = 0.013) after adjustment of tumor stage and TNFα_0. Also, high IL6_5 level was identified as the independent-related factor for postoperative infectious complications (OR = 2.69, 95% CI: 1.03-7.01, P = 0.043). CONCLUSIONS Perioperative high serum IL6 and TNFα levels are negatively associated with 5-year survival outcomes in patients with locally advanced gastric cancer, indicating the potential survival benefits from perioperative anti-inflammatory treatment.
Collapse
Affiliation(s)
- Zhenzhan Zhang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Binshu Weng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yaopeng Qiu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hao Feng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Renyi Zhang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiachen Zhang
- Clinical Research Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanfeng Hu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
21
|
Inflammation and Gastric Cancer. Diseases 2022; 10:diseases10030035. [PMID: 35892729 PMCID: PMC9326573 DOI: 10.3390/diseases10030035] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/16/2022] [Accepted: 06/19/2022] [Indexed: 11/17/2022] Open
Abstract
Gastric cancer remains a major killer globally, although its incidence has declined over the past century. It is the fifth most common cancer and the third most common reason for cancer-related deaths worldwide. Gastric cancer is the outcome of a complex interaction between environmental, host genetic, and microbial factors. There is significant evidence supporting the association between chronic inflammation and the onset of cancer. This association is particularly robust for gastrointestinal cancers in which microbial pathogens are responsible for the chronic inflammation that can be a triggering factor for the onset of those cancers. Helicobacter pylori is the most prominent example since it is the most widespread infection, affecting nearly half of the world’s population. It is well-known to be responsible for inducing chronic gastric inflammation progressing to atrophy, metaplasia, dysplasia, and eventually, gastric cancer. This review provides an overview of the association of the factors playing a role in chronic inflammation; the bacterial characteristics which are responsible for the colonization, persistence in the stomach, and triggering of inflammation; the microbiome involved in the chronic inflammation process; and the host factors that have a role in determining whether gastritis progresses to gastric cancer. Understanding these interconnections may improve our ability to prevent gastric cancer development and enhance our understanding of existing cases.
Collapse
|
|
22
|
Cancelliere R, Di Tinno A, Di Lellis AM, Contini G, Micheli L, Signori E. Cost-effective and disposable label-free voltammetric immunosensor for sensitive detection of interleukin-6. Biosens Bioelectron 2022; 213:114467. [PMID: 35760020 DOI: 10.1016/j.bios.2022.114467] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 11/29/2022]
Abstract
IL-6 detection is highly desirable since can monitor many diseases in humans and assess the response to treatments. Herein, two novel label-free voltammetric immunosensors for rapid and accurate interleukin-6 (IL-6) detection in human serum are presented. The immunosensors are fabricated by immobilising two different IL-6 antibodies, identified as mAb-IL-6 clone-5 and clone-7, on in-house produced screen-printed electrodes modified with inexpensive recycling biochar (Bio-SPEs). To ensure high structural fidelity and performance, an in-depth electrochemical characterization of the layer-by-layer assembly of the immunosensor was conducted by cyclic voltammetry (CV) and sensing was performed using square wave voltammetry (SWV). The two immunosensors showed good analytical performances in human serum, exhibiting a wide linear range (LR) between 26-125 and 30-138 pg/mL, a good limit of detection (LOD) of 4.8 and 5.4 pg/mL and selectivity for IL-6 over other common cytokines, including IL-1β and TNF-α. Performance comparison of IL-6 immunosensors with those of a commercial spectrophotometric ELISA kit (LOD of 20 pg/mL, RSD% of 15%) denotes a better sensitivity and reproducibility of the proposed label-free devices, associated with a reduced detection time (30 min instead of more than 3 h for ELISA test). Furthermore, the proposed immunosensors were successfully applied in blood samples (with only a dilution of 1:100 v/v in PBS and without additional treatments) with good sensitivity (LOD of 14.3 pg/mL) and reproducibility (RSD% < 11%), thus paving the way for their application as viable diagnostic and therapeutic point-of-care tools alternative to the IL-6 detection techniques routinely used (ELISA and Western Blot).
Collapse
Affiliation(s)
- Rocco Cancelliere
- Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Roma, Italy
| | - Alessio Di Tinno
- Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Roma, Italy; Department of Electrical and Information Engineering, University of Cassino and Southern Lazio, 03043, Cassino, FR, Italy
| | | | - Giorgio Contini
- Istituto di Struttura della Materia-CNR (ISM-CNR), Via Fosso del Cavaliere 100, 00133, Roma, Italy; Department of Physics, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Roma, Italy.
| | - Laura Micheli
- Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Roma, Italy.
| | - Emanuela Signori
- Istituto di Farmacologia Traslazionale-CNR (IFT-CNR), Via Fosso del Cavaliere 100, 00133, Roma, Italy.
| |
Collapse
|
|
23
|
Yang E, Chua W, Ng W, Roberts TL. Peripheral Cytokine Levels as a Prognostic Indicator in Gastric Cancer: A Review of Existing Literature. Biomedicines 2021; 9:1916. [PMID: 34944729 PMCID: PMC8698340 DOI: 10.3390/biomedicines9121916] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 12/16/2022] Open
Abstract
Although strong connections exist between the carcinogenesis of gastric cancer and chronic inflammation, gastric cancer is unique in that the chronic gastritis which frequently precedes carcinogenesis is strongly associated with H. pylori infection. The interplay between H. pylori virulence factors and host immune cells is complex but culminates in the activation of inflammatory pathways and transcription factors such as NF-κB, STAT3, and AP-1, all of which upregulate cytokine production. Due to the key role of cytokines in modulating the immune response against tumour cells as well as possibly stimulating tumour growth and proliferation, different patterns of cytokine secretion may be associated with varying patient outcomes. In relation to gastric cancer, interleukin-6, 8, 10, 17A, TNF, and IFN-γ may have pro-tumour properties, although interleukin-10, TNF, and IFN-γ may have anti-tumour effects. However, due to the lack of studies investigating patient outcomes, only a link between higher interleukin-6 levels and poorer prognosis has been demonstrated. Further investigations which link peripheral cytokine levels to patient prognosis may elucidate important pathological mechanisms in gastric cancer which adversely impact patient survival and allow treatments targeting these processes to be developed.
Collapse
Affiliation(s)
- Elton Yang
- School of Medicine, Western Sydney University, Campbelltown 2560, Australia; (E.Y.); (W.C.); (W.N.)
- Ingham Institute for Applied Medical Research, Liverpool 2170, Australia
| | - Wei Chua
- School of Medicine, Western Sydney University, Campbelltown 2560, Australia; (E.Y.); (W.C.); (W.N.)
- Ingham Institute for Applied Medical Research, Liverpool 2170, Australia
- Medical Oncology, Liverpool Hospital, Liverpool 2170, Australia
- Southwest Sydney Clinical School, University of New South Wales, Liverpool 2170, Australia
| | - Weng Ng
- School of Medicine, Western Sydney University, Campbelltown 2560, Australia; (E.Y.); (W.C.); (W.N.)
- Ingham Institute for Applied Medical Research, Liverpool 2170, Australia
- Medical Oncology, Liverpool Hospital, Liverpool 2170, Australia
- Southwest Sydney Clinical School, University of New South Wales, Liverpool 2170, Australia
| | - Tara Laurine Roberts
- School of Medicine, Western Sydney University, Campbelltown 2560, Australia; (E.Y.); (W.C.); (W.N.)
- Ingham Institute for Applied Medical Research, Liverpool 2170, Australia
- Southwest Sydney Clinical School, University of New South Wales, Liverpool 2170, Australia
| |
Collapse
|
|
24
|
Wang X, Li J, Liu W, Zhang X, Xue L. The diagnostic value of interleukin 6 as a biomarker for gastric cancer: A meta-analysis and systematic review. Medicine (Baltimore) 2021; 100:e27945. [PMID: 34964773 PMCID: PMC8615365 DOI: 10.1097/md.0000000000027945] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 11/01/2021] [Accepted: 11/01/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Gastric cancer is one of the most common cancers and a main cause of global cancer death. The expression of interleukin 6 is associated with the risk of gastric cancer. But the diagnostic accuracy of interleukin 6 remains unclear. This study was designed to assess the diagnostic performance of interleukin 6 in gastric cancer diagnosis. METHODS The related data was obtained from Oncomine and studied using bioinformatics analysis. The PubMed, Embase, Cochrane Library, Web of science databases were searched for related studies published from inception to July 14, 2020. Measuring tools of diagnostic performance including sensitivity, specificity, and diagnostic odds ratio were pooled using bivariate mixed-effects meta-analysis model. The summery receiver operator characteristic curves were plotted. RESULTS The result from Oncomine showed that the expression of interleukin 6 in gastric cancer (GC) patients was higher than the normal groups (P < .05). Furthermore, a total of 4 eligible articles were enrolled, containing 390 cases and 404 controls. The diagnostic results were as follows: a sensitivity of 0.80 (95% confidence interval [CI] 0.57-0.92), a specificity of 0.86 (95% CI 0.74-0.93), a positive likelihood ratio of 5.76 (95% CI 3.49-9.49), a negative likelihood ratio of 0.23 (95% CI 0.11-0.51) and a diagnostic odds ratio of 24.58 (95% CI 14.14-42.73). The summary area under the receiver operating characteristic curves was 0.90 (95% CI 0.87-0.93). CONCLUSION Higher interleukin 6 expression was detected in GC patients, and interleukin 6 could be a helpful indicator of diagnosis of gastric cancer. Further large-scale prospective studies are required for identifying the diagnostic value of interleukin 6 in gastric cancer.
Collapse
Affiliation(s)
- Xiaozi Wang
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China
| | - Jie Li
- Department of Hematology, Hebei General Hospital, Shijiazhuang, China
| | - Wenjing Liu
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China
| | - Xianghong Zhang
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China
| | - Liying Xue
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China
| |
Collapse
|
|
25
|
Inhibition of Interleukin-6-Induced Matrix Metalloproteinase-2 Expression and Invasive Ability of Lemon Peel Polyphenol Extract in Human Primary Colon Cancer Cells. Molecules 2021; 26:molecules26237076. [PMID: 34885656 PMCID: PMC8658805 DOI: 10.3390/molecules26237076] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/19/2021] [Indexed: 11/29/2022] Open
Abstract
Among matrix metalloproteinases (MMPs), MMP-9/2 are key enzymes involved in the proteolysis of extracellular matrices in the inflammatory process and in cancer. Since MMP-9/2 expression levels, activity, and secretion is up-regulated during inflammation in response to pro-inflammatory cytokines, such as interleukin-6 (IL-6), many efforts have been devoted to identifying factors that could inhibit the IL-6-induced MMP-9/2 expression. Up to now, several reports indicated that polyphenols from fruits and vegetables are among the major components of health promotion for their antioxidant properties and also for their anti-inflammatory and anti-cancer agents. Among plant derived polyphenols, lemon (Citrus limon) peel extract (LPE) shows anti-cancer properties in various cancer types. In our previous work, we demonstrated that LPE can reduce IL-6-induced migration/invasiveness and MMP-9/2 up-regulation in some gastric cancer cell lines. This study aims to exploit the anti-cancer properties of LPE using an in vitro system model of inflammation, consisting of IL-6-exposed human primary colon cancer cells. We first analyzed the effect of LPE on IL-6-induced cell migration and invasiveness by wound healing and Boyden chamber assay, respectively. The MMP-2 mRNA expression levels and gelatinolytic activity in the cell culture media were determined by q-PCR analysis and gelatin zymography, respectively, and finally, the effects of LPE on IL-6-induced JAK2/STAT3 signaling pathways have been investigated by Western blotting analysis. Our results show that LPE is able to inhibit the IL-6-dependent cell migration and invasiveness associated with the up-regulation of MMP-2 expression levels and that these effects are correlated to the STAT3 phosphorylation in human primary T88 and T93 colon cancer cells.
Collapse
|
|
26
|
Mosyichuk L, Tatarchuk O, Simonova O, Petishko O. Features of cytokine balance with the progression of structural changes in the gastric mucosa in patients with atrophic gastritis. Gastroenterology 2021; 55:67-73. [DOI: 10.22141/2308-2097.55.2.2021.233625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Background. Until now, the issue of the correlation between the cytokine balance and the progression of structural changes in the gastric mucosa remain completely uncertain. At the same time, the determination of the role of cytokine balance as a component of gastric carcinogenesis will make it possible to substantiate new approaches to managing patients with atrophic gastritis. The purpose was to assess the level of pro- and anti-inflammatory cytokines, vascular endothelial growth factor (VEGF) at the stages of progression of structural changes in the gastric mucosa of patients with atrophic gastritis. Materials and methods. The study included 79 individuals with atrophic gastritis who underwent narrow band imaging endoscopic examination. The patients were divided into groups taking into account the revealed structural changes in the gastric mucosa: group I— 7 people with gastric mucosal atrophy without intestinal metaplasia (IM); group II— 16 individuals with gastric mucosal atrophy with IM limited by the antrum; group III— 45 people with diffuse IM against the background of gastric mucosal atrophy; group IV— 10 individuals with gastric mucosal dysplasia. In all patients, we assessed the level of interleukins (IL-8, IL-10, IL-18), tumor necrosis factor alpha (TNF-α), VEGF. Results. In patients of group IV, the concentration of IL-8 in the blood serum was 18.6 (11.3; 23.9) pg/ml that was significantly higher than in group I (by 5.0 times, p<0.05), group II (by 3.6 times, p<0.05) and group III (by 3.4 times, p<0.05). According to the results of the Kruskal-Wallis test, the probability of a difference in the IL-8 level between the groups was 0.0260. The level of VEGF in the blood serum of patients with gastric mucosal dysplasia was significantly increased compared to that in people with gastric mucosal atrophy without IM (by 1.8 times, p<0.05) and those with gastric mucosal atrophy with IM (by 1.7times, p<0.05). Changes in the cytokine balance towards proinflammatory cytokines were most pronounced in patients of groups III and IV; according to the results of the Kruskal-Wallis test, the probability of a difference in the IL-8/IL-10 ratio between the groups was 0.0207. Conclusions. With the progression of structural changes in the gastric mucosa of patients with atrophic gastritis, an increase in the level of proinflammatory cytokines (IL-8, IL-18 and TNF-α) in the blood serum does not induce the secretion of anti-inflammatory cytokines (IL-10). According to the results of the ROC analysis, the diagnostic criteria for the formation of the risk group for detecting dysplastic changes in the gastric mucosa are VEGF level of more than 341.4 mU/ml (sensitivity— 90.0%, specificity— 77.2%) and the level of IL-8 above 14.4 pg/ml (sensitivity— 80.0%, specificity— 78.3%).
Collapse
|
|
27
|
Froeschle GM, Bedke T, Boettcher M, Huber S, Singer D, Ebenebe CU. T cell cytokines in the diagnostic of early-onset sepsis. Pediatr Res 2021; 90:191-196. [PMID: 33173181 DOI: 10.1038/s41390-020-01248-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 09/28/2020] [Accepted: 10/03/2020] [Indexed: 01/21/2023]
Abstract
BACKGROUND Early-onset sepsis (EOS) remains a substantial cause of morbidity and mortality among neonates. Yet, currently available biological parameters have not proven to be accurate enough to predict EOS reliably. This study aimed to determine serum concentrations of 13 cytokines in umbilical cord blood and evaluate their diagnostic value for EOS. METHODS A prospective single-center study that included analysis of umbilical cord blood of term and preterm neonates who were born from March 2017 to November 2017. Using ELISA analysis, 13 cytokines were simultaneously quantified and correlated with the development of EOS. RESULTS Four hundred and seventy-four neonates were included, of which seven met the criteria for culture-positive EOS. Interleukin (IL)-6 (p < 0.001), IL-9 (p = 0.003), and IL-21 (p < 0.001) were significantly increased in neonates with EOS compared to controls. Sensitivity and specificity for IL-6, IL-9, and IL-21 at the defined cut-off points were 85.7 and 77.3%, 71.4 and 62.5%, and 71.4 and 52.0%, respectively. CONCLUSIONS In neonates with EOS, IL-9 and IL-21 are significantly elevated and may be employed in the diagnostic of EOS. However, diagnostic accuracy remains lower than with IL-6. Values of 13 T cell cytokines may be used as reference values for future studies in neonates. IMPACT Interleukin-9 (IL-9) and interleukin-21 (IL-21) are significantly elevated in neonates with early-onset sepsis. IL-9 and IL-21 have been shown to play a specific role in neonatal sepsis. Neonatal reference values were generated for several cytokines. IL-9 and IL-21 might be attractive biomarkers for neonatal sepsis in future. This study is likely to promote further research in this area. Values of several T cell cytokines may be used as reference values for future studies in neonates.
Collapse
Affiliation(s)
- Glenn Malin Froeschle
- Division of Neonatology and Pediatric Intensive Care, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Tanja Bedke
- I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Michael Boettcher
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Samuel Huber
- I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Dominique Singer
- Division of Neonatology and Pediatric Intensive Care, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Chinedu Ulrich Ebenebe
- Division of Neonatology and Pediatric Intensive Care, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
| |
Collapse
|
|
28
|
Gómez-Valenzuela F, Escobar E, Pérez-Tomás R, Montecinos VP. The Inflammatory Profile of the Tumor Microenvironment, Orchestrated by Cyclooxygenase-2, Promotes Epithelial-Mesenchymal Transition. Front Oncol 2021; 11:686792. [PMID: 34178680 PMCID: PMC8222670 DOI: 10.3389/fonc.2021.686792] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 05/13/2021] [Indexed: 12/11/2022] Open
Abstract
The tumor microenvironment (TME) corresponds to a complex and dynamic interconnection between the extracellular matrix and malignant cells and their surrounding stroma composed of immune and mesenchymal cells. The TME has constant cellular communication through cytokines that sustain an inflammatory profile, which favors tumor progression, angiogenesis, cell invasion, and metastasis. Although the epithelial-mesenchymal transition (EMT) represents a relevant metastasis-initiating event that promotes an invasive phenotype in malignant epithelial cells, its relationship with the inflammatory profile of the TME is poorly understood. Previous evidence strongly suggests that cyclooxygenase-2 (COX-2) overexpression, a pro-inflammatory enzyme related to chronic unresolved inflammation, is associated with common EMT-signaling pathways. This review article summarizes how COX-2 overexpression, within the context of the TME, orchestrates the EMT process and promotes initial metastatic-related events.
Collapse
Affiliation(s)
- Fernán Gómez-Valenzuela
- Department of Hematology-Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Enrico Escobar
- Department of Oral Pathology and Medicine, Faculty of Dentistry, University of Chile, Santiago, Chile
| | - Ricardo Pérez-Tomás
- Department of Pathology and Experimental Therapy - Bellvitge, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Viviana P Montecinos
- Department of Hematology-Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile
| |
Collapse
|
|
29
|
Dutta N, Lillehoj PB, Estrela P, Dutta G. Electrochemical Biosensors for Cytokine Profiling: Recent Advancements and Possibilities in the Near Future. BIOSENSORS 2021; 11:94. [PMID: 33806879 PMCID: PMC8004910 DOI: 10.3390/bios11030094] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/14/2021] [Accepted: 03/18/2021] [Indexed: 02/07/2023]
Abstract
Cytokines are soluble proteins secreted by immune cells that act as molecular messengers relaying instructions and mediating various functions performed by the cellular counterparts of the immune system, by means of a synchronized cascade of signaling pathways. Aberrant expression of cytokines can be indicative of anomalous behavior of the immunoregulatory system, as seen in various illnesses and conditions, such as cancer, autoimmunity, neurodegeneration and other physiological disorders. Cancer and autoimmune diseases are particularly adept at developing mechanisms to escape and modulate the immune system checkpoints, reflected by an altered cytokine profile. Cytokine profiling can provide valuable information for diagnosing such diseases and monitoring their progression, as well as assessing the efficacy of immunotherapeutic regiments. Toward this goal, there has been immense interest in the development of ultrasensitive quantitative detection techniques for cytokines, which involves technologies from various scientific disciplines, such as immunology, electrochemistry, photometry, nanotechnology and electronics. This review focusses on one aspect of this collective effort: electrochemical biosensors. Among the various types of biosensors available, electrochemical biosensors are one of the most reliable, user-friendly, easy to manufacture, cost-effective and versatile technologies that can yield results within a short period of time, making it extremely promising for routine clinical testing.
Collapse
Affiliation(s)
- Nirmita Dutta
- School of Medical Science and Technology (SMST), Indian Institute of Technology Kharagpur, Kharagpur 721302, India;
| | - Peter B. Lillehoj
- Department of Mechanical Engineering, Rice University, Houston, TX 77005, USA;
| | - Pedro Estrela
- Centre for Biosensors, Bioelectronics and Biodevices (C3Bio) and Department of Electronic & Electrical Engineering, University of Bath, Bath BA2 7AY, UK
| | - Gorachand Dutta
- School of Medical Science and Technology (SMST), Indian Institute of Technology Kharagpur, Kharagpur 721302, India;
| |
Collapse
|
|
30
|
Tsujimoto H, Kobayashi M, Sugasawa H, Ono S, Kishi Y, Ueno H. Potential mechanisms of tumor progression associated with postoperative infectious complications. Cancer Metastasis Rev 2021; 40:285-296. [PMID: 33389285 DOI: 10.1007/s10555-020-09945-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023]
Abstract
There is increasing evidence that postoperative infectious complications (PICs) are associated with poor prognosis after potentially curative surgery. However, the role that PICs play in tumor development remains unclear. In this article, we reviewed the literature for novel insights on the mechanisms of cancer progression associated with PICs. The Medline and EMBASE databases were searched for publications regarding the role of suppression of antitumor immunity by PIC in tumor progression and selected 916 manuscripts were selected for this review. In addition, a summary of the authors' own experimental data from this field was set in the context of current knowledge regarding cancer progression under septic conditions. Initially, sepsis/microbial infection dramatically activates the systemic immune system with increases in pro-inflammatory mediators, which results in the development of systemic inflammatory response syndrome; however, when sepsis persists in septic patients, a shift toward an anti-inflammatory immunosuppressive state, characterized by macrophage deactivation, reduced antigen presentation, T cell anergy, and a shift in the T helper cell pattern to a predominantly TH2-type response, occurs. Thus, various cytokine reactions and the immune status dynamically change during microbial infection, including PIC. We proposed three possible mechanisms for the tumor progression associated with PIC: first, a mechanism in which microbes and/or microbial PAMPs may be directly involved in cancer growth; second, a mechanism in which factors released from immunocompetent cells during infections may affect tumor progression; and third, a mechanism in which factors suppress host tumor immunity during infections, which may result in tumor progression. A more detailed understanding by surgeons of the immunological features in cancer patients with PIC can subsequently open new avenues for improving unfavorable long-term oncological outcomes associated with PICs.
Collapse
Affiliation(s)
- Hironori Tsujimoto
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan.
| | - Minako Kobayashi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan
| | - Hidekazu Sugasawa
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan
| | - Satoshi Ono
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan
| | - Yoji Kishi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Japan
| |
Collapse
|
|
31
|
Mohammadi M. Role of Obesity in the Tumorigenesis of Gastric Cancer. Int J Prev Med 2020; 11:148. [PMID: 33209218 PMCID: PMC7643578 DOI: 10.4103/ijpvm.ijpvm_153_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 08/01/2019] [Indexed: 11/22/2022] Open
Abstract
Gastric cancer as a common cancer is a multi-factorial disease that is dependent on parallel effects of environment and genetics. Endogenous and host factors, including gender and several genetic backgrounds are known risk factors also many environmental factors, including smoking, diet, infection and increasing body weight and body mass index (BMI) are associated with the gastric cancer. Epidemiological data have consistently demonstrated a positive relation between obesity and gastric cancer, whereas mechanistic studies have sought to uncover obesity related carcinogenic pathways. Biological mechanisms and the relationship between obesity and cancer are complex and not well understood. Different effective factors include obesity-related hormones and adipokines, growth factors, modulation of energy balance and calorie restriction, inflammatory processes and multiple signaling pathways that affect cancer cell promotion and progression. In this review, we will discuss the recent advances in the understanding of the association of obesity changes in the gastric cancer.
Collapse
Affiliation(s)
- Masoumeh Mohammadi
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
32
|
El Aamri M, Yammouri G, Mohammadi H, Amine A, Korri-Youssoufi H. Electrochemical Biosensors for Detection of MicroRNA as a Cancer Biomarker: Pros and Cons. BIOSENSORS 2020; 10:E186. [PMID: 33233700 PMCID: PMC7699780 DOI: 10.3390/bios10110186] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 12/23/2022]
Abstract
Cancer is the second most fatal disease in the world and an early diagnosis is important for a successful treatment. Thus, it is necessary to develop fast, sensitive, simple, and inexpensive analytical tools for cancer biomarker detection. MicroRNA (miRNA) is an RNA cancer biomarker where the expression level in body fluid is strongly correlated to cancer. Various biosensors involving the detection of miRNA for cancer diagnosis were developed. The present review offers a comprehensive overview of the recent developments in electrochemical biosensor for miRNA cancer marker detection from 2015 to 2020. The review focuses on the approaches to direct miRNA detection based on the electrochemical signal. It includes a RedOx-labeled probe with different designs, RedOx DNA-intercalating agents, various kinds of RedOx catalysts used to produce a signal response, and finally a free RedOx indicator. Furthermore, the advantages and drawbacks of these approaches are highlighted.
Collapse
Affiliation(s)
- Maliana El Aamri
- Laboratory of Process Engineering & Environment, Faculty of Sciences and Techniques, Hassan II, University of Casablanca, B.P.146, Mohammedia 28806, Morocco; (M.E.A.); (G.Y.); (H.M.)
| | - Ghita Yammouri
- Laboratory of Process Engineering & Environment, Faculty of Sciences and Techniques, Hassan II, University of Casablanca, B.P.146, Mohammedia 28806, Morocco; (M.E.A.); (G.Y.); (H.M.)
| | - Hasna Mohammadi
- Laboratory of Process Engineering & Environment, Faculty of Sciences and Techniques, Hassan II, University of Casablanca, B.P.146, Mohammedia 28806, Morocco; (M.E.A.); (G.Y.); (H.M.)
| | - Aziz Amine
- Laboratory of Process Engineering & Environment, Faculty of Sciences and Techniques, Hassan II, University of Casablanca, B.P.146, Mohammedia 28806, Morocco; (M.E.A.); (G.Y.); (H.M.)
| | - Hafsa Korri-Youssoufi
- Université Paris-Saclay, CNRS, Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), Equipe de Chimie Biorganique et Bioinorganique (ECBB), Bât 420, 2 Rue du Doyen Georges Poitou, 91400 Orsay, France;
| |
Collapse
|
|
33
|
El Rami FE, Barsoumian HB, Khneizer GW. Hereditary diffuse gastric cancer therapeutic roadmap: current and novel approaches in a nutshell. Ther Adv Med Oncol 2020; 12:1758835920967238. [PMID: 33193828 PMCID: PMC7607792 DOI: 10.1177/1758835920967238] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 09/23/2020] [Indexed: 12/24/2022] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is a rare malignancy characterized by autosomal dominant inheritance of pathological variants of the CDH1 gene encoding E-cadherin, which is involved in cell–cell adhesion, maintenance of epithelial architecture, tumor suppression, and regulation of intracellular signaling pathways. Late-stage recognition of HDGC is typically associated with a poor clinical outcome due to its metastatic potential and risk of lobular breast cancer (LBC) development. The American College of Gastroenterology issued guidelines to evaluate HDGC, test for CDH1 genetic variants, and recommend prophylactic gastrectomy for carriers of CDH1 mutations. If surgery is not pursued, endoscopy is a surveillance alternative, although it carries a limited ability to detect malignant foci. As part of clinical research efforts, novel endoscopy advances are currently studied, and a center of excellence for HDGC was created for a comprehensive multidisciplinary team approach. Within this review, we cover current conventional treatment modalities such as gastrectomy and chemotherapy, as the mainstay treatments, in addition to Pembrolizumab, an immune checkpoint inhibitor, as the last therapeutic resort. We also shed light on novel and promising approaches with emphasis on immunotherapy to treat HDGC. We further break down the therapeutic paradigms to utilize molecular tools, antibodies against checkpoint inhibitors, TGF-β and tyrosine kinase inhibitors, cell-based adoptive therapies, and oncolytic viral therapies. We aim to expand the understanding on how to modulate the tumor microenvironment to tip the balance towards an anti-tumor phenotype, prevent metastasis of the primary disease, and potentially alter the therapeutic landscape for HDGC.
Collapse
Affiliation(s)
- Fadi E El Rami
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Gebran W Khneizer
- Department of Internal Medicine, Indiana University Hospital, 550 N University Blvd, Suite 1501, Indianapolis, IN 46202, USA
| |
Collapse
|
|
34
|
Chen HY, Hu Y, Lu NH, Zhu Y. Caudal type homeoboxes as a driving force in Helicobacter pylori infection-induced gastric intestinal metaplasia. Gut Microbes 2020; 12:1-12. [PMID: 33031021 PMCID: PMC7553748 DOI: 10.1080/19490976.2020.1809331] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
(H. pylori), a common pathogenic bacterium in the stomach, has been demonstrated to be a major cause of gastric cancer (GC). The typical pathological evolution of H. pylori infection-induced GC involves development from gastric atrophy, via intestinal metaplasia (IM) and dysplasia, to intestinal-type GC. During this process, IM is considered to be an "irreversible point" that significantly increases the risk for GC. Therefore, the elucidation of the mechanism underlying IM is of great significance for the prevention and treatment of gastric mucosal carcinogenesis associated with H. pylori infection. Caudal type homeoboxes (CDXs) are transcription factors involved in intestinal differentiation establishment and the maintenance of normal intestinal mucosa and IM. H. pylori infection increases the expression of CDXs through epigenetic regulation, the nuclear factor-kappaB signaling pathway and its downstream proinflammatory factors, and the transforming growth factor-beta signaling pathway, leading to the progression from normal gastric mucosa to IM. However, the precise mechanisms of gastric intestinal metaplasia have not yet been fully elucidated. In this review, we focus on research progress revealing the functions of CDXs in H. pylori infection-induced IM, as well as the regulators modulating this process.
Collapse
Affiliation(s)
- Hong-Yan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yi Hu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China,CONTACT Yin Zhu Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang330006, Jiangxi Province, China
| |
Collapse
|
|
35
|
Nakonieczna S, Grabarska A, Kukula-Koch W. The Potential Anticancer Activity of Phytoconstituents against Gastric Cancer-A Review on In Vitro, In Vivo, and Clinical Studies. Int J Mol Sci 2020; 21:E8307. [PMID: 33167519 PMCID: PMC7663924 DOI: 10.3390/ijms21218307] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/03/2020] [Accepted: 11/04/2020] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer belongs to the heterogeneous malignancies and, according to the World Health Organization, it is the fifth most commonly diagnosed cancer in men. The aim of this review is to provide an overview on the role of natural products of plant origin in the therapy of gastric cancer and to present the potentially active metabolites which can be used in the natural therapeutical strategies as the support to the conventional treatment. Many of the naturally spread secondary metabolites have been proved to exhibit chemopreventive properties when tested on the cell lines or in vivo. This manuscript aims to discuss the pharmacological significance of both the total extracts and the single isolated metabolites in the stomach cancer prevention and to focus on their mechanisms of action. A wide variety of plant-derived anticancer metabolites from different groups presented in the manuscript that include polyphenols, terpenes, alkaloids, or sulphur-containing compounds, underlines the multidirectional nature of natural products.
Collapse
Affiliation(s)
- Sylwia Nakonieczna
- Chair and Department of Pharmacognosy, Medical University of Lublin, 1, Chodzki str., 20-093 Lublin, Poland;
| | - Aneta Grabarska
- Chair and Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1, Chodźki, 20-093 Lublin, Poland
| | - Wirginia Kukula-Koch
- Chair and Department of Pharmacognosy, Medical University of Lublin, 1, Chodzki str., 20-093 Lublin, Poland;
| |
Collapse
|
|
36
|
Zhang N, Ning F, Guo R, Pei J, Qiao Y, Fan J, Jiang B, Liu Y, Chi Z, Mei Z, Abe M, Zhu J, Zhang R, Zhang C. Prognostic Values of Preoperative Inflammatory and Nutritional Markers for Colorectal Cancer. Front Oncol 2020; 10:585083. [PMID: 33215031 PMCID: PMC7670074 DOI: 10.3389/fonc.2020.585083] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Increasing evidence indicates that inflammation and nutritional status are associated with survival outcomes in patients with colorectal cancer (CRC). This study aimed to investigate the prognostic values of preoperative inflammatory and nutritional factors and develop a prognostic model individually predicting overall survival (OS) and disease-free survival (DFS) in patients with CRC. METHODS We retrospectively collected data on patients with CRC who underwent radical surgery. Independent prognostic inflammatory and nutritional markers were identified and novel prognostic models were developed incorporating the identified factors. The discriminative ability and model-fitting performance were evaluated by receiver operating characteristic curves and Akaike information criteria. Clinical usefulness was assessed by decision curve analysis. RESULTS A total of 400 eligible patients were identified. Multivariate analysis identified pN stage, tumor differentiation grade, neutrophil count, and body mass index as independent prognostic factors for OS, and pN stage, tumor differentiation grade, neutrophil count, neutrophil-lymphocyte ratio, and serum albumin as prognostic factors for DFS. The combined inflammatory and nutritional prognostic model showed better discriminative ability, model-fitting performance, and net benefits than the inflammatory and nutritional models alone, and the American Joint Committee on Cancer (AJCC) 8th TNM classification for predicting OS and DFS. CONCLUSION Preoperative nutritional and inflammatory factors have significant prognostic value in patients with CRC. A novel prognostic model incorporating preoperative inflammatory and nutritional markers provides better prognostic performance than the AJCC 8th TNM classification. A novel nomogram incorporating preoperative inflammatory and nutritional markers can individually predict OS and DFS in patients with CRC.
Collapse
Affiliation(s)
- Nannan Zhang
- State key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Feilong Ning
- Department of General Surgery, Xuzhou Hospital of Traditional Chinese Medicine, Xuzhou, China
| | - Rui Guo
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Junpeng Pei
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yun Qiao
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Jin Fan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Bo Jiang
- Department of Colorectal Anal Surgery, Shanxi Province Cancer Hospital & Institute, Taiyuan, China
| | - Yanlong Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhaocheng Chi
- Second Department of Gastrointestinal Surgery, Jilin Cancer Hospital, Changchun, China
| | - Zubing Mei
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Anorectal Surgery, Anorectal Disease Institute of Shuguang Hospital, Shanghai, China
| | - Masanobu Abe
- Division for Health Service Promotion, University of Tokyo, Tokyo, Japan
| | - Ji Zhu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Rui Zhang
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Chundong Zhang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
- Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
37
|
Wang J, Li Q, Cheng X, Zhang B, Lin J, Tang Y, Li F, Yang CS, Wang TC, Tu S. Bone Marrow-Derived Myofibroblasts Promote Gastric Cancer Metastasis by Activating TGF-β1 and IL-6/STAT3 Signalling Loop. Onco Targets Ther 2020; 13:10567-10580. [PMID: 33116635 PMCID: PMC7585554 DOI: 10.2147/ott.s266506] [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: 06/16/2020] [Accepted: 09/09/2020] [Indexed: 12/26/2022] Open
Abstract
Background Murine bone marrow-derived myofibroblasts (BMFs) have previously been shown to promote gastric cancer growth. However, whether BMFs promote gastric cancer cell metastasis remains largely unknown. Methods Wound healing assay, Transwell invasion and migration assay and 3D organotypic co-culture systems were conducted to study the effects of BMFs on invasion and migration of gastric cancer cells and the invasion and migration ability of gastric cancer stem cell-like cells (CSC-LCs) induced by BMFs. We employed two animal model to study the role of BMFs on the in vivo metastasis of gastric cancer cells and the metastatic ability of gastric BMF-induced CSC-LCs. A human gastric cancer tissue microarray and TCGA gastric cancer database were analysed to study the relationship between the expression of IL-6 and TGF-β1 and clinicopathological characteristics and survival in gastric cancer. Results We found that BMFs promoted the in vitro migration and invasion of gastric cancer cells. BMFs promoted liver, lung, subcutaneous, and splenic metastases of MKN28 cells in the spleen injection liver metastasis model and co-injection of caudal vein (IOCV) mouse model. BMFs reprogrammed non-gastric cancer stem cell (CSC) to CSC-LCs and enhanced CSC-LC migration and metastasis. BMF-derived IL-6 and gastric cancer cell-secreted TGF-β1 mediated the interaction between BMFs and gastric cancer cells, promoting tumour metastasis. BMFs enhanced the expressions of STAT3 and p-STAT3 in co-cultured gastric cancer cells. A combination of Napabucasin and Galunisertib exhibited the strongest inhibition of cell migration compared to when administered alone. Gastric cancer tissue array and TCGA database indicated that the overexpression of IL-6 and TGF-β1 was associated with gastric cancer metastasis. Conclusion Our results demonstrated that BMFs promote gastric cancer metastasis through the activation of the TGF-β1 and IL-6/STAT3 signalling pathways. Targeting the inhibition of these interactions may be a potent therapeutic strategy for addressing gastric cancer metastasis.
Collapse
Affiliation(s)
- Jianzheng Wang
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China
| | - Qingli Li
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China
| | - Xiaojiao Cheng
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China
| | - Baiwen Zhang
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China
| | - Jiacheng Lin
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China
| | - Yao Tang
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China
| | - Fuli Li
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China
| | - Chung S Yang
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Timothy C Wang
- Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA
| | - Shuiping Tu
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China
| |
Collapse
|
|
38
|
Merhi M, Raza A, Inchakalody VP, Siveen KS, Kumar D, Sahir F, Mestiri S, Hydrose S, Allahverdi N, Jalis M, Relecom A, Al Zaidan L, Hamid MSE, Mostafa M, Gul ARZ, Uddin S, Al Homsi M, Dermime S. Persistent anti-NY-ESO-1-specific T cells and expression of differential biomarkers in a patient with metastatic gastric cancer benefiting from combined radioimmunotherapy treatment: a case report. J Immunother Cancer 2020; 8:e001278. [PMID: 32913031 PMCID: PMC7484873 DOI: 10.1136/jitc-2020-001278] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2020] [Indexed: 12/14/2022] Open
Abstract
Combined radioimmunotherapy is currently being investigated to treat patients with cancer. Anti-programmed cell death-1 (PD-1) immunotherapy offers the prospect of long-term disease control in solid tumors. Radiotherapy has the ability to promote immunogenic cell death leading to the release of tumor antigens, increasing infiltration and activation of T cells. New York esophageal squamous cell carcinoma-1 (NY-ESO-1) is a cancer-testis antigen expressed in 20% of advanced gastric cancers and known to induce humoral and cellular immune responses in patients with cancer. We report on the dynamic immune response to the NY-ESO-1 antigen and important immune-related biomarkers in a patient with metastatic gastric cancer treated with radiotherapy combined with anti-PD-1 pembrolizumab antibody.Our patient was an 81-year-old man diagnosed with locally advanced unresectable mismatch repair-deficient gastric cancer having progressed to a metastatic state under a second line of systemic treatment consisting of an anti-PD-1 pembrolizumab antibody. The patient was subsequently treated with local radiotherapy administered concomitantly with anti-PD-1, with a complete response on follow-up radiologic assessment. Disease control was sustained with no further therapy for a period of 12 months before relapse. We have identified an NY-ESO-1-specific interferon-γ (IFN-γ) secretion from the patients' T cells that was significantly increased at response (****p˂0.0001). A novel promiscuous immunogenic NY-ESO-1 peptide P39 (P153-167) restricted to the four patient's HLA-DQ and HLA-DP alleles was identified. Interestingly, this peptide contained the known NY-ESO-1-derived HLA-A2-02:01(P157-165) immunogenic epitope. We have also identified a CD107+ cytotoxic T cell subset within a specific CD8+/HLA-A2-NY-ESO-1 T cell population that was low at disease progression, markedly increased at disease resolution and significantly decreased again at disease re-progression. Finally, we identified two groups of cytokines/chemokines. Group 1 contains five cytokines (IFN-γ, tumor necrosis factor-α, interleukin-2 (IL-2), IL-5 and IL-6) that were present at disease progression, significantly downregulated at disease resolution and dramatically upregulated again at disease re-progression. Group 2 contains four biomarkers (perforin, soluble FAS, macrophage inflammatory protein-3α and C-X-C motif chemokine 11/Interferon-inducible T Cell Alpha Chemoattractant that were present at disease progression, significantly upregulated at disease resolution and dramatically downregulated again at disease re-progression. Combined radioimmunotherapy can enhance specific T cell responses to the NY-ESO-1 antigen that correlates with beneficial clinical outcome of the patient.
Collapse
Affiliation(s)
- Maysaloun Merhi
- Medical Oncology, Hamad Medical Corporation, Doha, Ad Dawhah, Qatar
| | - Afsheen Raza
- Medical Oncology, Hamad Medical Corporation, Doha, Ad Dawhah, Qatar
| | | | | | - Deepak Kumar
- Computational Biology, Carnegie Mellon University - Qatar Campus, Doha, Ad Dawhah, Qatar
| | | | | | | | | | - Munir Jalis
- Hamad Medical Corporation, Doha, Ad Dawhah, Qatar
| | | | | | | | - Mai Mostafa
- Hamad Medical Corporation, Doha, Ad Dawhah, Qatar
| | | | - Shahab Uddin
- Hamad Medical Corporation, Doha, Ad Dawhah, Qatar
| | | | - Said Dermime
- Medical Oncology, National Center for Cancer Care and Research, Doha, Qatar
| |
Collapse
|
|
39
|
Nienhüser H, Crnovrsanin N, Nerz D, Heckler M, Sisic L, Lasitschka F, Schneider M, Schmidt T. Expression of Angiogenic Proteins in Tumor and Stroma Affects Survival in Patients With Gastric Cancer. J Surg Res 2020; 255:172-180. [PMID: 32563757 DOI: 10.1016/j.jss.2020.05.045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 04/20/2020] [Accepted: 05/06/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer is one of the most frequent malignancies worldwide. Angiogenic growth factors play a crucial role in mediating the crosstalk between cancer cells and the surrounding microenvironment. In this exploratory study, we investigate the impact of angiogenic proteins within the tumor cell or stroma compartment on survival of patients with gastric cancer. MATERIALS AND METHODS In 29 patients, tumor and stromal compartments were separated using laser capture microdissection. Angiogenic protein expression was measured using a bead-based immunoassay and correlated with tumor stage and overall survival. RESULTS Overall survival was significantly shorter in patients with a high stroma concentration of vascular endothelial growth factor (VEGF)-A (23.5 (±17.6) versus 33.6 (±21.0) mo; P = 0.009) and stem cell factor (22.2 (±18.5) versus 33.6 (±21.8) mo; P = 0.01) compared with patients with a low stroma concentration. High stromal VEGF-D showed a trend toward worse survival (26.8 (±22.0) versus 37.2 (±19.0) mo; P = 0.09). We did not observe any significant correlation between tumor-specific expression of angiogenic cytokines and survival. CONCLUSIONS This translational study highlights the difference in clinical impact between tumor and stromal expression of angiogenic proteins. Compartment-specific concentrations of VEGF-A and stem cell factor affect the clinical prognosis and help to identify the best therapy for patients with gastric cancer.
Collapse
Affiliation(s)
- Henrik Nienhüser
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - Nerma Crnovrsanin
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - Daniel Nerz
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - Max Heckler
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - Leila Sisic
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | | | - Martin Schneider
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany.
| |
Collapse
|
|
40
|
Shinsyu A, Bamba S, Kurihara M, Matsumoto H, Sonoda A, Inatomi O, Andoh A, Takebayashi K, Kojima M, Iida H, Tani M, Sasaki M. Inflammatory cytokines, appetite-regulating hormones, and energy metabolism in patients with gastrointestinal cancer. Oncol Lett 2020; 20:1469-1479. [PMID: 32724390 DOI: 10.3892/ol.2020.11662] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 12/17/2019] [Indexed: 12/18/2022] Open
Abstract
This study investigated energy metabolism and its association with inflammatory cytokines and appetite- regulating hormones in patients with gastrointestinal cancer. Subjects were inpatients scheduled to undergo therapeutic intervention for diagnosed gastrointestinal cancer. Nutritional status on admission was assessed based on anthropometric measurements, nutrition screening results, food intake rate (energy intake/energy provided in hospital food), and biochemical test results. Fat-free mass (FFM) was measured using the bioelectrical impedance analysis. Resting energy expenditure (REE) and respiratory quotient were measured with indirect calorimetry, and basal energy expenditure (BEE) was calculated using the Harris-Benedict equation. A total 51 patients with gastrointestinal cancer were enrolled (17 with esophageal cancer, 15 with gastric cancer, and 19 with colorectal cancer); 16 had stage I disease, 11 had stage II, 13 had stage III, and 11 had stage IV. The levels of inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α increased significantly with cancer stage progression (P<0.001; Jonckheere-Terpstra trend test). The REE/body weight and the REE/FFM tended to increase with cancer stage progression (P=0.064 and P=0.053, respectively; Jonckheere-Terpstra trend test). FFM showed a significant negative correlation with the level of TNF-α (P=0.008; Spearman's correlation coefficient). Also, food intake rate showed a significant negative correlation with levels of IL-6 and TNF-α (P<0.001). The level of active ghrelin was positively correlated with that of IL-6 and energy metabolism (P=0.004 and 0.016, respectively) and negatively correlated with food intake rate (P=0.035), which suggests a state of ghrelin resistance. In conclusion, this study confirmed increases in the levels of inflammatory cytokines with the progression of gastrointestinal cancer and suggested the possible association of such increases with decreased FFM and the increased energy metabolism. However, the increased levels of active ghrelin failed to compensate for cachexia in cancer patients.
Collapse
Affiliation(s)
- Ayaka Shinsyu
- Division of Clinical Nutrition, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Shigeki Bamba
- Division of Clinical Nutrition, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Mika Kurihara
- Division of Clinical Nutrition, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Hiroshi Matsumoto
- Division of Gastroenterology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Ayano Sonoda
- Division of Gastroenterology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Osamu Inatomi
- Division of Gastroenterology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Akira Andoh
- Division of Gastroenterology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Katsushi Takebayashi
- Division of Gastrointestinal Surgery, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Masatsugu Kojima
- Division of Gastrointestinal Surgery, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Hiroya Iida
- Division of Gastrointestinal Surgery, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Masaji Tani
- Division of Gastrointestinal Surgery, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Masaya Sasaki
- Division of Clinical Nutrition, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| |
Collapse
|
|
41
|
Cytokine and Cancer Biomarkers Detection: The Dawn of Electrochemical Paper-Based Biosensor. SENSORS 2020; 20:s20071854. [PMID: 32230808 PMCID: PMC7180619 DOI: 10.3390/s20071854] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 03/24/2020] [Accepted: 03/24/2020] [Indexed: 12/14/2022]
Abstract
Although the established ELISA-based sensing platforms have many benefits, the importance of cytokine and cancer biomarkers detection for point-of-care diagnostics has propelled the search for more specific, sensitive, simple, accessible, yet economical sensor. Paper-based biosensor holds promise for future in-situ applications and can provide rapid analysis and data without the need to conduct in a laboratory. Electrochemical detection plays a vital role in interpreting results obtained from qualitative assessment to quantitative determination. In this review, various factors affecting the design of an electrochemical paper-based biosensor are highlighted and discussed in depth. Different detection methods, along with the latest development in utilizing them in cytokine and cancer biomarkers detection, are reviewed. Lastly, the fabrication of portable electrochemical paper-based biosensor is ideal in deliberating positive societal implications in developing countries with limited resources and accessibility to healthcare services.
Collapse
|
|
42
|
Qeadan F, Bansal P, Hanson JA, Beswick EJ. The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach. J Transl Med 2020; 18:137. [PMID: 32216812 PMCID: PMC7098132 DOI: 10.1186/s12967-020-02294-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 03/11/2020] [Indexed: 02/07/2023] Open
Abstract
Background Gastric cancer is associated with chronic inflammation, but there is still much to understand about the tumor microenvironment and the underlying tumor-promoting mechanisms. The Map kinase-activated protein kinase 2 (MK2) pathway is a regulator of inflammatory cytokine production that we have been studying in gastrointestinal cancers. Here, we set out to determine the significance of this gene in gastric cancer along with its downstream mediators and if there were differences in the primary tumors with and without metastasis. Methods Human gastric cancer tissues with and without metastasis were examined for MK2 expression and cytokine profile in organ culture supernatants. Advanced statistical methods including a lower triangular correlation matrix, novel rooted correlation network, linear and logistic regression modeling along with Kruskal–Wallis testing with Sidak correction for multiple testing were applied to gain understanding of cytokines/chemokines linked to metastasis. Results The MK2 pathway is strongly linked with metastasis and a panel of cytokines. Gene expression was able to classify gastric cancer metastasis 85.7% of the time. A significant association with a panel of cytokines was found, including G-CSF, GM-CSF, Mip-1β, IFN-α, MCP-1, IL-1β, IL-6, and TNF-α. Mip-1β was found to have the strongest association with MK2 and metastasis after Sidak correction for multiple testing. Conclusions MK2 gene expression and a novel associated cytokine panel are linked to gastric cancer metastasis. G-CSF is the strongest cytokine to differentiate between metastasis and non-metastasis patients and had the lowest P value, while Mip-1β showed the strongest association with MK2 and metastasis after Sidak correction. MK2 and associated cytokines are potential biomarkers for gastric cancer metastasis. The novel intercorrelation analysis approach is a promising method for understanding the complex nature of cytokine/chemokine regulation and links to disease outcome.
Collapse
Affiliation(s)
- Fares Qeadan
- Department of Family and Preventative Medicine, University of Utah, Salt Lake City, UT, USA
| | - Pranshu Bansal
- New Mexico Oncology Hematology Consultants, Albuquerque, NM, USA
| | - Joshua A Hanson
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Ellen J Beswick
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
| |
Collapse
|
|
43
|
Limpakan Yamada S, Wongsirisin P, Yodkeeree S, Chakrabandhu B, Chongruksut W, Limtrakul Dejkriengkraikul P. Interleukin-8 associated with chemosensitivity and poor chemotherapeutic response to gastric cancer. J Gastrointest Oncol 2020; 10:1120-1132. [PMID: 31949929 DOI: 10.21037/jgo.2019.09.02] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background Gastric cancer (GC) patients have been found to have developed chemotherapy resistance that has resulted in a lowering of their overall survival rates. Interleukin-6 (IL-6) and interleukin-8 (IL-8) could be responsible as the predictive biomarkers in monitoring drug resistance. We have developed a protocol to monitor drug treatment by testing ex vivo chemosensitivity and cytokine levels of primary gastric cultures obtained from endoscopic biopsies. Methods We studied 49 patients with distal GC who underwent primary surgical resection between June 2014 and December 2016 in the northern endemic region of Thailand. The clinical and pathological data of patients were recorded, and the cancer sub-type was classified. The correlation of cytokine IL-6 and IL-8 protein expression levels and chemotherapy sensitivity in primary gastric cultures was investigated. Endoscopic biopsies were collected before and/or after chemotherapy treatment followed by FOLFOXIV regimen (oxaliplatin + 5-FU/leucovorin). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to examine ex vivo chemosensitivity to cisplatin, oxaliplatin, 5-fluorouracil (5-FU) and irinotecan. Enzyme-linked immunosorbent assay (ELISA) was performed to investigate cytokine levels. Results Ex vivo drug treatment of 49 primary gastric cultures from naive patients revealed a significant correlation between basal levels of IL-8 and chemosensitivity to cisplatin (P=0.001) and oxaliplatin (P=0.001). IL-8 protein expression levels were significantly decreased in the early phase after cisplatin and oxaliplatin treatments leading to an increase in cell sensitivity to drug treatments. Among 49 patients, 11 patients were classified as partial or poor responders after drug interventions, in which case, second endoscopic biopsies were performed for determination of chemosensitivity and cytokine levels. The results demonstrated significant decreases in sensitivity to cisplatin (P=0.049) and oxaliplatin (P=0.014), meanwhile IL-8 protein expression levels were significantly increased by P=0.0423 in both drug treatments. There was no correlation of IL-6 and drug resistance when treatments of the primary gastric cultures involved each of the four chemotherapeutic drugs (P=0.0663). Conclusions Upregulation of IL-8 after drug intervention might be useful as predictive biomarker in monitoring drug resistance in GC patients; however, this needs to be confirmed among a larger number of patients and with control groups that are properly age-paired. The established primary gastric culture could serve as a valuable tool for chemotherapy screening, while the repeated usage of platinum drugs may result in drug resistance via upregulation of IL-8 levels.
Collapse
Affiliation(s)
- Sirikan Limpakan Yamada
- Division of Gastrointestinal Surgery and Endoscopy, Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Gastric Cancer Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pattama Wongsirisin
- Anticarcinogenesis and Apoptosis Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Supachai Yodkeeree
- Anticarcinogenesis and Apoptosis Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
| | - Bandhuphat Chakrabandhu
- Division of Gastrointestinal Surgery and Endoscopy, Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Gastric Cancer Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Wilaiwan Chongruksut
- Division of Gastrointestinal Surgery and Endoscopy, Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Gastric Cancer Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pornngarm Limtrakul Dejkriengkraikul
- Anticarcinogenesis and Apoptosis Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
| |
Collapse
|
|
44
|
Lemon Peel Polyphenol Extract Reduces Interleukin-6-Induced Cell Migration, Invasiveness, and Matrix Metalloproteinase-9/2 Expression in Human Gastric Adenocarcinoma MKN-28 and AGS Cell Lines. Biomolecules 2019; 9:biom9120833. [PMID: 31817563 PMCID: PMC6995574 DOI: 10.3390/biom9120833] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/26/2019] [Accepted: 12/03/2019] [Indexed: 12/15/2022] Open
Abstract
Among plant polyphenols, lemon peels extract (LPE) from the residues of the industrial processing of lemon (Citrus limon) shows anti-proliferative properties in cancer cells and anticholinesterase activity. In this study, we analyze the anti-cancer properties of LPE on migration and invasiveness in MKN-28 and AGS human gastric cancer cell lines either in the absence or presence of the pro-inflammatory cytokine IL-6. We find that the pretreatment with non-cytotoxic concentrations (0.5–1 μg/ml of gallic acid equivalent) of LPE inhibits interleukin-6 (IL-6)-induced cell migration and invasiveness in MKN-28 and AGS cells, as analyzed by wound and matrigel assays. Pretreatment with LPE is able to prevent either IL-6-induced matrix metalloproteinases (MMP)-9/2 activity, as assessed by gel zymography, or mRNA and protein MMP-9/2 expression, as evaluated by qPCR and Western blotting analysis, respectively. These LPE effects are associated with an IL-6-dependent STAT3 signaling pathway in MKN-28 and AGS cells. Furthermore, LPE shows acetylcholinesterase inhibitory activity when assayed by the Ellman method. In conclusion, our results demonstrate that LPE reduces the invasiveness of gastric MKN-28 and AGS cancer cells through the reduction of IL-6-induced MMP-9/2 up-regulation. Therefore, these data suggest that LPE exerts a protective role against the metastatic process in gastric cancer.
Collapse
|
|
45
|
Kersy O, Loewenstein S, Lubezky N, Sher O, Simon NB, Klausner JM, Lahat G. Omental Tissue-Mediated Tumorigenesis of Gastric Cancer Peritoneal Metastases. Front Oncol 2019; 9:1267. [PMID: 31803630 PMCID: PMC6876669 DOI: 10.3389/fonc.2019.01267] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 11/01/2019] [Indexed: 12/21/2022] Open
Abstract
The peritoneal cavity, especially the omentum, is a common site for gastric cancer metastasis, representing advanced disease stage and poor prognosis. Here, we studied the effects of omental tissue on gastric cancer tumor progression in vitro and in vivo. Utilizing in vitro models, we found that omental tissue secreted factors increased gastric cancer cellular growth (by 30–67%, P < 0.05), motility (>8-fold, P < 0.05), invasiveness (>7-fold, P < 0.05) and chemoresistance to platinum-based chemotherapeutic agents (>1.2-fold for oxaliplatin and >1.6-fold for cisplatin, P < 0.05). Using a robust proteomic approach, we identified numerous molecules secreted into the omental tissue conditioned medium (CM) which may promote gastric cancer cellular aggressiveness (i.e., IL-6, IL-8, MMP9, FN1, and CXCL-5). Next, an in vivo xenograft mouse model showed an increased human gastric adenocarcinoma tumor volume of cells co-cultured with human omental tissue secreted factors; 1.6 ± 0.55 vs. 0.3 ± 0.19 cm3 (P < 0.001), as well as increased angiogenesis. Finally, exosomes were isolated from human omental tissue CM of gastric cancer patients. These exosomes were taken up by gastric cancer cells enhancing their growth (>8-fold, P < 0.01) and invasiveness (>8-fold, P < 0.001). Proteomic analysis of the content of these exosomes identified several established cancer- related proteins (i.e., IL-6, IL-8, ICAM-1, CCl2, and OSM). Taken together, our findings imply that the omentum play an active role in gastric cancer metastasis. The data also describe specific cytokines that are involved in this cross talk, and that omental tissue- derived exosomes may contribute to these unique cellular interactions with gastric cancer cells. Further studies aimed at understanding the biology of gastric cancer intra peritoneal spread are warranted. Hopefully, such data will enable to develop future novel therapeutic strategies for the treatment of metastatic gastric cancer.
Collapse
Affiliation(s)
- Olga Kersy
- Laboratory of Surgical Oncology, Tel-Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel.,Division of Surgery, Tel-Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
| | - Shelly Loewenstein
- Laboratory of Surgical Oncology, Tel-Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel.,Division of Surgery, Tel-Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
| | - Nir Lubezky
- Division of Surgery, Tel-Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
| | - Osnat Sher
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel.,Institute of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
| | - Natalie B Simon
- College of Arts and Sciences, University of Virginia, Charlottesville, VA, United States
| | - Joseph M Klausner
- Division of Surgery, Tel-Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel.,The Nikolas and Elizabeth Shlezak Cathedra for Experimental Surgery, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
| | - Guy Lahat
- Laboratory of Surgical Oncology, Tel-Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel.,Division of Surgery, Tel-Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel
| |
Collapse
|
|
46
|
More Than an Adipokine: The Complex Roles of Chemerin Signaling in Cancer. Int J Mol Sci 2019; 20:ijms20194778. [PMID: 31561459 PMCID: PMC6801800 DOI: 10.3390/ijms20194778] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/18/2019] [Accepted: 09/23/2019] [Indexed: 12/24/2022] Open
Abstract
Chemerin is widely recognized as an adipokine, with diverse biological roles in cellular differentiation and metabolism, as well as a leukocyte chemoattractant. Research investigating the role of chemerin in the obesity-cancer relationship has provided evidence both for pro- and anti-cancer effects. The tumor-promoting effects of chemerin primarily involve direct effects on migration, invasion, and metastasis as well as growth and proliferation of cancer cells. Chemerin can also promote tumor growth via the recruitment of tumor-supporting mesenchymal stromal cells and stimulation of angiogenesis pathways in endothelial cells. In contrast, the majority of evidence supports that the tumor-suppressing effects of chemerin are immune-mediated and result in a shift from immunosuppressive to immunogenic cell populations within the tumor microenvironment. Systemic chemerin and chemerin produced within the tumor microenvironment may contribute to these effects via signaling through CMKLR1 (chemerin1), GPR1 (chemerin2), and CCLR2 on target cells. As such, inhibition or activation of chemerin signaling could be beneficial as a therapeutic approach depending on the type of cancer. Additional studies are required to determine if obesity influences cancer initiation or progression through increased adipose tissue production of chemerin and/or altered chemerin processing that leads to changes in chemerin signaling in the tumor microenvironment.
Collapse
|
|
47
|
Taniguchi Y, Kurokawa Y, Hagi T, Takahashi T, Miyazaki Y, Tanaka K, Makino T, Yamasaki M, Nakajima K, Mori M, Doki Y. Methylprednisolone Inhibits Tumor Growth and Peritoneal Seeding Induced by Surgical Stress and Postoperative Complications. Ann Surg Oncol 2019; 26:2831-2838. [DOI: 10.1245/s10434-019-07585-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Indexed: 08/30/2023]
|
|
48
|
Liu S, Zhou Y, Zhao L, Wang J, Ji R, Wang Y, Wu J, Yan X. IL-6 and miR-1271 expression levels in elderly and young gastric cancer patients and correlation analysis with prognosis. Oncol Lett 2019; 17:5419-5424. [PMID: 31186760 PMCID: PMC6507464 DOI: 10.3892/ol.2019.10230] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 03/18/2019] [Indexed: 12/26/2022] Open
Abstract
Differences in inflammatory factors IL-6 and miR-1271 expression levels between elderly and young gastric cancer patients were investigated. A retrospective analysis of 146 cases of gastric cancer tissue and normal fresh tissue specimens diagnosed in The First Hospital of Lanzhou University from January 2013 to January 2015, was performed. Patients aged ≥60 years were the elderly group (76 cases), and patients ≤40 years were the youth group (70 cases). RT-qPCR was used to detect the relative expression levels of IL-6 and miR-1271, and Kaplan-Meier for a postoperative 3-year survival analysis of young and elderly gastric cancer patients. The expression level of IL-6 and miR-1271 was significantly higher in young gastric cancer tissues than that in elderly gastric cancer tissues (P<0.001). The expression levels of IL-6 and miR-1271 were correlated with age, tumor size, lymph node metastasis, distant metastasis, clinical stage and differentiation degree of gastric cancer patients (P<0.05). The 3-year overall survival rate of patients with a low expression of IL-6 and miR-1271 was better than that of patients with a high expression in young and elderly gastric cancer (P<0.05). IL-6 was highly expressed but miR-1271 expression was low in gastric cancer tissues. The 3-year overall survival rate of patients with the low expression of IL-6 was better than that of patients with the high expression in young and elderly gastric cancer. The high expression of miR-1271 was better than that of patients with the low expression in young and elderly gastric cancer. Findings of the present study provide data support for the clinical evaluation of differences between young and elderly gastric cancer and their prognosis.
Collapse
Affiliation(s)
- Shixiong Liu
- Department of Geriatrics (II), The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Yun Zhou
- Department of Geriatrics (II), The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Li Zhao
- Department of Ultrasound, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, Gansu 730020, P.R. China
| | - Jing Wang
- Department of Geriatrics (II), The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Rui Ji
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Yiqing Wang
- Department of Geriatrics (II), The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Jiyin Wu
- Department of Geriatrics (II), The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Xiang Yan
- Department of Geriatrics (II), The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| |
Collapse
|
|
49
|
Resolution of Gastric Cancer-Promoting Inflammation: A Novel Strategy for Anti-cancer Therapy. Curr Top Microbiol Immunol 2019; 421:319-359. [PMID: 31123895 DOI: 10.1007/978-3-030-15138-6_13] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The connection between inflammation and cancer was initially recognized by Rudolf Virchow in the nineteenth century. During the last decades, a large body of evidence has provided support to his hypothesis, and now inflammation is recognized as one of the hallmarks of cancer, both in etiopathogenesis and ongoing tumor growth. Infection with the pathogen Helicobacter pylori is the primary causal factor in 90% of gastric cancer (GC) cases. As we increase our understanding of how chronic inflammation develops in the stomach and contributes to carcinogenesis, there is increasing interest in targeting cancer-promoting inflammation as a strategy to treat GC. Moreover, once cancer develops and anti-cancer immune responses are suppressed, there is evidence of a substantial shift in the microenvironment and new targets for immune therapy emerge. In this chapter, we provide insight into inflammation-related factors, including T lymphocytes, macrophages, pro-inflammatory chemokines, and cytokines, which promote H. pylori-associated GC initiation and growth. While intervening with chronic inflammation is not a new practice in rheumatology or gastroenterology, this approach has not been fully explored for its potential to prevent carcinogenesis or to contribute to the treatment of GC. This review highlights current and possible strategies for therapeutic intervention including (i) targeting pro-inflammatory mediators, (ii) targeting growth factors and pathways involved in angiogenesis in the gastric tumor microenvironment, and (iii) enhancing anti-tumor immunity. In addition, we highlight a significant number of clinical trials and discuss the importance of individual tumor characterization toward offering personalized immune-related therapy.
Collapse
|
|
50
|
Clotaire DZJ, Du X, Wei Y, Yang D, Hua J. miR-19b-3p integrates Jak-Stat signaling pathway through Plzf to regulate self-renewal in dairy goat male germline stem cells. Int J Biochem Cell Biol 2018; 105:104-114. [PMID: 30393202 DOI: 10.1016/j.biocel.2018.10.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 10/19/2018] [Accepted: 10/25/2018] [Indexed: 12/27/2022]
Abstract
Jak-Stat pathway is the first pathway identified to stimulate spermatogonial stem cells (SSCs) self-renewal and maintenance activity. Recent studies have showed that stat3 a crucial gene implicated in this pathway can regulate self-renewal in male germline stem cell. In our previous study, we demonstrated that miR-19b-3p induces cell proliferation and reduces heterochromatin through Plzf which also regulates the balance between cell self-renewal and differentiation. Because miRNA can target several genes and to understand more about Plzf, a crucial transcription factor of SSCs, we performed microarray and found that miR-19b-3p integrate Jak-Stat through Plzf to regulate cell self-renewal. Our results demonstrated that miR-19b-3p induces Jak-Stat when Plzf is downregulated; overexpression of Plzf reversed the trend and shown an existence of feedback (-/+) between Plzf and GHR. The cell self-renewal markers CD49f, GFRα1, Oct4 and cKIT analyzed in the both groups miR-19b-3p and Plzf-overexpressing compared to their respective control confirm miR-19b-3p regulates cell pluripotency and self-renewal in goat male germline stem cells through Plzf. Together our finding revels that miR-19b-3p control Jak-Stat signaling through Plzf.
Collapse
Affiliation(s)
- Daguia Zambe John Clotaire
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100 China; Laboratoire des sciences Agronomiques et Biologiques pour le Développement (LASBAD), Faculty of Science, University of Bangui, P.O Box 908, Central Africa, Central African Republic
| | - Xiaomin Du
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100 China
| | - Yudong Wei
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100 China
| | - Donghui Yang
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100 China
| | - Jinlian Hua
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100 China.
| |
Collapse
|