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Zhong H, Jiang J, Hussain M, Zhang H, Chen L, Guan R. The Encapsulation Strategies for Targeted Delivery of Probiotics in Preventing and Treating Colorectal Cancer: A Review. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2500304. [PMID: 40192333 PMCID: PMC12079478 DOI: 10.1002/advs.202500304] [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] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/01/2025] [Indexed: 05/16/2025]
Abstract
Colorectal cancer (CRC) ranks as the third most prevalent cancer worldwide. It is associated with imbalanced gut microbiota. Probiotics can help restore this balance, potentially reducing the risk of CRC. However, the hostile environment and constant changes in the gastrointestinal tract pose significant challenges to the efficient delivery of probiotics to the colon. Traditional delivery methods are often insufficient due to their low viability and lack of targeting. To address these challenges, researchers are increasingly focusing on innovative encapsulation technologies. One such approach is single-cell encapsulation, which involves applying nanocoatings to individual probiotic cells. This technique can improve their resistance to the harsh gastrointestinal environment, enhance mucosal adhesion, and facilitate targeted release, thereby increasing the effectiveness of probiotic delivery. This article reviews the latest developments in probiotic encapsulation methods for targeted CRC treatment, emphasizing the potential benefits of emerging single-cell encapsulation techniques. It also analyzes and compares the advantages and disadvantages of current encapsulation technologies. Furthermore, it elucidates the underlying mechanisms through which probiotics can prevent and treat CRC, evaluates the efficacy and safety of probiotics in CRC treatment and adjuvant therapy, and discusses future directions and potential challenges in the targeted delivery of probiotics for CRC treatment and prevention.
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Affiliation(s)
- Hao Zhong
- College of Food Science and TechnologyZhejiang University of TechnologyHangzhou310014China
| | - Jin Jiang
- College of Food Science and TechnologyZhejiang University of TechnologyHangzhou310014China
| | - Muhammad Hussain
- College of Food Science and TechnologyZhejiang University of TechnologyHangzhou310014China
- Moganshan Institute ZJUTKangqianDeqing313200China
| | - Haoxuan Zhang
- College of Food Science and TechnologyZhejiang University of TechnologyHangzhou310014China
| | - Ling Chen
- Sanya Branch of Hainan Academy of Inspection and TestingSan Ya572011China
| | - Rongfa Guan
- College of Food Science and TechnologyZhejiang University of TechnologyHangzhou310014China
- Moganshan Institute ZJUTKangqianDeqing313200China
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Safaei S, Yari A, Pourbagherian O, Maleki LA. The role of cytokines in shaping the future of Cancer immunotherapy. Cytokine 2025; 189:156888. [PMID: 40010034 DOI: 10.1016/j.cyto.2025.156888] [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: 10/28/2024] [Revised: 01/13/2025] [Accepted: 02/05/2025] [Indexed: 02/28/2025]
Abstract
As essential immune system regulators, cytokines are essential for modulating both innate and adaptive immunological responses. They have become important tools in cancer immunotherapy, improving the immune system's capacity to identify and destroy tumor cells. This article examines the background, workings, and therapeutic uses of cytokines, such as interleukins, interferons, and granulocyte-macropHage colony-stimulating factors, in the management of cancer. It examines the many ways that cytokines affect immune cell activation, signaling pathways, tumor development, metastasis, and prognosis by modifying the tumor microenvironment. Despite the limited effectiveness of cytokine-based monotherapy, recent developments have concentrated on new fusion molecules such as immunocytokines, cytokine delivery improvements, and combination techniques to maximize treatment efficacy while reducing adverse effects. Current FDA-approved cytokine therapeutics and clinical trial results are also included in this study, which offers insights into how cytokines might be used with other therapies including checkpoint inhibitors, chemotherapy, and radiation therapy to address cancer treatment obstacles. This study addresses the intricacies of cytokine interactions in the tumor microenvironment, highlighting the possibility for innovative treatment methods and suggesting fresh techniques for enhancing cytokine-based immunotherapies. PEGylation, viral vector-mediated cytokine gene transfer, antibody-cytokine fusion proteins (immunocytokines), and other innovative cytokine delivery techniques are among the novelties of this work, which focuses on the most recent developments in cytokine-based immunotherapy. Additionally, the study offers a thorough examination of the little-reviewed topic of cytokine usage in conjunction with other treatment techniques. It also discusses the most recent clinical studies and FDA-approved therapies, providing a modern perspective on the developing field of cancer immunotherapy and suggesting creative ways to improve treatment effectiveness while lowering toxicity. BACKGROUND: Cytokines are crucial in cancer immunotherapy for regulating immune responses and modifying the tumor microenvironment (TME). However, challenges with efficacy and safety have driven research into advanced delivery methods and combination therapies to enhance their therapeutic potential.
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Affiliation(s)
- Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - AmirHossein Yari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Omid Pourbagherian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Li H, Li X, Meng Q, Han J, Zhao W, Chen J, Su W, Song M, Shi C, Wang L. Electric field-induced alignment of Ag/Au nanowires for ultrasensitive in situ detection of Interleukin-6. Biosens Bioelectron 2025; 271:117033. [PMID: 39671960 DOI: 10.1016/j.bios.2024.117033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 11/25/2024] [Accepted: 12/03/2024] [Indexed: 12/15/2024]
Abstract
Interleukin-6 (IL-6) is a key parameter and critical role in cancer progression. However, for detection of IL-6 in colorectal cancer diagnosis, developing a sensitive biosensor is necessary and very important. In this paper, to enhance the sensitivity of IL-6 electrochemical biosensor, the electric field was used to orient arrangement of silver nanowires (AgNWs) to be free-standing AgNWs electrode. Gold nanoparticles (AuNPs) were electro-reduced around the surface of each AgNWs to solve the rapid oxidization problem of the AgNWs at very low potential (<70 mV) during the electrochemical detection. Oxidation peak current of the free-standing AgNWs/AuNPs electrode only decreased by 5% after 500 scanning cycles, while the free-standing AgNWs electrode without AuNPs decreased by 90.7% after 8 CV scanning cycles. The oxidation peak current of free-standing AgNWs/AuNPs electrode was 500 times of bare electrode. This biosensor showed a wide linear range from 0.001 ng ml-1 to 100 ng ml-1 and a low detection limit of 0.322 pg ml-1 for IL-6. In the end, IL-6 secreted by Caco-2 cell was detected by the fabricated biosensor which integrated into the gut-on-a-chip. IL-6 secretion achieved 11.3 pg ml-1 during 10-days culturing.
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Affiliation(s)
- Huimin Li
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China; Shandong Institute of Mechanical Design and Research, Jinan, 250353, China
| | - Xinyu Li
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Qi Meng
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China; Shandong Institute of Mechanical Design and Research, Jinan, 250353, China
| | - Junlei Han
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China; Shandong Institute of Mechanical Design and Research, Jinan, 250353, China
| | - Weilong Zhao
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China; Shandong Institute of Mechanical Design and Research, Jinan, 250353, China
| | - Jun Chen
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China; Shandong Institute of Mechanical Design and Research, Jinan, 250353, China
| | - Weiguang Su
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China; Shandong Institute of Mechanical Design and Research, Jinan, 250353, China
| | - Ming Song
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China; Shandong Institute of Mechanical Design and Research, Jinan, 250353, China
| | - Chaoyang Shi
- School of Mechanical Engineering, Key Laboratory of Mechanism Theory and Equipment Design of Ministry of Education, Tianjin University, Tianjin, China
| | - Li Wang
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China; Shandong Institute of Mechanical Design and Research, Jinan, 250353, China.
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Matos P, Jordan P. Alternative Splicing at the Crossroad of Inflammatory Bowel Diseases and Colitis-Associated Colon Cancer. Cancers (Basel) 2025; 17:219. [PMID: 39858001 PMCID: PMC11764256 DOI: 10.3390/cancers17020219] [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: 12/04/2024] [Revised: 01/06/2025] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
The risk of developing colorectal cancer (CRC) is increased in ulcerative colitis patients compared to the general population. This increased risk results from the state of chronic inflammation, a well-known tumour-promoting condition. This review explores the pathologic and molecular characteristics of colitis-associated colon cancer (CAC), emphasizing the distinct features from sporadic CRC. We focus on the key signalling pathways involved in the transition to CAC, highlighting the emerging role of alternative splicing in these processes, namely on how inflammation-induced alternative splicing can significantly contribute to the increased CRC risk observed among UC patients. This review calls for more transcriptomic studies to elucidate the molecular mechanisms through which inflammation-induced alternative splicing drives CAC pathogenesis. A better understanding of these splicing events is crucial as they may reveal novel biomarkers for disease progression and have the potential to target changes in alternative splicing as a therapeutic strategy.
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Affiliation(s)
- Paulo Matos
- Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal
- BioISI—Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal
| | - Peter Jordan
- Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal
- BioISI—Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal
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Ding R, Kan Q, Wang T, Xiao R, Song Y, Li D. Ginsenoside Rh2 regulates triple-negative breast cancer proliferation and apoptosis via the IL-6/JAK2/STAT3 pathway. Front Pharmacol 2025; 15:1483896. [PMID: 39845783 PMCID: PMC11751231 DOI: 10.3389/fphar.2024.1483896] [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: 08/22/2024] [Accepted: 12/05/2024] [Indexed: 01/24/2025] Open
Abstract
Introduction Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer to treat. While previous studies have demonstrated that ginsenoside Rh2 induces apoptosis in TNBC cells, the specific molecular targets and underlying mechanisms remain poorly understood. This study aims to uncover the molecular mechanisms through which ginsenoside Rh2 regulates apoptosis and proliferation in TNBC, offering new insights into its therapeutic potential. Methods Network analysis and transcriptome sequencing were utilized to explore the potential mechanisms of ginsenoside Rh2 in treating TNBC. In vivo imaging and immunohistochemistry were employed to examine the effects of ginsenoside Rh2 in a TNBC mouse model. Functional assays were conducted to assess the impact of ginsenoside Rh2 on TNBC cell behavior. Additionally, ELISA, Western blot, and quantitative real-time PCR were used to further investigate the mechanisms of ginsenoside Rh2-induced apoptosis in TNBC cells. Results Through network analysis, 47 common targets were identified, and Gene Ontology (GO) enrichment analysis suggested that ginsenoside Rh2 may exert therapeutic effects in TNBC by influencing apoptosis, cell proliferation, and protein kinase activity. Both transcriptomic analysis and network analysis revealed the JAK/STAT signaling pathway as a key mechanism. Ginsenoside Rh2 inhibited tumor growth in TNBC mice and reduced the expression of IL- 6, IL-6R, STAT3, Bcl-2, and Bcl-xL in tumor tissues. The ability of ginsenoside Rh2 to inhibit TNBC cell proliferation was further confirmed by attenuating the activation of the IL-6/JAK2/STAT3 apoptosis pathway and reducing the expression of protein kinases AMPK-α1 and PKA-Cα. Conclusion Based on network analysis and experimental validation, our findings demonstrate that ginsenoside Rh2 regulates TNBC proliferation and apoptosis through suppression of the IL-6/JAK2/STAT3 pathway, both in vitro and in vivo. This comprehensive approach represents a significant advancement in understanding the therapeutic potential of ginsenoside Rh2 in treating TNBC.
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Affiliation(s)
| | | | | | | | | | - Duolu Li
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Amara A, Trabelsi S, Hai A, Zaidi SHH, Siddiqui F, Alsaeed S. Equivocating and Deliberating on the Probability of COVID-19 Infection Serving as a Risk Factor for Lung Cancer and Common Molecular Pathways Serving as a Link. Pathogens 2024; 13:1070. [PMID: 39770330 PMCID: PMC11728627 DOI: 10.3390/pathogens13121070] [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: 11/06/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 01/30/2025] Open
Abstract
The COVID-19 infection caused by SARS-CoV-2 in late 2019 posed unprecedented global health challenges of massive proportions. The persistent effects of COVID-19 have become a subject of significant concern amongst the medical and scientific community. This article aims to explore the probability of a link between the COVID-19 infection and the risk of lung cancer development. First, this article reports that SARS-CoV-2 induces severe inflammatory response and cellular stress, potentially leading to tumorigenesis through common pathways between SARS-CoV-2 infection and cancer. These pathways include the JAK/STAT3 pathway which is activated after the initiation of cytokine storm following SARS-CoV-2 infection. This pathway is involved in cellular proliferation, differentiation, and immune homeostasis. The JAK/STAT3 pathway is also hyperactivated in lung cancer which serves as a link thereof. It predisposes patients to lung cancer through myriad molecular mechanisms such as DNA damage, genomic instability, and cell cycle dysregulation. Another probable pathway to tumorigenesis is based on the possibility of an oncogenic nature of SARS-CoV-2 through hijacking the p53 protein, leading to cell oxidative stress and interfering with the DNA repair mechanisms. Finally, this article highlights the overexpression of the SLC22A18 gene in lung cancer. This gene can be overexpressed by the ZEB1 transcription factor, which was found to be highly expressed during COVID-19 infection.
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Affiliation(s)
- Abdelbasset Amara
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Northern Border University, Arar 91431, Saudi Arabia; (A.H.); (F.S.); (S.A.)
- Center for Health Research, Northern Border University, Arar 91431, Saudi Arabia;
| | - Saoussen Trabelsi
- Center for Health Research, Northern Border University, Arar 91431, Saudi Arabia;
- Department of Community Health, Faculty of Applied Medical Sciences, Northern Border University, Arar 91431, Saudi Arabia
| | - Abdul Hai
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Northern Border University, Arar 91431, Saudi Arabia; (A.H.); (F.S.); (S.A.)
| | - Syeda Huma H. Zaidi
- Department of Chemistry, Faculty of Science, Northern Border University, Arar 91431, Saudi Arabia;
| | - Farah Siddiqui
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Northern Border University, Arar 91431, Saudi Arabia; (A.H.); (F.S.); (S.A.)
| | - Sami Alsaeed
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Northern Border University, Arar 91431, Saudi Arabia; (A.H.); (F.S.); (S.A.)
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Hjortborg M, Edin S, Böckelman C, Kaprio T, Li X, Gkekas I, Hagström J, Strigård K, Haglund C, Gunnarsson U, Palmqvist R. Systemic inflammatory response in colorectal cancer is associated with tumour mismatch repair and impaired survival. Sci Rep 2024; 14:29738. [PMID: 39613865 DOI: 10.1038/s41598-024-80803-6] [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: 06/25/2024] [Accepted: 11/21/2024] [Indexed: 12/01/2024] Open
Abstract
The systemic inflammatory response (SIR), defined as elevated levels of circulating C-reactive protein (CRP), is an important predictor of impaired survival in colorectal cancer. The aim of this study was to explore the prognostic role of SIR and its association with tumour mismatch repair status and the immune response. Immune activity profiles of mononuclear cells isolated from CRC tissues and blood in the U-CAN exploration cohort (n = 69), were analysed by flow cytometry. In the U-CAN validation cohort (n = 257), T-helper cells (T-bet+), cytotoxic T cells (CD8+), regulatory T cells (FoxP3+), B cells (CD20+), and macrophages (CD68+) were analysed by multispectral imaging. Microsatellite instability was determined using five mononucleotide-repeat microsatellite markers. Patients with high CRP levels (> 10 mg/l) were significantly more often diagnosed with high-grade tumours and tumours exhibiting microsatellite instability. However, some patients with high CRP levels were found to have microsatellite-stable tumours. Furthermore, high CRP levels were associated with specific tumour immune traits including an augmented macrophage response and were significantly linked to poorer cancer-specific survival, particularly in patients with microsatellite-stable tumours. In conclusion, our findings suggest an interplay between SIR and mismatch repair status in CRC prognosis which needs to be further explored.
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Affiliation(s)
- Mats Hjortborg
- Department of Diagnostics and Intervention, Umeå University, Umeå, Sweden
| | - Sofia Edin
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Camilla Böckelman
- Department of Gastrointestinal Surgery, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Tuomas Kaprio
- Department of Gastrointestinal Surgery, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Xingru Li
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Ioannis Gkekas
- Department of Diagnostics and Intervention, Umeå University, Umeå, Sweden
| | - Jaana Hagström
- Department of Pathology, Department of Oral Pathology and Radiology, University of Helsinki, University of Turku, Helsinki, Finland
| | - Karin Strigård
- Department of Diagnostics and Intervention, Umeå University, Umeå, Sweden
| | - Caj Haglund
- Department of Gastrointestinal Surgery, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Ulf Gunnarsson
- Department of Diagnostics and Intervention, Umeå University, Umeå, Sweden
| | - Richard Palmqvist
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
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Shakeri A, Najm L, Khan S, Tian L, Ladouceur L, Sidhu H, Al-Jabouri N, Hosseinidoust Z, Didar TF. Noncontact 3D Bioprinting of Proteinaceous Microarrays for Highly Sensitive Immunofluorescence Detection within Clinical Samples. ACS NANO 2024; 18:31506-31523. [PMID: 39468857 DOI: 10.1021/acsnano.4c12460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/30/2024]
Abstract
Immunofluorescence assays are extensively used for the detection of disease-associated biomarkers within patient samples for direct diagnosis. Unfortunately, these 2D microarrays suffer from low repeatability and fail to attain the low limits of detection (LODs) required to accurately discern disease progression for clinical monitoring. While three-dimensional microarrays with increased biorecognition molecule density stand to circumvent these limitations, their viscous component materials are not compatible with current microarray fabrication protocols. Herein, we introduce a platform for 3D microarray bioprinting, wherein a two-step printing approach enables the high-throughput fabrication of immunosorbent hydrogels. The hydrogels are composed entirely of cross-linked proteins decorated with clinically relevant capture antibodies. Compared to two-dimensional microarrays, these proteinaceous microarrays offer 3-fold increases in signal intensity. When tested with clinically relevant biomarkers, ultrasensitive single-plex and multiplex detection of interleukin-6 (LOD 0.3 pg/mL) and tumor necrosis factor receptor 1 (LOD 1 pg/mL) is observed. When challenged with clinical samples, these hydrogel microarrays consistently discern elevated levels of interleukin-6 in blood plasma derived from patients with systemic blood infections. Given their easy-to-implement, high-throughput fabrication, and ultrasensitive detection, these three-dimensional microarrays will enable better clinical monitoring of disease progression, yielding improved patient outcomes.
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Affiliation(s)
- Amid Shakeri
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada M5S 3G9
| | - Lubna Najm
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
| | - Shadman Khan
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
| | - Lei Tian
- Department of Chemical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
| | - Liane Ladouceur
- Department of Mechanical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
| | - Hareet Sidhu
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1
| | - Nadine Al-Jabouri
- Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1
| | - Zeinab Hosseinidoust
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
- Department of Chemical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
- Institute for Infectious Disease Research (IIDR), 1280 Main St W, McMaster University, Hamilton, Ontario, Canada L8S 4L8
- Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1
| | - Tohid F Didar
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
- Department of Mechanical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4L8
- Institute for Infectious Disease Research (IIDR), 1280 Main St W, McMaster University, Hamilton, Ontario, Canada L8S 4L8
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Ishii K, Naito K, Tanaka D, Koto Y, Kurata K, Shimizu H. Molecular Mechanisms of Skatole-Induced Inflammatory Responses in Intestinal Epithelial Caco-2 Cells: Implications for Colorectal Cancer and Inflammatory Bowel Disease. Cells 2024; 13:1730. [PMID: 39451248 PMCID: PMC11505633 DOI: 10.3390/cells13201730] [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: 08/17/2024] [Revised: 10/06/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), in intestinal epithelial cells significantly contribute to inflammatory bowel disease (IBD) and colorectal cancer (CRC). Given our previous findings that TNF-α is upregulated in intestinal epithelial Caco-2 cells induced by skatole, a tryptophan-derived gut microbiota metabolite, the present study aimed to explore the relationship between skatole and IL-6, alongside TNF-α. Skatole elevated the promoter activity of IL-6 as well as TNF-α, and increased IL-6 mRNA expression and protein secretion. In addition to activating NF-κB, the NF-κB inhibitor BAY 11-7082 reduced skatole-induced cell survival and the mRNA expression of IL-6 and TNF-α. NF-κB activation was attenuated by the extracellular signal-regulated kinase (ERK) pathway inhibitor U0126 and the p38 inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP600125. U126 and SB203580 also decreased the skatole-induced increase in IL-6 expression. When skatole-induced AhR activation was inhibited by CH223191, in addition to promoting NF-κB activation, IL-6 expression was enhanced in a manner similar to that previously reported for TNF-α. Taken together, these results suggest that skatole-elicited NF-κB activation induces IL-6 and TNF-α expression, although AhR activation partially suppresses this process. The ability of skatole to increase the expression of IL-6 and TNF-α may significantly affect the development and progression of these diseases. Moreover, the balance between NF-κB and AhR activation appears to govern the skatole-induced increases in IL-6 and TNF-α expression. Therefore, the present findings provide new insights into the mechanisms linking tryptophan-derived gut microbiota metabolites with colorectal disease.
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Affiliation(s)
- Katsunori Ishii
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Kazuma Naito
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Dai Tanaka
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Yoshihito Koto
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Koichi Kurata
- Graduate School of Life and Environmental Science, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Hidehisa Shimizu
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Graduate School of Life and Environmental Science, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Tottori, Japan
- Estuary Research Center, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Interdisciplinary Center for Science Research, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
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Pîrvu BF, Clenciu D, Beldie LA, Dica CC, Burticală MA, Ţenea-Cojan TŞ, Mitrea A, Amzolini AM, Efrem IC, Mogoş GFR, Vladu IM. The burden of cancer in metabolic dysfunction-associated steatotic liver disease. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2024; 65:627-635. [PMID: 39957024 PMCID: PMC11924906 DOI: 10.47162/rjme.65.4.09] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 01/08/2025] [Indexed: 02/18/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and has become a major public health problem. MASLD frequently progresses to cirrhosis and hepatocellular carcinoma, but recent studies also show a frequent association with extrahepatic cancers. One of the mechanisms involved in both locations is insulin resistance and hyperinsulinemia. The aim of this narrative review was to present the main etiopathogenic mechanisms involved in cancer development in patients with MASLD.
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Affiliation(s)
- Bianca Florentina Pîrvu
- Department of Diabetes, Nutrition and Metabolic Diseases, Emergency County Clinical Hospital, Craiova, Romania
| | - Diana Clenciu
- Department of Diabetes, Nutrition and Metabolic Diseases, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania
| | - Luiza Andreea Beldie
- Department of Diabetes, Nutrition and Metabolic Diseases, Emergency County Clinical Hospital, Craiova, Romania
| | - Cristina Camelia Dica
- Department of Diabetes, Nutrition and Metabolic Diseases, Emergency County Clinical Hospital, Craiova, Romania
| | | | | | - Adina Mitrea
- Department of Diabetes, Nutrition and Metabolic Diseases, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania
| | - Anca Maria Amzolini
- Department of Medical Semiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania
| | - Ion Cristian Efrem
- Department of Medical Semiology, Faculty of Dentistry, University of Medicine and Pharmacy of Craiova, Romania
| | | | - Ionela Mihaela Vladu
- Department of Diabetes, Nutrition and Metabolic Diseases, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania
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11
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Abdelazeem NM, Gouhar SA, Fahmy CA, Elshahid ZA, El-Hussieny M. Evaluation of newly synthesized 2-(thiophen-2-yl)-1H-indole derivatives as anticancer agents against HCT-116 cell proliferation via cell cycle arrest and down regulation of miR-25. Sci Rep 2024; 14:20045. [PMID: 39209915 PMCID: PMC11362284 DOI: 10.1038/s41598-024-68815-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
In the present study, we prepared new sixteen different derivatives. The first series were prepared (methylene)bis(2-(thiophen-2-yl)-1H-indole) derivatives which have (indole and thiophene rings) by excellent yield from the reaction (2 mmol) 2-(thiophen-2-yl)-1H-indole and (1 mmol) from aldehyde. The second series were synthesized (2-(thiophen-2-yl)-1H-indol-3-yl) methyl) aniline derivatives at a relatively low yield from multicomponent reaction of three components 2-(thiophen-2-yl)-1H-indole, N-methylaniline and desired aldehydes. The anticancer effect of the newly synthesized derivatives was determined against different cancers, colon, lung, breast and skin. The counter screening was done against normal Epithelial cells (RPE-1). The effect on cell cycle and mechanisms underlying of the antitumor effect were also studied. All new compounds were initially tested at a single dose of 100 μg/ml against this panel of 5 human tumor cell lines indicated that the compounds under investigation exhibit selective cytotoxicity against HCT-116 cell line and compounds (4g, 4a, 4c) showed potent anticancer activity against HCT-116 cell line with the inhibitory concentration IC50 values were, 7.1±0.07, 10.5± 0.07 and 11.9± 0.05 μΜ/ml respectively. Also, the active derivatives caused cell cycle arrest at the S and G2/M phase with significant(p < 0.0001) increase in the expression levels of tumor suppressors miR-30C, and miR-107 and a tremendous decrease in oncogenic miR-25, IL-6 and C-Myc levels. It is to conclude that the anticancer activity could be through direct interaction with tumor cell DNA like S-phase-dependent chemotherapy drugs. Which can interact with DNA or block DNA synthesis such as doxorubicin, cisplatin, or 5-fluorouracil and which were highly effective in killing the cancer cells. This data ensures the efficiency of the 3 analogues on inducing cell cycle arrest and preventing cancer cell growth. The altered expressions explained the molecular mechanisms through which the newly synthesized analogues exert their anticancer action.
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Affiliation(s)
- Nagwa M Abdelazeem
- Organometallic and Organometalloid Chemistry Department, National Research Centre, Dokki, 12622, Cairo, Egypt
| | - Shaimaa A Gouhar
- Medical Biochemistry Department, Medicine and Clinical Studies Research Institute, National Research Centre, Dokki, 12622, Cairo, Egypt
| | - Cinderella A Fahmy
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Dokki, 12622, Cairo, Egypt
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Dokki, Cairo, Egypt
| | - Zeinab A Elshahid
- Chemistry of Natural and Microbial Products, National Research Centre, Dokki, 12622, Cairo, Egypt.
| | - Marwa El-Hussieny
- Organometallic and Organometalloid Chemistry Department, National Research Centre, Dokki, 12622, Cairo, Egypt.
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12
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Omran TA, Tunsjø HS, Jahanlu D, Brackmann SA, Bemanian V, Sæther PC. Decoding immune-related gene-signatures in colorectal neoplasia. Front Immunol 2024; 15:1407995. [PMID: 38979413 PMCID: PMC11229009 DOI: 10.3389/fimmu.2024.1407995] [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: 03/27/2024] [Accepted: 06/10/2024] [Indexed: 07/10/2024] Open
Abstract
Background Colorectal cancer (CRC) is a significant health issue, with notable incidence rates in Norway. The immune response plays a dual role in CRC, offering both protective effects and promoting tumor growth. This research aims to provide a detailed screening of immune-related genes and identify specific genes in CRC and adenomatous polyps within the Norwegian population, potentially serving as detection biomarkers. Methods The study involved 69 patients (228 biopsies) undergoing colonoscopy, divided into CRC, adenomatous polyps, and control groups. We examined the expression of 579 immune genes through nCounter analysis emphasizing differential expression in tumor versus adjacent non-tumorous tissue and performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) across patient categories. Results Key findings include the elevated expression of CXCL1, CXCL2, IL1B, IL6, CXCL8 (IL8), PTGS2, and SPP1 in CRC tissues. Additionally, CXCL1, CXCL2, IL6, CXCL8, and PTGS2 showed significant expression changes in adenomatous polyps, suggesting their early involvement in carcinogenesis. Conclusions This study uncovers a distinctive immunological signature in colorectal neoplasia among Norwegians, highlighting CXCL1, CXCL2, IL1B, IL6, CXCL8, PTGS2, and SPP1 as potential CRC biomarkers. These findings warrant further research to confirm their role and explore their utility in non-invasive screening strategies.
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Affiliation(s)
- Thura Akrem Omran
- Department of Life Sciences and Health, Oslo Metropolitan University, Oslo, Norway
| | - Hege Smith Tunsjø
- Department of Life Sciences and Health, Oslo Metropolitan University, Oslo, Norway
| | - David Jahanlu
- Department of Life Sciences and Health, Oslo Metropolitan University, Oslo, Norway
| | - Stephan Andreas Brackmann
- Division of Medicine, Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
- Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Vahid Bemanian
- Department of Pathology, Akershus University Hospital, Lørenskog, Norway
| | - Per Christian Sæther
- Department of Immunology and Transfusion Medicine, Akershus University Hospital, Lørenskog, Norway
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13
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Mager LF, Krause T, McCoy KD. Interaction of microbiota, mucosal malignancies, and immunotherapy-Mechanistic insights. Mucosal Immunol 2024; 17:402-415. [PMID: 38521413 DOI: 10.1016/j.mucimm.2024.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 03/09/2024] [Accepted: 03/17/2024] [Indexed: 03/25/2024]
Abstract
The microbiome has emerged as a crucial modulator of host-immune interactions and clearly impacts tumor development and therapy efficacy. The microbiome is a double-edged sword in cancer development and therapy as both pro-tumorigenic and anti-tumorigenic bacterial taxa have been identified. The staggering number of association-based studies in various tumor types has led to an enormous amount of data that makes it difficult to identify bacteria that promote tumor development or modulate therapy efficacy from bystander bacteria. Here we aim to comprehensively summarize the current knowledge of microbiome-host immunity interactions and cancer therapy in various mucosal tissues to find commonalities and thus identify potential functionally relevant bacterial taxa. Moreover, we also review recent studies identifying specific bacteria and mechanisms through which the microbiome modulates cancer development and therapy efficacy.
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Affiliation(s)
- Lukas F Mager
- Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada; Department of Internal Medicine I, Faculty of Medicine, University of Tübingen, Germany; M3 Research Center for Malignom, Metabolome and Microbiome, Faculty of Medicine University Tübingen, Germany
| | - Tim Krause
- Department of Internal Medicine I, Faculty of Medicine, University of Tübingen, Germany; M3 Research Center for Malignom, Metabolome and Microbiome, Faculty of Medicine University Tübingen, Germany
| | - Kathy D McCoy
- Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Canada.
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14
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Gulubova M, Chonov D, Aleksandrova E, Ivanova K, Ignatova MM, Vlaykova T. Interleukin-6-Positive Immune Cells as a Possible New Immunologic Marker Associated With the Colorectal Cancer Prognosis. Appl Immunohistochem Mol Morphol 2024; 32:233-243. [PMID: 38712586 PMCID: PMC11073565 DOI: 10.1097/pai.0000000000001198] [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: 06/02/2023] [Accepted: 03/15/2024] [Indexed: 05/08/2024]
Abstract
Chronic inflammation creates tumor microenvironment (TME) that facilitates colorectal cancer (CRC) cell proliferation, migration, metastasis, and tumor progression. Interleukin-6 (IL-6) is a proinflammatory cytokine with a pleiotropic effect on CRC development. We aimed to evaluate IL-6 expression in tumor cells and in immune cells in TME, to assess the serum level and IL6 -174 G/C genotype distribution and to correlate the results with selected morphologic and clinical parameters that may add useful information in understanding the mechanisms of human CRC progression. A total of 153 patients with CRC were recruited in the current study. We assessed the IL-6 serum concentration through the ELISA method, the expression of IL-6 in tumor and in immune cells by immunohistochemical and double immunofluorescence staining, the MSI status by immunоhistochemistry for 4 mismatch repair (MMR) proteins, and the genotype distributions for IL6 -174G/C (rs1800795) single-nucleotide polymorphism through PCR-RFLP method. Our results showed that serum IL-6 level were increased in CRC patients as compared with healthy controls (P<0.0001), and in patients with cancers with advanced histologic type (type IV). However, the higher concentration (above the median of 55.71 pg/mL) was with borderline association with longer survival of the patients after surgical therapy (P=0.055, Log rank test). We also found that IL-6+ immune cells prevailed in the invasive front (IF) of tumors compared with the tumor stroma (TS) (P<0.0001). More IL-6+ cells were recruited in the tumors with less advanced histologic type (I+II), with stronger inflammatory infiltrate in the IF, in early pTNM stages (I+II), without lymph node and distant metastases and the higher levels of IL-6+ cells, especially in the IF, were associated with longer survival (P=0.012). The results of our study suggest that although the serum levels of IL-6 are higher in CRC, the increased IL-6+ cells in tumor microenvironment, both in the invasive front and in tumor stroma, as well as the higher serum levels are associated with good prognostic variables and longer survival of the patients mainly in the early stages of CRC.
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Affiliation(s)
- Maya Gulubova
- Department of General and Clinical Pathology, Forensic Medicine and Deontology
- Department of Surgery
| | - Dimitur Chonov
- Department of Medical Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
| | - Elina Aleksandrova
- Department of Anatomy, Histology and Embriology, Pathology, Latin language, Forensic Medicine and Deontology, Faculty of Medicine, University Prof. Dr. Assen Zlatarov, Burgas
| | - Koni Ivanova
- Department of General and Clinical Pathology, Forensic Medicine and Deontology
| | | | - Tatyana Vlaykova
- Department of Anatomy, Histology and Embriology, Pathology, Latin language, Forensic Medicine and Deontology, Faculty of Medicine, University Prof. Dr. Assen Zlatarov, Burgas
- Department of Medical Biochemistry, Faculty of Pharmacy, Medical University of Plovdiv, Plovdiv, Bulgaria
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15
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Lin T, Zhang S, Tang Y, Xiao M, Li M, Gong H, Xie H, Wang Y. ART1 knockdown decreases the IL-6-induced proliferation of colorectal cancer cells. BMC Cancer 2024; 24:354. [PMID: 38504172 PMCID: PMC10953198 DOI: 10.1186/s12885-024-12120-0] [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: 11/23/2023] [Accepted: 03/13/2024] [Indexed: 03/21/2024] Open
Abstract
Colorectal cancer (CRC) is a worldwide health concern. Chronic inflammation is a risk factor for CRC, and interleukin-6 (IL-6) plays a pivotal role in this process. Arginine-specific mono-ADP-ribosyltransferase-1 (ART1) positively regulates inflammatory cytokines. ART1 knockdown reduces the level of glycoprotein 130 (gp130), a key transducer in the IL-6 signalling pathway. However, the relationship between ART1 and IL-6 and the resulting effects on IL-6-induced proliferation in CRC cells remain unclear. The aims of this study were to investigate the effects of ART1 knockdown on IL-6-induced cell proliferation in vitro and use an in vivo murine model to observe the growth of transplanted tumours. The results showed that compared with the control, ART1-sh cancer cells induced by IL-6 exhibited reduced viability, a lower rate of colony formation, less DNA synthesis, decreased protein levels of gp130, c-Myc, cyclin D1, Bcl-xL, and a reduced p-STAT3/STAT3 ratio (P < 0.05). Moreover, mice transplanted with ART1-sh CT26 cells that had high levels of IL-6 displayed tumours with smaller volumes (P < 0.05). ART1 and gp130 were colocalized in CT26, LoVo and HCT116 cells, and their expression was positively correlated in human CRC tissues. Overall, ART1 may serve as a promising regulatory factor for IL-6 signalling and a potential therapeutic target for human CRC.
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Affiliation(s)
- Ting Lin
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Shuxian Zhang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Yi Tang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Ming Xiao
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Ming Li
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Hanjuan Gong
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Hailun Xie
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Yalan Wang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China.
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, P.R. China.
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P.R. China.
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16
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Chung YC, Chen SJ, Huang CC, Liu WC, Lai MT, Kao TY, Yang WS, Yang CH, Hsu CP, Chang JF. Tocilizumab Exerts Anti-Tumor Effects on Colorectal Carcinoma Cell Xenografts Corresponding to Expression Levels of Interleukin-6 Receptor. Pharmaceuticals (Basel) 2024; 17:127. [PMID: 38256960 PMCID: PMC10820566 DOI: 10.3390/ph17010127] [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: 11/24/2023] [Revised: 12/29/2023] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
The use of tocilizumab against the interleukin-6 receptor (IL-6R) has been demonstrated as inhibiting the progression of diverse cancers in vitro and in vivo. Nonetheless, evidence regarding the anti-tumor effects of tocilizumab on human colorectal carcinoma (CRC) corresponding to IL-6R expression levels remains scarce. To investigate the influence of IL-6R expression, SW480 and HT-29 cells inoculated subcutaneously into NU/NU mice were used as human CRC xenograft models with anti-IL-6R antibody (tocilizumab) therapy. The IL-6R expression levels, histology of CRC growth/invasiveness, and tumor growth-related signaling pathway were estimated by H&E and immunohistochemical staining. SW480 tumor cells with higher IL-6R expression levels showed better responsiveness in tocilizumab therapy than in the treated HT-29 group. Likewise, therapeutic effects of tocilizumab on the proliferative ability with mitotic index and Ki-67 expressions, invasiveness with MMP-9 proteinase expressions, and ERK 1/2 and STAT3 signaling transduction in the SW480 treatment group were superior to the HT-29 treatment group. In light of our results, IL-6R is the key indicator for the efficacy of tocilizumab treatment in CRC xenografts. From the perspective of precision medicine, tumor response to anti-IL-6R antibody therapy could be predicted on the basis of IL-6R expression levels. In this manner, tocilizumab may serve as a targeted and promising anti-CRC therapy.
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Affiliation(s)
- Yuan-Chiang Chung
- Department of Surgery, Kuang Tien General Hospital, Taichung 433, Taiwan;
- Department of Surgery, Chung-Kang Branch, Cheng-Ching General Hospital, Taichung 407, Taiwan
| | - Szu-Jung Chen
- Department of Radiation Oncology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 330, Taiwan;
| | - Chiu-Chen Huang
- Department of Post-Baccalaureate Veterinary Medicine, Asia University, Taichung 413, Taiwan;
| | - Wei-Chun Liu
- Department of Pathology, Hsin-Chu Branch, National Taiwan University Hospital, Hsinchu 300, Taiwan;
| | - Ming-Tsung Lai
- Department of Pathology, Taichung Hospital, Ministry of Health and Welfare, Taichung 403, Taiwan;
| | - Ting-Yu Kao
- Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan;
| | - Wei-Shun Yang
- Department of Internal Medicine, Hsin-Chu Branch, National Taiwan University Hospital, Hsinchu 300, Taiwan;
| | - Chien-Hui Yang
- Department of Business Administration, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan;
| | - Chih-Ping Hsu
- Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan;
- Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
| | - Jia-Feng Chang
- Division of Nephrology, Department of Internal Medicine, Taoyuan Branch, Taipei Veterans General Hospital, Taoyuan 330, Taiwan
- Department of Nursing, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
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17
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Zheng Y, Zhong G, He C, Li M. Targeted splicing therapy: new strategies for colorectal cancer. Front Oncol 2023; 13:1222932. [PMID: 37664052 PMCID: PMC10470845 DOI: 10.3389/fonc.2023.1222932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 08/07/2023] [Indexed: 09/05/2023] Open
Abstract
RNA splicing is the process of forming mature mRNA, which is an essential phase necessary for gene expression and controls many aspects of cell proliferation, survival, and differentiation. Abnormal gene-splicing events are closely related to the development of tumors, and the generation of oncogenic isoform in splicing can promote tumor progression. As a main process of tumor-specific splicing variants, alternative splicing (AS) can promote tumor progression by increasing the production of oncogenic splicing isoforms and/or reducing the production of normal splicing isoforms. This is the focus of current research on the regulation of aberrant tumor splicing. So far, AS has been found to be associated with various aspects of tumor biology, including cell proliferation and invasion, resistance to apoptosis, and sensitivity to different chemotherapeutic drugs. This article will review the abnormal splicing events in colorectal cancer (CRC), especially the tumor-associated splicing variants arising from AS, aiming to offer an insight into CRC-targeted splicing therapy.
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Affiliation(s)
| | | | - Chengcheng He
- Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
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18
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Yamamoto T, Tsunedomi R, Nakajima M, Suzuki N, Yoshida S, Tomochika S, Xu M, Nakagami Y, Matsui H, Tokumitsu Y, Shindo Y, Watanabe Y, Iida M, Takeda S, Hazama S, Tanabe T, Ioka T, Hoshii Y, Kiyota A, Takizawa H, Kawakami Y, Ueno T, Nagano H. IL-6 Levels Correlate with Prognosis and Immunosuppressive Stromal Cells in Patients with Colorectal Cancer. Ann Surg Oncol 2023; 30:5267-5277. [PMID: 37222942 DOI: 10.1245/s10434-023-13527-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 04/05/2023] [Indexed: 05/22/2023]
Abstract
BACKGROUND The prognosis for patients with colorectal cancer (CRC) is determined by tumor characteristics as well as the host immune response. This study investigated the relationship between an immunosuppressive state and patient prognosis by evaluating the systemic and tumor microenvironment (TME) interleukin (IL)-6 levels. METHODS Preoperative serum IL-6 levels were measured using an electrochemiluminescence assay. Expression of IL-6 in tumor and stromal cells was evaluated immunohistochemically in 209 patients with resected CRC. Single-cell analysis of tumor-infiltrating immune cells was performed using mass cytometry in 10 additional cases. RESULTS Elevated serum IL-6 levels were associated with elevated stromal IL-6 levels and a poor prognosis for patients with CRC. High IL-6 expression in stromal cells was associated with low-density subsets of CD3+ and CD4+ T cells as well as FOXP3+ cells. Mass cytometry analysis showed that IL-6+ cells among tumor-infiltrating immune cells were composed primarily of myeloid cells and rarely of lymphoid cells. In the high-IL-6-expression group, the percentages of myeloid-derived suppressor cells (MDSCs) and CD4+FOXP3highCD45RA- effector regulatory T cells (eTreg) were significantly higher than in the low-IL-6-expression group. Furthermore, the proportion of IL-10+ cells in MDSCs and that of IL-10+ or CTLA-4+ cells in eTregs correlated with IL-6 levels. CONCLUSION Elevated serum IL-6 levels were associated with stromal IL-6 levels in CRC. High IL-6 expression in tumor-infiltrating immune cells also was associated with accumulation of immunosuppressive cells in the TME.
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Affiliation(s)
- Tsunenori Yamamoto
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Ryouichi Tsunedomi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Masao Nakajima
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Nobuaki Suzuki
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Shin Yoshida
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Shinobu Tomochika
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Ming Xu
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Yuki Nakagami
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
- Department of Public Health and Preventive Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Hiroto Matsui
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Yukio Tokumitsu
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Yoshitaro Shindo
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Yusaku Watanabe
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Michihisa Iida
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Shigeru Takeda
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Shoichi Hazama
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Tsuyoshi Tanabe
- Department of Public Health and Preventive Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Tatsuya Ioka
- Oncology Center, Yamaguchi University Hospital, Ube, Yamaguchi, Japan
| | - Yoshinobu Hoshii
- Department of Diagnostic Pathology, Yamaguchi University Hospital, Ube, Yamaguchi, Japan
| | - Akifumi Kiyota
- Center for Medical Sciences, Kumamoto University International Research, Kumamoto, Kumamoto, Japan
| | - Hitoshi Takizawa
- Center for Medical Sciences, Kumamoto University International Research, Kumamoto, Kumamoto, Japan
| | - Yutaka Kawakami
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Tomio Ueno
- Department of Digestive Surgery, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
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Fan X, Meng M, Li B, Chen H, Tan J, Xu K, Xiao S, Kwan HY, Liu Z, Su T. Brevilin A is a potent anti-metastatic CRC agent that targets the VEGF-IL6-STAT3 axis in the HSCs-CRC interplay. J Transl Med 2023; 21:260. [PMID: 37062842 PMCID: PMC10105967 DOI: 10.1186/s12967-023-04087-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 03/25/2023] [Indexed: 04/18/2023] Open
Abstract
BACKGROUND More than half of the colorectal cancer (CRC) patients will develop liver metastasis that underlies the cancer mortality. In the hepatic tumor microenvironment, the interplay between CRC cells and hepatic stellate cells (HSCs), and the activation of HSCs to become carcinoma-associated fibroblasts (CAFs) will further promote the cancer development. Nevertheless, the critical signaling molecule that involved in these processes remains unknown, which hinders the development of effective therapeutic agents for the treatment of metastatic CRC (mCRC). METHODS Conditioned medium system and co-cultured system were used to examine the interplay between CRC cells and HSCs. Luminex liquid suspension chip detection and enzyme-linked immunosorbent assay were used to screen for the mediators in the conditioned medium that facilitated the CRC-HSCs interplay and HSCs-to-CAFs differentiation. Cell and animal models were used to examine whether brevilin A inhibited CRC liver metastasis via the VEGF-IL6-STAT3 axis. RESULTS In the CRC-HSCs interplay, CRC promoted HSCs-to-CAFs differentiation by releasing vascular endothelial growth factor (VEGF); and HSCs released interleukin 6 (IL6) that activated signal transducer and activator of transcription 3 (STAT3) in the CRC and hence increased the cancer metastatic potential. The functions of the VEGF-IL6-STAT3 axis in the HSCs-CRC interplay were further validated by VEGF recombinant protein and IL6 neutralizing antibody. More importantly, brevilin A, an active compound isolated from Centipeda minima (L.) A. Br. et Aschers, targeted the VEGF-IL6-STAT3 axis in the CRC-HSCs interplay, hence significantly inhibited colorectal liver metastasis and cancer growth both in vitro and in vivo. CONCLUSIONS We are the first to demonstrate brevilin A possesses potent anti-mCRC effect by targeting the VEGF-IL6-STAT3 axis in the CRC-HSCs interplay. Our findings not only support the development of brevilin A as a novel therapeutic agent for mCRC treatment, but also pave the path for the development of other VEGF-IL6-STAT3 targeting therapeutic strategies.
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Affiliation(s)
- Xueying Fan
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Mingjing Meng
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Baoting Li
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Hui Chen
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Jincheng Tan
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Keyang Xu
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Shilin Xiao
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Hiu-Yee Kwan
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Zhongqiu Liu
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China.
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China.
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
| | - Tao Su
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China.
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China.
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
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20
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Wei W, Wang J, Huang P, Gou S, Yu D, Zong L. Tumor necrosis factor-α induces proliferation and reduces apoptosis of colorectal cancer cells through STAT3 activation. Immunogenetics 2023; 75:161-169. [PMID: 36933092 DOI: 10.1007/s00251-023-01302-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 02/14/2023] [Indexed: 03/19/2023]
Abstract
Tumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory factor that plays an important role in establishing a complicated connection between inflammation and cancer. TNF-α promotes tumor proliferation, migration, invasion, and angiogenesis according to numerous studies. Studies have shown the significant role of STAT3, a downstream transcription factor of another important inflammatory cytokine, IL-6 in the development and progression of different tumors especially colorectal cancer. In the present study, we investigated whether TNF-α has a role in proliferation and apoptosis of colorectal cancer cells through STAT3 activation. HCT116 cell line as human colorectal cancer cells was used in this study. Major assays were MTT assay, reverse transcription-PCR (RT-PCR), flow cytometric analysis, and ELISA. Results showed that TNF-α significantly increased the phosphorylation of STAT3 and expression of all the STAT3 target genes related to cell proliferation, survival, and metastasis compared with control. Moreover, our data showed that the STAT3 phosphorylation and expression of its target genes significantly were reduced in the presence of TNF-α + STA-21 compared with TNF-α-treated group demonstrating that the increase in genes expression partially was due to the TNF-α-induced STAT3 activation. On the other hand, STAT3 phosphorylation and mRNA levels of its target genes were partially decreased in the presence of TNF-α + IL-6R supporting the indirect pathway of STAT3 activation by TNF-α through inducing IL-6 production in cancer cells. Given the growing evidence for STAT3 as a key mediator of inflammation-induced colon cancer, our findings support further investigation of STAT3 inhibitors as potential cancer therapies.
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Affiliation(s)
- Wei Wei
- Department of Pathology, Xi'an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, People's Republic of China
| | - Juanhong Wang
- Department of Pathology, Xi'an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, People's Republic of China
| | - Pu Huang
- Department of Pathology, Xi'an Hospital of Traditional Chinese Medicine, Xi'an, Shaanxi, 710021, People's Republic of China
| | - Siqi Gou
- Department of Pathology, Xi'an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, People's Republic of China
| | - Daihua Yu
- Department of Critical Care Medicine, Xi'an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, People's Republic of China
| | - Lei Zong
- Department of Critical Care Medicine, Xi'an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, People's Republic of China.
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21
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Qu Y, Yang H, Li S, Li L, Li Y, Wang D. The involvement of Th1 cell differentiation in the anti-tumor effect of purified polysaccharide from Sanghuangporus vaninii in colorectal cancer via multi-omics analysis. Int J Biol Macromol 2023; 237:123927. [PMID: 36889619 DOI: 10.1016/j.ijbiomac.2023.123927] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 02/26/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023]
Abstract
Sanghuangporus vaninii is a medicinal mushroom, which has been used as a treatment for various diseases; however, the therapeutic potential and mechanism of action of S. vaninii in colorectal cancer (CRC) remain unknown. Herein, human colon adenocarcinoma cells were used to analyze the anti-CRC effects of the purified polysaccharide of S. vaninii (SVP-A-1) in vitro. In SVP-A-1-treated B6/JGpt-Apcem1Cin (Min)/Gpt male (ApcMin/+) mice, 16S rRNA sequencing was performed on cecal feces, metabolites were examined in serum, and LC-MS/MS protein detection was performed in colorectal tumors. Protein changes were further confirmed by various biochemical detection methods. Water-soluble SVP-A-1 with a molecular weight of 22.5 kDa was first obtained. SVP-A-1 prevented gut microbiota dysbiosis related to metabolic pathways of L-arginine biosynthesis, increased L-citrulline levels in the serum of ApcMin/+ mice, mediated L-arginine synthesis, and improved antigen presentation in dendritic cells and activated CD4+ T cells; the resulting Th1 cells released IFN-γ and TNF-α to act on tumor cells and promoted the sensitivity of tumor cells to cytotoxic T lymphocytes. In summary, SVP-A-1 exerted anti-CRC effects and has excellent potential for CRC treatment.
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Affiliation(s)
- Yidi Qu
- School of Life Sciences, Jilin University, Changchun 130012, China.
| | - Hongxin Yang
- School of Life Sciences, Jilin University, Changchun 130012, China.
| | - Siyu Li
- School of Life Sciences, Jilin University, Changchun 130012, China.
| | - Lanzhou Li
- Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun 130118, China.
| | - Yu Li
- Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun 130118, China.
| | - Di Wang
- School of Life Sciences, Jilin University, Changchun 130012, China; Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun 130118, China.
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22
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Karimi N, Moghaddam SJ. KRAS-Mutant Lung Cancer: Targeting Molecular and Immunologic Pathways, Therapeutic Advantages and Restrictions. Cells 2023; 12:749. [PMID: 36899885 PMCID: PMC10001046 DOI: 10.3390/cells12050749] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 03/02/2023] Open
Abstract
RAS mutations are among the most common oncogenic mutations in human cancers. Among RAS mutations, KRAS has the highest frequency and is present in almost 30% of non-small-cell lung cancer (NSCLC) patients. Lung cancer is the number one cause of mortality among cancers as a consequence of outrageous aggressiveness and late diagnosis. High mortality rates have been the reason behind numerous investigations and clinical trials to discover proper therapeutic agents targeting KRAS. These approaches include the following: direct KRAS targeting; synthetic lethality partner inhibitors; targeting of KRAS membrane association and associated metabolic rewiring; autophagy inhibitors; downstream inhibitors; and immunotherapies and other immune-modalities such as modulating inflammatory signaling transcription factors (e.g., STAT3). The majority of these have unfortunately encountered limited therapeutic outcomes due to multiple restrictive mechanisms including the presence of co-mutations. In this review we plan to summarize the past and most recent therapies under investigation, along with their therapeutic success rate and potential restrictions. This will provide useful information to improve the design of novel agents for treatment of this deadly disease.
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Affiliation(s)
- Nastaran Karimi
- Faculty of Medicine, Marmara University, Istanbul 34899, Turkey
| | - Seyed Javad Moghaddam
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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23
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Arai J, Otoyama Y, Nozawa H, Kato N, Yoshida H. The immunological role of ADAMs in the field of gastroenterological chronic inflammatory diseases and cancers: a review. Oncogene 2023; 42:549-558. [PMID: 36572816 PMCID: PMC9937921 DOI: 10.1038/s41388-022-02583-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 12/27/2022]
Abstract
Metalloproteinases cleave transmembrane proteins that play critical roles in inflammation and cancers. Metalloproteinases include a disintegrin and metalloprotease (ADAM), which we previously examined using a fluorescence assay system, and described their association with resistance to systemic therapy in cancer patients. There are also many reports on the relation between ADAM expression and the prognosis of patients with gastroenterological chronic inflammatory diseases and cancers. Inhibiting their immunomodulating activity in chronic inflammation restores innate immunity and potentially prevents the development of various cancers. Among the numerous critical immune system-related molecules, we focus on major histocompatibility complex class I polypeptide-related sequence A (MICA), MICB, intracellular adhesion molecule (ICAM)-1, TNF-α, IL-6 receptor (IL-6R), and Notch. This review summarizes our current understanding of the role of ADAMs in gastroenterological diseases with regard to the immune system. Several Food and Drug Administration (FDA)-approved inhibitors of ADAMs have been identified, and potential therapies for targeting ADAMs in the treatment of chronic inflammatory diseases and cancers are discussed. Some ongoing clinical trials for cancers targeting ADAMs are also introduced.
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Affiliation(s)
- Jun Arai
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
| | - Yumi Otoyama
- grid.410714.70000 0000 8864 3422Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Hisako Nozawa
- grid.410714.70000 0000 8864 3422Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Naoya Kato
- grid.136304.30000 0004 0370 1101Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hitoshi Yoshida
- grid.410714.70000 0000 8864 3422Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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24
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Gattupalli M, Dey P, Poovizhi S, Patel RB, Mishra D, Banerjee S. The Prospects of RNAs and Common Significant Pathways in Cancer Therapy and Regenerative Medicine. Regen Med 2023. [DOI: 10.1007/978-981-19-6008-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
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25
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Abstract
The gut microbiota (GM) is associated with colorectal cancer (CRC) development. However, studies demonstrating the role of GM in CRC are limited to metagenomic analyses. These studies lack direct evidence proving that the candidate strains are involved in CRC, and isolated probiotics for bacteriotherapy. Therefore, to identify novel GM with anti-CRC activity, we previously isolated gut bacteria from the feces of healthy individuals, screened the isolated GM's anti-CRC activity, and discovered that cell-free supernatants of GM isolates demonstrated antiproliferative activity against CRC cells. Here, our study identified one of them as Eubacterium callanderi and chose it for further study because the genus Eubacterium has been suggested to contribute to various aspects of gut health; however, the functions are unknown. First, we confirmed that E. callanderi cell-free supernatant (EcCFS) exerted antiproliferative activity-by inducing apoptosis and cell cycle arrest-that was dose-dependent and specific to cancer cell lines. Next, we discovered that EcCFS active molecules were heat stable and protease insensitive. High-performance liquid chromatography analysis revealed that EcCFS contained high butyrate concentrations possessing anticancer activity. Additionally, gas chromatography-mass spectrometry analysis of the aqueous phase of ethyl acetate-extracted EcCFS and an antiproliferation assay of the aqueous phase and 4-aminobutanoic acid (GABA) suggested that GABA is a possible anti-CRC agent. Finally, in the CT26 allograft mouse model, E. callanderi oral administration and EcCFS peri-tumoral injection inhibited tumor growth in vivo. Therefore, our study reveals that E. callanderi has an anti-CRC effect and suggests that it may be a potential candidate for developing probiotics to control CRC. IMPORTANCE The gut microbiota has been reported to be involved in colorectal cancer, as suggested by metagenomic analysis. However, metagenomic analysis has limitations, such as bias in the analysis and the absence of bacterial resources for follow-up studies. Therefore, we attempted to discover gut microorganisms that are related to colorectal cancer using the culturomics method. In this study, we discovered that Eubacterium callanderi possesses anti-colorectal cancer activity in vitro and in vivo, suggesting that E. callanderi could be used in bacteriotherapy for colorectal cancer treatment.
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26
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Usenko OY, Khomenko IP, Kovalenko AE, Saliutin RV. Stress and surgical diseases of thyroid gland in environment of the armed conflict (review of literature and own observations). KLINICHESKAIA KHIRURGIIA 2022. [DOI: 10.26779/2522-1396.2022.3-4.73] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Stress and surgical diseases of thyroid gland in environment of the armed conflict (review of literature and own observations)
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27
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Budek M, Nuszkiewicz J, Piórkowska A, Czuczejko J, Szewczyk-Golec K. Inflammation Related to Obesity in the Etiopathogenesis of Gastroenteropancreatic Neuroendocrine Neoplasms. Biomedicines 2022; 10:2660. [PMID: 36289922 PMCID: PMC9599081 DOI: 10.3390/biomedicines10102660] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/17/2022] [Accepted: 10/19/2022] [Indexed: 11/24/2022] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare neoplasms, which, due to their heterogeneous nature, non-specific symptoms, and lack of specific tumor markers pose many diagnostic and clinical challenges. In recent years, the effectiveness of GEP-NEN diagnosis has increased, which is probably associated with the greater availability of diagnostic tests and the cooperation of many experienced specialists in various scientific disciplines. In addition to the possible genetic etiology, the cause of GEP-NET development is not fully understood. Inflammation and obesity are known risks that contribute to the development of many diseases. Chronic inflammation accompanying obesity affects the hormonal balance and cell proliferation and causes the impairment of the immune system function, leading to neoplastic transformation. This review explores the role of inflammation and obesity in GEP-NETs. The exact mechanisms inducing tumor growth are unknown; however, the profile of inflammatory factors released in the GEP-NET tumor microenvironment is responsible for the progression or inhibition of tumor growth. Both the excess of adipose tissue and the impaired function of the immune system affect not only the initiation of cancer but also reduce the comfort and lifetime of patients.
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Affiliation(s)
- Marlena Budek
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 24 Karłowicza St., 85-092 Bydgoszcz, Poland
| | - Jarosław Nuszkiewicz
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 24 Karłowicza St., 85-092 Bydgoszcz, Poland
| | - Anna Piórkowska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 24 Karłowicza St., 85-092 Bydgoszcz, Poland
| | - Jolanta Czuczejko
- Department of Psychiatry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 9 M. Curie-Skłodowskiej St., 85-094 Bydgoszcz, Poland
- Department of Nuclear Medicine, Oncology Centre Prof. Franciszek Łukaszczyk Memorial Hospital, 2 Dr. I. Romanowskiej St., 85-796 Bydgoszcz, Poland
| | - Karolina Szewczyk-Golec
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 24 Karłowicza St., 85-092 Bydgoszcz, Poland
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28
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Li W, Wu Z, Meng W, Zhang C, Cheng M, Chen Y, Zou Y, Li K, Lin S, Xiong W, Wang Y, Lin Y, Ma W, Zhou W. Blockade of IL-6 inhibits tumor immune evasion and improves anti–PD-1 immunotherapy. Cytokine 2022; 158:155976. [DOI: 10.1016/j.cyto.2022.155976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 07/05/2022] [Accepted: 07/21/2022] [Indexed: 12/01/2022]
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29
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Hashimoto S, Hashimoto A, Muromoto R, Kitai Y, Oritani K, Matsuda T. Central Roles of STAT3-Mediated Signals in Onset and Development of Cancers: Tumorigenesis and Immunosurveillance. Cells 2022; 11:cells11162618. [PMID: 36010693 PMCID: PMC9406645 DOI: 10.3390/cells11162618] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/12/2022] [Accepted: 08/20/2022] [Indexed: 02/07/2023] Open
Abstract
Since the time of Rudolf Virchow in the 19th century, it has been well-known that cancer-associated inflammation contributes to tumor initiation and progression. However, it remains unclear whether a collapse of the balance between the antitumor immune response via the immunological surveillance system and protumor immunity due to cancer-related inflammation is responsible for cancer malignancy. The majority of inflammatory signals affect tumorigenesis by activating signal transducer and activation of transcription 3 (STAT3) and nuclear factor-κB. Persistent STAT3 activation in malignant cancer cells mediates extremely widespread functions, including cell growth, survival, angiogenesis, and invasion and contributes to an increase in inflammation-associated tumorigenesis. In addition, intracellular STAT3 activation in immune cells causes suppressive effects on antitumor immunity and leads to the differentiation and mobilization of immature myeloid-derived cells and tumor-associated macrophages. In many cancer types, STAT3 does not directly rely on its activation by oncogenic mutations but has important oncogenic and malignant transformation-associated functions in both cancer and stromal cells in the tumor microenvironment (TME). We have reported a series of studies aiming towards understanding the molecular mechanisms underlying the proliferation of various types of tumors involving signal-transducing adaptor protein-2 as an adaptor molecule that modulates STAT3 activity, and we recently found that AT-rich interactive domain-containing protein 5a functions as an mRNA stabilizer that orchestrates an immunosuppressive TME in malignant mesenchymal tumors. In this review, we summarize recent advances in our understanding of the functional role of STAT3 in tumor progression and introduce novel molecular mechanisms of cancer development and malignant transformation involving STAT3 activation that we have identified to date. Finally, we discuss potential therapeutic strategies for cancer that target the signaling pathway to augment STAT3 activity.
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Affiliation(s)
- Shigeru Hashimoto
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
- Correspondence: (S.H.); (T.M.)
| | - Ari Hashimoto
- Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Ryuta Muromoto
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Yuichi Kitai
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Kenji Oritani
- Department of Hematology, International University of Health and Welfare, Narita 286-8686, Japan
| | - Tadashi Matsuda
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
- Correspondence: (S.H.); (T.M.)
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30
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Bhat AA, Nisar S, Singh M, Ashraf B, Masoodi T, Prasad CP, Sharma A, Maacha S, Karedath T, Hashem S, Yasin SB, Bagga P, Reddy R, Frennaux MP, Uddin S, Dhawan P, Haris M, Macha MA. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun (Lond) 2022; 42:689-715. [PMID: 35791509 PMCID: PMC9395317 DOI: 10.1002/cac2.12295] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/28/2022] [Accepted: 04/24/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
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Affiliation(s)
- Ajaz A. Bhat
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Mayank Singh
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Bazella Ashraf
- Department of BiotechnologySchool of Life SciencesCentral University of KashmirGanderbalJammu & Kashmir191201India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Chandra P. Prasad
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Atul Sharma
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Selma Maacha
- Division of Translational MedicineResearch BranchSidra MedicineDoha26999Qatar
| | | | - Sheema Hashem
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Syed Besina Yasin
- Department of PathologySher‐I‐Kashmir Institute of Medical SciencesSrinagarJammu & Kashmir190011India
| | - Puneet Bagga
- Department of Diagnostic ImagingSt. Jude Children's Research HospitalMemphisTN38105USA
| | - Ravinder Reddy
- Center for Advanced Metabolic Imaging in Precision MedicineDepartment of RadiologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA19104USA
| | | | - Shahab Uddin
- Translational Research InstituteHamad Medical CorporationDoha3050Qatar
| | - Punita Dhawan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
- Laboratory Animal Research CenterQatar UniversityDoha2713Qatar
| | - Muzafar A. Macha
- Watson‐Crick Centre for Molecular MedicineIslamic University of Science and TechnologyAwantiporaJammu & Kashmir192122India
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31
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Goodla L, Xue X. The Role of Inflammatory Mediators in Colorectal Cancer Hepatic Metastasis. Cells 2022; 11:2313. [PMID: 35954156 PMCID: PMC9367504 DOI: 10.3390/cells11152313] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/24/2022] [Accepted: 07/26/2022] [Indexed: 01/27/2023] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of death in cancer patients in the USA, whereas the major cause of CRC deaths is hepatic metastases. The liver is the most common site of metastasis in patients with CRC due to hepatic portal veins receiving blood from the digestive tract. Understanding the cellular and molecular mechanisms of hepatic metastases is of dire need for the development of potent targeted therapeutics. Immuno-signaling molecules including cytokines and chemokines play a pivotal role in hepatic metastases from CRC. This brief review discusses the involvement of three representative cytokines (TNF-α, IL-6 and IL-1β), a lipid molecule PGE2 and two chemokines (CXCL1 and CXCL2) in the process of CRC liver metastases.
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Affiliation(s)
| | - Xiang Xue
- Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA;
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32
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Farc O, Berindan‑Neagoe I, Zaharie F, Budisan L, Zanoaga O, Cristea V. A role for serum cytokines and cell adhesion molecules in the non‑invasive diagnosis of colorectal cancer. Oncol Lett 2022; 24:323. [PMID: 35949613 PMCID: PMC9353784 DOI: 10.3892/ol.2022.13443] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 04/21/2022] [Indexed: 11/06/2022] Open
Abstract
Colorectal cancer (CRC) remains a major cause of cancer-related mortality. Consequently, new diagnostic and therapeutic approaches are being investigated including the serum levels of cytokines and other molecules, although the results are often inconclusive. Thus, the present study aimed to determine whether serum level of cytokines, cell adhesion molecules or matrix metalloproteinases (MMPs), alone or in combination, may contribute to the non-invasive diagnosis of CRC. The serum levels of nine cytokines [ILs; IL-1β, IL-4, IL-6, IL-8, IL-10, IL-17, IL-22 and IL-33, and interferon (IFN)-γ], two cell adhesion molecules (intercellular adhesion molecule-1 and P-selectin) and an MMP-7 were measured by ELISA in 33 patients with CRC and 35 healthy controls. Combined capacity of all molecules to detect the presence of CRC was assessed by logistic regression. Molecules and molecule combinations were tested for all stages and tumor grades. A significant increase was identified for IL-8 in patients compared with healthy controls; IL-10 was found to be significantly decreased. The biomarker potential of each significantly modified molecule was tested: IL-8 had a sensitivity of 0.865, a specificity of 0.600 and an area under the curve (AUC) of 0.777; for IL-10, sensitivity was 0.65, specificity was 0.69, with an AUC of 0.689. Logistic regression determined the best discriminative potential between patients and control groups for the combination IL-4 + IL-6 + IL-8 + IFN-γ, with 0.97 sensitivity and 0.58 specificity. For the early stages of CRC, the combination IL-6 + IL-8 + IL-22 showed good performance. It was concluded that increased IL-8 had potential as single biomarker in CRC. Cytokine combinations are superior to single cytokine analysis in showing the presence of CRC.
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Affiliation(s)
- Ovidiu Farc
- Department of Immunology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj‑Napoca, Romania
| | - Ioana Berindan‑Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj‑Napoca, Romania
| | - Florin Zaharie
- Department of Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj‑Napoca, Romania
| | - Liviuta Budisan
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj‑Napoca, Romania
| | - Oana Zanoaga
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj‑Napoca, Romania
| | - Victor Cristea
- Department of Immunology, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj‑Napoca, Romania
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The role of microRNA-30c in targeting interleukin 6, as an inflammatory cytokine, in the mesenchymal stem cell: a therapeutic approach in colorectal cancer. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04123-w. [PMID: 35876950 DOI: 10.1007/s00432-022-04123-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/07/2022] [Indexed: 10/16/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC) is the third most prevalent cancer and the second significant cause of cancer-associated death worldwide. The microRNA-30 is a substantial member of the miRNA family and plays a vital role in expanding several cancers. This microRNA potentially targets interleukin 6 as an inflammatory cytokine in CRC. MATERIALS AND METHODS MSCs were isolated and identified from mice bone marrow and then transduced with lentiviruses containing miR-30C. Transfected MSCs were collected to evaluate IL-6 levels, CT-26 cells were also co-cultured with MSCs, and the effect of apoptosis and IL-6 on the supernatant was assessed. RESULTS Our result showed the expression of IL-6 mRNA and the level of protein were decreased in the supernatant of miR-30-transduced MSC cells compared to the control group. In addition, the rate of apoptosis was assessed, and the obtained data revealed the induction of apoptosis in CT-26 cells when they are in the vicinity of miR-30c-transduced MSCs. DISCUSSION AND CONCLUSION We demonstrated that downregulation of miR-30c was significantly correlated with CRC progression and survival. So, the present study elucidated the anticancer effects of miR-30c in CRC and presented a novel target for CRC therapy.
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Chen J, Wei Y, Yang W, Huang Q, Chen Y, Zeng K, Chen J. IL-6: The Link Between Inflammation, Immunity and Breast Cancer. Front Oncol 2022; 12:903800. [PMID: 35924148 PMCID: PMC9341216 DOI: 10.3389/fonc.2022.903800] [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: 03/24/2022] [Accepted: 06/20/2022] [Indexed: 11/24/2022] Open
Abstract
Breast cancer is one of the leading causes of mortality in females. Over the past decades, intensive efforts have been made to uncover the pathogenesis of breast cancer. Interleukin-6 (IL-6) is a pleiotropic factor which has a vital role in host defense immunity and acute stress. Moreover, a wide range of studies have identified the physiological and pathological roles of IL-6 in inflammation, immune and cancer. Recently, several IL-6 signaling pathway-targeted monoclonal antibodies have been developed for cancer and immune therapy. Combination of IL-6 inhibitory antibody with other pathways blockage drugs have demonstrated promising outcome in both preclinical and clinical trials. This review focuses on emerging studies on the strong linkages of IL-6/IL-6R mediated regulation of inflammation and immunity in cancer, especially in breast cancer.
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Affiliation(s)
- Juan Chen
- Department of Medicine and Rehabilitation, Tung Wah Eastern Hospital, Hong Kong, Hong Kong SAR, China
| | - Yanghui Wei
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
- *Correspondence: Yanghui Wei, ; Jiawei Chen,
| | - Weiqin Yang
- School of Biomedical Sciences, The Chinese, University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Qingnan Huang
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Yong Chen
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Kai Zeng
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Jiawei Chen
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
- *Correspondence: Yanghui Wei, ; Jiawei Chen,
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Huang Q, Wu M, Wu X, Zhang Y, Xia Y. Muscle-to-tumor crosstalk: The effect of exercise-induced myokine on cancer progression. Biochim Biophys Acta Rev Cancer 2022; 1877:188761. [PMID: 35850277 DOI: 10.1016/j.bbcan.2022.188761] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 07/11/2022] [Accepted: 07/11/2022] [Indexed: 02/07/2023]
Abstract
Physical exercise has gradually become a focus in cancer treatment due to its pronounced role in reducing cancer risk, enhancing therapeutic efficacy, and improving prognosis. In recent decades, skeletal muscles have been considered endocrine organs, exerting their biological functions via the endocrine, autocrine, and paracrine systems by secreting various types of myokines. The amount of myokines secreted varies depending on the intensity, type, and duration of exercise. Recent studies have shown that muscle-derived myokines are highly involved the effects of exercise on cancer. Multiple myokines, such as interleukin-6 (IL-6), oncostatin M (OSM), secreted protein acidic and rich in cysteine (SPARC), and irisin, directly mediate cancer progression by influencing the proliferation, apoptosis, stemness, drug resistance, metabolic reprogramming, and epithelial-mesenchymal transformation (EMT) of cancer cells. In addition, IL-6, interleukin-8 (IL-8), interleukin-15 (IL-15), brain-derived neurotrophic factor (BDNF), and irisin can improve obesity-induced inflammation by stimulating lipolysis of adipose tissues, promoting glucose uptake, and accelerating the browning of white fat. Furthermore, some myokines could regulate the tumor microenvironment, such as angiogenesis and the immune microenvironment. Cancer cachexia occurs in up to 80% of cancer patients and is responsible for 22%-30% of patient deaths. It is characterized by systemic inflammation and decreased muscle mass. Exercise-induced myokine production is important in regulating cancer cachexia. This review summarizes the roles and underlying mechanisms of myokines, such as IL-6, myostatin, IL-15, irisin, fibroblast growth factor 21 (FGF21) and musclin, in cancer cachexia. Through comprehensive analysis, we conclude that myokines are potential targets for inhibiting cancer progression and the associated cachexia.
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Affiliation(s)
- Qianrui Huang
- Department of Rehabilitation Medicine, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mengling Wu
- Department of Rehabilitation Medicine, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuyi Wu
- Department of Rehabilitation Medicine, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Rehabilitation Medicine in Sichuan Province/Rehabilitation Medicine Research Institute, Chengdu 610041, China
| | - Yiwen Zhang
- Department of Rehabilitation Medicine, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Yong Xia
- Department of Rehabilitation Medicine, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Rehabilitation Medicine in Sichuan Province/Rehabilitation Medicine Research Institute, Chengdu 610041, China.
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Consensus molecular subtype differences linking colon adenocarcinoma and obesity revealed by a cohort transcriptomic analysis. PLoS One 2022; 17:e0268436. [PMID: 35560039 PMCID: PMC9106217 DOI: 10.1371/journal.pone.0268436] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 04/29/2022] [Indexed: 11/22/2022] Open
Abstract
Colorectal cancer (CRC) is the third-leading cause of cancer-related deaths in the United States and worldwide. Obesity—a worldwide public health concern—is a known risk factor for cancer including CRC. However, the mechanisms underlying the link between CRC and obesity have yet to be fully elucidated in part because of the molecular heterogeneity of CRC. We hypothesized that obesity modulates CRC in a consensus molecular subtype (CMS)-dependent manner. RNA-seq data and associated tumor and patient characteristics including body weight and height data for 232 patients were obtained from The Cancer Genomic Atlas–Colon Adenocarcinoma (TCGA-COAD) database. Tumor samples were classified into the four CMSs with the CMScaller R package; body mass index (BMI) was calculated and categorized as normal, overweight, and obese. We observed a significant difference in CMS categorization between BMI categories. Differentially expressed genes (DEGs) between obese and overweight samples and normal samples differed across the CMSs, and associated prognostic analyses indicated that the DEGs had differing associations on survival. Using Gene Set Enrichment Analysis, we found differences in Hallmark gene set enrichment between obese and overweight samples and normal samples across the CMSs. We constructed Protein-Protein Interaction networks and observed differences in obesity-regulated hub genes for each CMS. Finally, we analyzed and found differences in predicted drug sensitivity between obese and overweight samples and normal samples across the CMSs. Our findings support that obesity impacts the CRC tumor transcriptome in a CMS-specific manner. The possible associations reported here are preliminary and will require validation using in vitro and animal models to examine the CMS-dependence of the genes and pathways. Once validated the obesity-linked genes and pathways may represent new therapeutic targets to treat colon cancer in a CMS-dependent manner.
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Lin Q, Liu M, Yue GGL, Cheung MK, Lai Z, Kwok FHF, Lee JKM, Wang Z, Lau CBS, Tan N. Anti-inflammatory activities of natural cyclopeptide RA-XII in colitis-associated colon cancer mouse model and its effect on gut microbiome. Phytother Res 2022; 36:2641-2659. [PMID: 35537703 DOI: 10.1002/ptr.7482] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 04/07/2022] [Accepted: 04/09/2022] [Indexed: 12/19/2022]
Abstract
Colorectal cancer (CRC), the third most common cancer globally, is associated with intestinal inflammation that leads to poor prognosis. RA-XII, a natural cyclopeptide, has previously been reported to possess anti-tumor activities. Here, the anti-inflammatory activities of RA-XII were investigated in colitis-associated colon cancer mice and a co-culture in vitro model, in which colon cancer cells HCT116 and macrophages RAW264.7 were grown together to mimic the inflammatory microenvironment of CRC. Changes of inflammatory-related molecules and protein expressions in cells were evaluated after RA-XII incubation. Besides, azoxymethane and dextran sulfate sodium-induced colitis-associated colon cancer mice were treated with RA-XII for 24 days, inflammatory parameters and gut microbiome alterations were studied. Our results showed that RA-XII reversed the inflammatory responses of RAW264.7 cells induced by LPS and modulated the protein expressions of AKT, STAT3/p-STAT3, P70S6K, NF-κB and GSK3β and suppressed the expression of LC3A/B in HCT116 cells in co-culture system. RA-XII treatment restored the colitis damage in colon, reduced colon tumors numbers and decreased inflammatory factors (IL-6, IL-10 and TNF-α). The role of RA-XII on regulating gut microbiome was also demonstrated for the first time. In conclusion, our findings provided new scientific evidence for developing RA-XII as a potent anti-inflammatory agent for CRC.
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Affiliation(s)
- Qianwen Lin
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Mingyu Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Grace Gar-Lee Yue
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Man Kit Cheung
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Zhixing Lai
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Frankie Hin-Fai Kwok
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Julia Kin-Ming Lee
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Zhe Wang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Clara Bik-San Lau
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ninghua Tan
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
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Manore SG, Doheny DL, Wong GL, Lo HW. IL-6/JAK/STAT3 Signaling in Breast Cancer Metastasis: Biology and Treatment. Front Oncol 2022; 12:866014. [PMID: 35371975 PMCID: PMC8964978 DOI: 10.3389/fonc.2022.866014] [Citation(s) in RCA: 141] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 02/16/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most commonly diagnosed cancer in women. Metastasis is the primary cause of mortality for breast cancer patients. Multiple mechanisms underlie breast cancer metastatic dissemination, including the interleukin-6 (IL-6)-mediated signaling pathway. IL-6 is a pleiotropic cytokine that plays an important role in multiple physiological processes including cell proliferation, immune surveillance, acute inflammation, metabolism, and bone remodeling. IL-6 binds to the IL-6 receptor (IL-6Rα) which subsequently binds to the glycoprotein 130 (gp130) receptor creating a signal transducing hexameric receptor complex. Janus kinases (JAKs) are recruited and activated; activated JAKs, in turn, phosphorylate signal transducer and activator of transcription 3 (STAT3) for activation, leading to gene regulation. Constitutively active IL-6/JAK/STAT3 signaling drives cancer cell proliferation and invasiveness while suppressing apoptosis, and STAT3 enhances IL-6 signaling to promote a vicious inflammatory loop. Aberrant expression of IL-6 occurs in multiple cancer types and is associated with poor clinical prognosis and metastasis. In breast cancer, the IL-6 pathway is frequently activated, which can promote breast cancer metastasis while simultaneously suppressing the anti-tumor immune response. Given these important roles in human cancers, multiple components of the IL-6 pathway are promising targets for cancer therapeutics and are currently being evaluated preclinically and clinically for breast cancer. This review covers the current biological understanding of the IL-6 signaling pathway and its impact on breast cancer metastasis, as well as, therapeutic interventions that target components of the IL-6 pathway including: IL-6, IL-6Rα, gp130 receptor, JAKs, and STAT3.
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Affiliation(s)
- Sara G Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Daniel L Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States.,Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, United States
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Kumarasamy V, Atroosh WM, Anbazhagan D, Abdalla MMI, Azzani M. Association of Blastocystis hominis with colorectal cancer: A systematic review of in vitro and in vivo evidences. World J Gastrointest Oncol 2022; 14:734-745. [PMID: 35321272 PMCID: PMC8919012 DOI: 10.4251/wjgo.v14.i3.734] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/16/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recently, there have been several findings that showed intestinal colonisation of Blastocystis hominis (Blastocystis) as a risk factor to the worsening of colorectal cancer (CRC). However, studies have shown controversial results in the pathogenicity of Blastocystis.
AIM To review systematically the evidence available on the association between CRC and Blastocystis and the prevalence of Blastocystis in CRC patients and to investigate cytopathic and immunological effects of Blastocystis in in vitro and in vivo studies.
METHODS PRISMA guidelines were utilised in conducting this systematic review. Original articles published before February 2, 2020 were included. PubMed, Science Direct, Scopus and Google scholar databases were searched. Manual searching was carried out to find articles missed during the online search.
RESULTS Out of 12 studies selected for this systematic review, seven studies confirmed the prevalence of Blastocystis and found it to be between 2%-28% in CRC patients, whereby subtype 1 and subtype 3 were predominantly seen. A total of four studies employing in vitro human colorectal carcinoma cell line study models showed significant cytopathic and immunological effects of Blastocystis. In addition, one in vivo experimental animal model study showed that there was a significant effect of infection with Blastocystis on exacerbation of colorectal carcinogenesis.
CONCLUSION Blastocystis is a commonly identified microorganism in CRC patients. These studies have provided supportive data that Blastocystis could exacerbate existing CRC via alteration in host immune response and increased oxidative damage. Future studies of CRC and Blastocystis should attempt to determine the various stages of CRC that are most likely to be associated with Blastocystis and its relationship with other intestinal bacteria.
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Affiliation(s)
- Vinoth Kumarasamy
- Department of Microbiology and Parasitology, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom 42610, Selangor, Malaysia
- Department of Preclinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang 43000, Selangor, Malaysia
| | - Wahib Mohammed Atroosh
- Department of Parasitology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Wilayah Persekutuan, Malaysia
- Department of Microbiology and Parasitology, Faculty of Medicine and Health Sciences, University of Aden, Aden 00, Yemen
| | - Deepa Anbazhagan
- Department of Microbiology and Parasitology, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom 42610, Selangor, Malaysia
| | | | - Meram Azzani
- Department of Community Medicine, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom 42610, Selangor, Malaysia
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Pereira JFS, Bessa C, Matos P, Jordan P. Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells. Cancers (Basel) 2022; 14:1393. [PMID: 35326545 PMCID: PMC8946262 DOI: 10.3390/cancers14061393] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/06/2022] [Accepted: 03/07/2022] [Indexed: 02/04/2023] Open
Abstract
An inflammatory microenvironment is a tumour-promoting condition that provides survival signals to which cancer cells respond with gene expression changes. One example is the alternative splicing variant Rat Sarcoma Viral Oncogene Homolog (Ras)-Related C3 Botulinum Toxin Substrate 1 (RAC1)B, which we previously identified in a subset of V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF)-mutated colorectal tumours. RAC1B was also increased in samples from inflammatory bowel disease patients or in an acute colitis mouse model. Here, we used an epithelial-like layer of polarized Caco-2 or T84 colorectal cancer (CRC) cells in co-culture with fibroblasts, monocytes or macrophages and analysed the effect on RAC1B expression in the CRC cells by RT-PCR, Western blot and confocal fluorescence microscopy. We found that the presence of cancer-associated fibroblasts and M1 macrophages induced the most significant increase in RAC1B levels in the polarized CRC cells, accompanied by a progressive loss of epithelial organization. Under these conditions, we identified interleukin (IL)-6 as the main trigger for the increase in RAC1B levels, associated with Signal Transducer and Activator of Transcription (STAT)3 activation. IL-6 neutralization by a specific antibody abrogated both RAC1B overexpression and STAT3 phosphorylation in polarized CRC cells. Our data identify that pro-inflammatory extracellular signals from stromal cells can trigger the overexpression of tumour-related RAC1B in polarized CRC cells. The results will help to understand the tumour-promoting effect of inflammation and identify novel therapeutic strategies.
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Affiliation(s)
- Joana F. S. Pereira
- Department of Human Genetics, National Institute of Health ‘Dr. Ricardo Jorge’, 1649-016 Lisbon, Portugal; (J.F.S.P.); (C.B.); (P.M.)
- BioISI—Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal
| | - Cláudia Bessa
- Department of Human Genetics, National Institute of Health ‘Dr. Ricardo Jorge’, 1649-016 Lisbon, Portugal; (J.F.S.P.); (C.B.); (P.M.)
- BioISI—Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal
| | - Paulo Matos
- Department of Human Genetics, National Institute of Health ‘Dr. Ricardo Jorge’, 1649-016 Lisbon, Portugal; (J.F.S.P.); (C.B.); (P.M.)
- BioISI—Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal
| | - Peter Jordan
- Department of Human Genetics, National Institute of Health ‘Dr. Ricardo Jorge’, 1649-016 Lisbon, Portugal; (J.F.S.P.); (C.B.); (P.M.)
- BioISI—Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal
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Zahirović A, Plavec TV, Berlec A. Dual Functionalized Lactococcus lactis Shows Tumor Antigen Targeting and Cytokine Binding in Vitro. Front Bioeng Biotechnol 2022; 10:822823. [PMID: 35155394 PMCID: PMC8826564 DOI: 10.3389/fbioe.2022.822823] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/10/2022] [Indexed: 01/19/2023] Open
Abstract
Pro-inflammatory cytokines play an important role in the development and progression of colorectal cancer (CRC). Tumor-targeting bacteria that can capture pro-inflammatory cytokines in the tumor microenvironment and thus block their tumor-promoting effects might provide clinical benefits in inflammation-associated CRC. The aim of this study was to develop bacteria with dual functionality for selective delivery of cytokine-binding proteins to the tumor by targeting specific receptors on cancer cells. We engineered a model lactic acid bacterium, Lactococcus lactis, to co-display on its surface a protein ligand for tumor antigens (EpCAM-binding affitin; HER2-binding affibody) and a ligand for pro-inflammatory cytokines (IL-8-binding evasin; IL-6-binding affibody). Genes that encoded protein binders were cloned into a lactococcal dual promoter plasmid, and protein co-expression was confirmed by Western blotting. To assess the removal of IL-8 and IL-6 by the engineered bacteria, we established inflammatory cell models by stimulating cytokine secretion in human colon adenocarcinoma cells (Caco-2; HT-29) and monocyte-like cells (THP-1; U-937). The engineered L. lactis removed considerable amounts of IL-8 from the supernatant of Caco-2 and HT-29 cells, and depleted IL-6 from the supernatant of THP-1 and U-937 cells as determined by ELISA. The tumor targeting properties of the engineered bacteria were evaluated in human embryonic kidney epithelial cells HEK293 transfected to overexpress EpCAM or HER2 receptors. Fluorescence microscopy revealed that the engineered L. lactis specifically adhered to transfected HEK293 cells, where the EpCAM-targeting bacteria exhibited greater adhesion efficiency than the HER2-targeting bacteria. These results confirm the concept that L. lactis can be efficiently modified to display two proteins simultaneously on their surface: a tumor antigen binder and a cytokine binder. Both proteins remain biologically active and provide the bacteria with tumor antigen targeting and cytokine binding ability.
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Affiliation(s)
- Abida Zahirović
- Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
| | - Tina Vida Plavec
- Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
| | - Aleš Berlec
- Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
- *Correspondence: Aleš Berlec,
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Herczeg G, Somogyi A, Herold M, Fodor A, Rosta K, Dank M, Lang Z, Herold Z. Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer? Open Med (Wars) 2022; 17:160-173. [PMID: 35071777 PMCID: PMC8760180 DOI: 10.1515/med-2021-0407] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 11/05/2021] [Accepted: 11/15/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND A large variety of factors can affect colorectal cancer (CRC) survival, including type 2 diabetes mellitus (T2DM) and paraneoplastic thrombocytosis. Although several common factors play a role in their development and platelets are damaged in both diseases, the combined relationship of the three conditions was never investigated previously. METHODS A prospective, real-life observational cohort study was conducted with the inclusion of 108 CRC patients and 166 voluntary non-CRC subjects. Plasma interleukin-6 and thrombopoietin levels were measured. RESULTS Study participants were divided into cohorts based on the presence of T2DM. Platelet count (p < 0.0500) and interleukin-6 (p < 0.0100) level were significantly higher in the CRC groups. Thrombopoietin level was higher in the T2DM, CRC, and CRC + T2DM groups (p < 0.0500). Analysis of parameter changes over time and survival models revealed that neither platelet count, interleukin-6, nor thrombopoietin levels were affected by T2DM. Death of patients was associated with higher baseline platelet count (p = 0.0042) and interleukin-6 level (p < 0.0001). CONCLUSION Although the independent, disease-worsening effect of paraneoplastic thrombocytosis and T2DM is known, the coexistence of the two did not further impair the survival of CRC patients, suggesting that T2DM has no significant effect over paraneoplastic thrombocytosis.
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Affiliation(s)
- Gyorgy Herczeg
- Department of General Surgery, Szent Imre University Teaching Hospital, Budapest, Hungary
| | - Aniko Somogyi
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
| | - Magdolna Herold
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
| | - Agnes Fodor
- Department of General Surgery, Szent Imre University Teaching Hospital, Budapest, Hungary
| | - Klara Rosta
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Magdolna Dank
- Department of Internal Medicine and Oncology, Division of Oncology, Semmelweis University, Budapest, Hungary
| | - Zsolt Lang
- Department of Biomathematics and Informatics, University of Veterinary Medicine Budapest, Budapest, Hungary
| | - Zoltan Herold
- Department of Internal Medicine and Haematology, Semmelweis University, Szentkiralyi utca 46., H-1088 Budapest, Hungary
- Department of Internal Medicine and Oncology, Division of Oncology, Semmelweis University, Tomo utca 25-29., H-1083 Budapest, Hungary
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43
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Manganese-Doped N-Hydroxyphthalimide-Derived Carbon Dots-Theranostics Applications in Experimental Breast Cancer Models. Pharmaceutics 2021; 13:pharmaceutics13111982. [PMID: 34834397 PMCID: PMC8674762 DOI: 10.3390/pharmaceutics13111982] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/19/2021] [Accepted: 11/19/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Theranostics, a novel concept in medicine, is based on the use of an agent for simultaneous diagnosis and treatment. Nanomaterials provide promising novel approaches to theranostics. Carbon Dots have been shown to exhibit anti-tumoral properties in various cancer models. The aim of the present study is to develop gadolinium, Fe3+, and Mn2+-doped N-hydroxyphthalimide-derived Carbon Dots. The resulted doped Carbon Dots should preserve the anti-tumoral properties while gaining magnetic resonance imaging properties. METHODS Normal and cancer cell lines have been treated with doped Carbon Dots, and the cell viability has been measured. The doped Carbon Dots that exhibited the most prominent anti-tumoral effect accompanied by the lowest toxicity have been further in vivo tested. Magnetic resonance imaging evaluates both in vitro and in vivo the possibility of using doped Carbon Dots as a contrast agent. RESULTS According to the results obtained from both the in vitro and in vivo experimental models used in our study, Mn2+-doped Carbon Dots (Mn-CDs-NHF) exhibit anti-tumoral properties, do not significantly impair the cell viability of normal cells, and reduce lung metastasis and the volume of mammary primary tumors while allowing magnetic resonance imaging. CONCLUSIONS Our findings prove that Mn-CDs-NHF can be used as theranostics agents in pre-clinical models.
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44
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Expression Levels of Il-6 and Il-18 in Acute Myeloid Leukemia and Its Relation with Response to Therapy and Acute GvHD After Bone Marrow Transplantation. Indian J Surg Oncol 2021; 12:465-471. [PMID: 34658572 DOI: 10.1007/s13193-021-01358-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 05/26/2021] [Indexed: 12/17/2022] Open
Abstract
Cytokines seem to play a crucial role in physiological and pathological conditions of acute myeloid leukemia (AML). The aim of this study was to evaluate the expression levels of interleukins-6 (IL-6) and IL-18 in patients with AML and its correlation with response to therapy and graft versus host disease (GvHD) after bone marrow transplantation. The expression levels of IL-6 and IL-18 genes were done in all patients and compared with matched control. Complete remission (CR) was used for evaluation of the effects of these cytokines on response to treatment in patients group. The expression level of these cytokines was also evaluated in patients who underwent bone marrow transplantation and experienced acute GvHD in compare with patients without aGvHD. Il-6 gene expression level was significantly higher in these patients in comparison with control but Il-18 gene expression level was not statistically significant compared to control group. Il-6 and also Il-18 expression levels were significantly higher in patients without a response to treatment according to CR compared to patient's whit response to treatment as well as patients experienced aGvHD after bone marrow transplantation. IL-6 and Il-18 are important markers in the progression of the disease and could be considered as a prognostic marker in acute leukemia. It is recommended that more studies with larger study groups and more involved cytokines are needed for more evaluation of the cytokine roles in pathophysiology and progression of acute leukemia.
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45
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Maleki M, Golchin A, Javadi S, Khelghati N, Morovat P, Asemi Z, Alemi F, Vaghari-Tabari M, Yousefi B, Majidinia M. Role of exosomal miRNA in chemotherapy resistance of Colorectal cancer: A systematic review. Chem Biol Drug Des 2021; 101:1096-1112. [PMID: 34480511 DOI: 10.1111/cbdd.13947] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/25/2021] [Accepted: 08/30/2021] [Indexed: 12/13/2022]
Abstract
The third most common malignancy has been identified as Colorectal cancer (CRC) that conducive to death in most cases. Chemoresistance is a common obstacle to CRC treatment. Circulating exosomal microRNAs (miRNAs) have been shown to reverse chemo-resistance and are promising biomarkers for CRC. The capacity of engineered exosomes to cross biological barriers and deliver functional miRNAs could be used to achieve these proposes. The object of this review is the investigation of the role of exosomal miRNA in the chemo-resistance, diagnosis, and prognosis of CRC. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, electronic databases, PubMed, EMBASE, Web of Science, Scopus were searched from January 1990 to November 2020. Ultimately, eight articles included five in vitro (16 cell lines) and three in vivo examinations. Three studies demonstrated that increasing or decreasing mRNA expression was associated with increasing and decreasing cell proliferation in vitro. The presence of miRNA in two studies increased the sensitivity of the drug and exhibited a considerable growth inhibitory effect on cancer cell proliferation. The apoptotic rate was significantly increased in four studies by increased mRNA expression and reduced mrna expression. Tumor volume of xenograft models in three studies suppressed by antitumor miRNA activity. In contrast, anti-miRNA activity in one study decreased the tumor volume. Exosomal miRNAs can be regulators of chemo-resistance and predict adverse outcomes in CRC patients. In sum, exosomes containing miRNAs can be a promising biomarker for the prognosis and diagnosis of CRC. Subsequent research should be a focus on delineating the function of exosomal miRNA before clinical use.
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Affiliation(s)
- Masomeh Maleki
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Asal Golchin
- Department of Clinical Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Samira Javadi
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Nafiseh Khelghati
- Department of Clinical Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Pejman Morovat
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Forough Alemi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mostafa Vaghari-Tabari
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
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46
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Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer. Nat Commun 2021; 12:4441. [PMID: 34290255 PMCID: PMC8295257 DOI: 10.1038/s41467-021-24687-4] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 07/01/2021] [Indexed: 12/19/2022] Open
Abstract
BRD4, a Bromodomain and Extraterminal (BET) protein family member, is a promising anti-cancer drug target. However, resistance to BET inhibitors targeting BRD4 is common in solid tumors. Here, we show that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. BRD4 phosphorylation at tyrosine 97/98 also displays increased binding to chromatin but reduced binding to BET inhibitors, resulting in resistance to BET inhibitors. We further show that BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. Our study reveals a stromal mechanism for BRD4 activation and BET inhibitor resistance, which provides a rationale for developing strategies to treat CRC more effectively. BRD4 has a pro-tumorigenic role but non-cell-autonomous mechanisms of BRD4 activation need to be elucidated. Here the authors unravel a mechanism by which CAFs activate BRD4 and induce resistance to BET inhibitors in cancer cells through IL6/IL8 signaling.
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47
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Kang DY, Sp N, Jo ES, Rugamba A, Kim HD, Kim IH, Park JC, Bae SW, Jang KJ, Yang YM. Non-toxic sulfur inhibits LPS-induced inflammation by regulating TLR-4 and JAK2/STAT3 through IL-6 signaling. Mol Med Rep 2021; 24:485. [PMID: 33907855 PMCID: PMC8127030 DOI: 10.3892/mmr.2021.12124] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 03/29/2021] [Indexed: 01/22/2023] Open
Abstract
Janus kinase 2 (JAK2) and STAT3 signaling is considered a major pathway in lipopolysaccharide (LPS)‑induced inflammation. Toll‑like receptor 4 (TLR‑4) is an inflammatory response receptor that activates JAK2 during inflammation. STAT3 is a transcription factor for the pro‑inflammatory cytokine IL‑6 in inflammation. Sulfur is an essential element in the amino acids and is required for growth and development. Non‑toxic sulfur (NTS) can be used in livestock feeds as it lacks toxicity. The present study aimed to inhibit LPS‑induced inflammation in C2C12 myoblasts using NTS by regulating TLR‑4 and JAK2/STAT3 signaling via the modulation of IL‑6. The 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay was conducted to analyze cell viability and reverse transcription polymerase chain reaction and western blotting performed to measure mRNA and protein expression levels. Chromatin immunoprecipitation and enzyme‑linked immunosorbent assays were used to determine the binding activity of proteins. The results indicated that NTS demonstrated a protective effect against LPS‑induced cell death and inhibited LPS‑induced expression of TLR‑4, JAK2, STAT3 and IL‑6. In addition, NTS inhibited the expression of nuclear phosphorylated‑STAT3 and its binding to the IL‑6 promoter. Therefore, NTS may be a potential candidate drug for the treatment of inflammation.
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Affiliation(s)
- Dong Young Kang
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju, North Chungcheong 27478, Republic of Korea
| | - Nipin Sp
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju, North Chungcheong 27478, Republic of Korea
| | - Eun Seong Jo
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju, North Chungcheong 27478, Republic of Korea
| | - Alexis Rugamba
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju, North Chungcheong 27478, Republic of Korea
| | - Hyoung Do Kim
- Nara Bio Co., Ltd., Gunsan, Jeollabuk-do 54006, Republic of Korea
| | - Il Ho Kim
- Nara Bio Co., Ltd., Gunsan, Jeollabuk-do 54006, Republic of Korea
| | - Jong-Chan Park
- Plant Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong, Daejeon 34141, Republic of Korea
| | - Se Won Bae
- Department of Chemistry and Cosmetics, Jeju National University, Jeju-si, Jeju-do 63243, Republic of Korea
| | - Kyoung-Jin Jang
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju, North Chungcheong 27478, Republic of Korea
| | - Young Mok Yang
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju, North Chungcheong 27478, Republic of Korea
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48
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Shahnazari M, Samadi P, Pourjafar M, Jalali A. Cell-based immunotherapy approaches for colorectal cancer: main achievements and challenges. Future Oncol 2021; 17:3253-3270. [PMID: 34156258 DOI: 10.2217/fon-2020-1218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Immunotherapy is becoming as a major treatment modality for multiple types of solid tumors, including subsets of colorectal cancers (CRCs). The successes with immunotherapy alone has largely been achieved in patients with advanced-stage mismatch-repair-deficient and microsatellite instability-high (dMMR-MSI-H) CRCs. However, the benefits of immunotherapy have not been demonstrated to be effective in patients with proficient mismatch repair (pMMR) CRC, who are microsatellite-stable (MSS) or have low levels of microsatellite instability (MSI-L). Here, we provide a comprehensive review on the immune microenvironment of CRC tumors and describe the rapid pace of scientific changes. We discuss the tremendous promise of cell-based immunotherapy strategies that are under preclinical studies/clinical trials or being used in therapeutic paradigms.
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Affiliation(s)
- Mina Shahnazari
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Shahid fahmideh boulevard, 6517838687, Hamadan, Iran
| | - Pouria Samadi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Shahid fahmideh boulevard, 6517838687, Hamadan, Iran
| | - Mona Pourjafar
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Shahid fahmideh boulevard, 6517838687, Hamadan, Iran.,Department of Biological & Chemical Engineering Immunological Biotechnology, Aarhus University, Inge Lehmanns Gade 10, 8000 Aarhus C, Aarhus, Denmark
| | - Akram Jalali
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Shahid fahmideh boulevard, 6517838687, Hamadan, Iran
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Dzobo K, Dandara C. Architecture of Cancer-Associated Fibroblasts in Tumor Microenvironment: Mapping Their Origins, Heterogeneity, and Role in Cancer Therapy Resistance. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2021; 24:314-339. [PMID: 32496970 DOI: 10.1089/omi.2020.0023] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The tumor stroma, a key component of the tumor microenvironment (TME), is a key determinant of response and resistance to cancer treatment. The stromal cells, extracellular matrix (ECM), and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and therapeutic outcomes. Of the stromal cells present in the TME, much attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and important in cancer initiation, progression, and therapy resistance. Besides releasing several factors, CAFs also synthesize the ECM, a key component of the tumor stroma. In this expert review, we examine the role of CAFs in the regulation of tumor cell behavior and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. Importantly, CAFs display both phenotypic and functional heterogeneity, with significant ramifications on CAF-directed therapies. Principal anti-cancer therapies targeting CAFs take the form of: (1) CAFs' ablation through use of immunotherapies, (2) re-education of CAFs to normalize the cells, (3) cellular therapies involving CAFs delivering drugs such as oncolytic adenoviruses, and (4) stromal depletion via targeting the ECM and its related signaling. The CAFs' heterogeneity could be a result of different cellular origins and the cancer-specific tumor microenvironmental effects, underscoring the need for further multiomics and biochemical studies on CAFs and the subsets. Lastly, we present recent advances in therapeutic targeting of CAFs and the success of such endeavors or their lack thereof. We recommend that to advance global public health and personalized medicine, treatments in the oncology clinic should be combinatorial in nature, strategically targeting both cancer cells and stromal cells, and their interactions.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.,Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Collet Dandara
- Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
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50
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Circulating Biomarkers of Colorectal Cancer (CRC)-Their Utility in Diagnosis and Prognosis. J Clin Med 2021; 10:jcm10112391. [PMID: 34071492 PMCID: PMC8199026 DOI: 10.3390/jcm10112391] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/25/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
The global burden of colorectal cancer (CRC) is expected to increase, with 2.2 million new cases and 1.1 million annual deaths by 2030. Therefore, the establishment of novel biomarkers useful in the early diagnosis of CRC is of utmost importance. A number of publications have documented the significance of the overexpression of several specific proteins, such as inflammatory mediators, in CRC progression. However, little is known about the potential utility of these proteins as circulating blood tumor biomarkers of CRC. Therefore, in the present review we report the results of our previous original studies as well as the findings of other authors who investigated whether inflammatory mediators might be used as novel biomarkers in the diagnosis and prognosis of CRC. Our study revealed that among all of the tested proteins, serum M-CSF, CXCL-8, IL-6 and TIMP-1 have the greatest value in the diagnosis and progression of CRC. Serum TIMP-1 is useful in differentiating between CRC and colorectal adenomas, whereas M-CSF and CRP are independent prognostic factors for the survival of patients with CRC. This review confirms the promising significance of these proteins as circulating biomarkers for CRC. However, due to their non-specific nature, further validation of their sensitivity and specificity is required.
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