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Martinez P, Grant WB. Vitamin D: What role in obesity-related cancer? Semin Cancer Biol 2025; 112:135-149. [PMID: 40194750 DOI: 10.1016/j.semcancer.2025.03.007] [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: 12/06/2024] [Revised: 03/16/2025] [Accepted: 03/29/2025] [Indexed: 04/09/2025]
Abstract
Obesity is an important risk factor for incidence and death for many types of cancer. Vitamin D reduces risk of incidence and death for many types of cancer. This review outlines the mechanisms by which obesity increases risk of cancer, how vitamin D reduces risk of cancer, and the extent to which vitamin D counters the effects of obesity in cancer. Vitamin D is a partial ally against some of obesity's pro-carcinogenic effects, notably by reducing inflammation and regulating sex hormone receptors, leptin resistance, cellular energy metabolism, the microbiome, and hypoxia. However, it can act stronger in against the renin-angiotensin system, insulin resistance, and oxidative stress in cancer. Additionally, excess fat tissue sequesters vitamin D and, along with its dilution in increased body volume, further reduces its bioavailability and serum concentration, limiting its protective effects against cancer. In conclusion, while vitamin D cannot reverse obesity, it plays a significant role in mitigating its pro-carcinogenic effects by targeting several mechanisms.
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Affiliation(s)
| | - William B Grant
- Sunlight, Nutrition, and Health Research Center, 1745 Pacific Ave., Ste. 504, San Francisco, CA 94109, USA.
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Veronez LC, Silveira DSCD, Lopes-Júnior LC, Dos Santos JC, Barbisan LF, Pereira-da-Silva G. Jacalin Attenuates Colitis-Associated Colorectal Carcinogenesis by Inhibiting Tumor Cell Proliferation and Intestinal Inflammation. Inflamm Bowel Dis 2025; 31:1344-1354. [PMID: 39745886 DOI: 10.1093/ibd/izae303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) remains a significant cause of morbidity and mortality worldwide. In patients with inflammatory bowel disease, who have twice the risk of developing CRC, chronic inflammation has been recognized to contribute to colitis-associated cancer (CAC) development. Jacalin, a lectin extracted from jackfruit seeds, has been shown to recognize altered glycosylation and to exert antiproliferative and cytotoxic effects in CRC. However, its activity in CAC remains unknown. Herein, we sought to investigate the effects of jacalin in CAC progression using the dextran sulfate sodium (DSS) and azoxymethane (AOM) mouse model. METHODS Colitis-associated cancer induction was performed in male C57BL/6 mice by an intraperitoneal injection of AOM, followed by 3 cycles of 2.5% DSS diluted in drinking water for 7 days, intercalated by 2 weeks of normal drinking water. After 1 week of daily pretreatment, mice were orally treated with phosphate-buffered saline (control group), 100 or 500 µg of jacalin three times a week for an additional 11 weeks. RESULTS We showed that jacalin-treated mice presented tumors with reduced volumes and mean size compared to the control group. In addition, both doses of jacalin reduced the number of proliferating cells (Ki-67 positive cells) in tumor tissues, while the higher dose (500 µg) showed also a similar effect in "normal-appearing" colonic crypts. Jacalin treatment attenuated the clinical scores of inflammations, which was accompanied by a reduction of intestinal and/or tumoral production of IL-1β, IL-23, and IL-17. CONCLUSIONS Collectively, our findings demonstrated that jacalin suppresses CAC development, highlighting its anti-inflammatory and antitumoral role in the AOM/DSS-induced model.
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Affiliation(s)
- Luciana Chain Veronez
- Graduate Program in Basic and Applied Immunology, Biochemistry and Immunology Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14040-902, Brazil
| | - Denise Sayuri Calheiros da Silveira
- Graduate Program in Basic and Applied Immunology, Biochemistry and Immunology Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14040-902, Brazil
| | - Luis Carlos Lopes-Júnior
- Nursing Department, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Jéssica Cristina Dos Santos
- Graduate Program in Basic and Applied Immunology, Biochemistry and Immunology Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14040-902, Brazil
| | - Luis Fernando Barbisan
- Structural and Functional Biology Department, São Paulo State University (UNESP), Institute of Biosciences, Botucatu, São Paulo 18618-689, Brazil
| | - Gabriela Pereira-da-Silva
- Graduate Program in Basic and Applied Immunology, Biochemistry and Immunology Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14040-902, Brazil
- Maternal-Infant and Public Health Nursing Department, Ribeirão Preto School of Nursing, University of São Paulo, Ribeirão Preto, São Paulo 14040-902, Brazil
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Santerre A, Huizar-López MDR, Coronilla-Martínez J, Ortiz-Lazareno PC, Casas-Solís J. Lacticaseibacillus casei 393 modulates KRAS and APC expression and cytokine levels in colitis-associated colon cancer. J Gastrointest Oncol 2025; 16:568-579. [PMID: 40386603 PMCID: PMC12078812 DOI: 10.21037/jgo-24-667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 02/26/2025] [Indexed: 05/20/2025] Open
Abstract
Background Colitis-associated colon cancer (CAC) is a specific subset of colorectal cancer (CRC) affecting patients with inflammatory bowel diseases (IBDs). Chronic colon inflammation orchestrates immune surveillance or escape and may drive neoplastic initiation and progression. Lacticaseibacillus casei 393 (L. casei 393) is a lactic acid microorganism that, beyond its nutritional value, provides health benefits. To explore the therapeutic potential of this probiotic against CAC, we evaluated colon histopathology, circulating cytokines, and the expression of the Kristen rat viral sarcoma oncogene homolog (KRAS) and the adenomatosis polyposis coli (APC) tumor-suppressing gene in the murine model of CAC induced with azoxymethane (AOM) and dextran sodium sulfate (DSS). Methods BALB/c mice (n=7/group) received two doses of AOM (10 mg/kg body weight) followed by three 5-day cycles of 2% DSS. L. casei 393 was administered orally [1×106 colony forming units (CFU)/100 µL/mouse/twice a week/6 months] either alone, before AOM-DSS, or starting at the same time as AOM-DSS. Colon histopathology was assessed by hematoxylin-eosin staining, circulating cytokines by flow cytometry, and the expression of colonic KRAS and APC by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Results AOM-DSS induced CAC in BALB/c mice, which presented severe colon damage, high cytokine levels, and altered KRAS and APC expression. Conversely, L. casei 393 ingestions, starting at the same time as CAC induction, restored colon architecture and modulated cytokine levels and gene expression. Conclusions The present experimental work supports the therapeutic potential of L. casei 393 against CAC, as it shows that its ingestion restored the damaging effect of AOM-DSS through its anti-inflammatory properties that helped modulate KRAS and APC mRNA expression.
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Affiliation(s)
- Anne Santerre
- Cellular and Molecular Biology Department, University of Guadalajara, Zapopan, Mexico
| | | | | | - Pablo Cesar Ortiz-Lazareno
- Immunology Unit, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Mexico
| | - Josefina Casas-Solís
- Cellular and Molecular Biology Department, University of Guadalajara, Zapopan, Mexico
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Gutiu AG, Zhao L, Marrah AJ, Maher AJ, Voss BB, Mayberry TG, Cowan BC, Wakefield MR, Fang Y. Promising immunotherapeutic treatments for colon cancer. Med Oncol 2025; 42:175. [PMID: 40266497 DOI: 10.1007/s12032-025-02724-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Accepted: 04/14/2025] [Indexed: 04/24/2025]
Abstract
Colon cancer continues to predominate as one of the most common causes of morbidity and mortality worldwide due to its subtle symptomology and multifactorial etiology. Currently, the standard treatment approach involves surgical resection for localized tumors and adjuvant chemotherapy (AC) for cancers that have spread or invaded locally. Unfortunately, this treatment strategy may not be effective for advanced, metastatic stages of the disease or in instances of recurrence. However, advancements in immunotherapy have demonstrated promising results in the field of medical oncology, which could redefine the way patients and clinicians view the disease. These treatments have shown benefit and have the potential to be superior to the current interventions available for afflicted patients. The application of immunotherapy in conjunction with traditional treatments may improve the outcomes of patients suffering from colon cancer and decrease the burden this disease has on patients. Furthermore, more effective treatments in the form of conjunction immunological, surgical, and chemotherapeutic techniques may shorten treatment courses and lead to better long-term effects. This review paper investigates immunotherapeutic interventions for colon cancer, which include immune checkpoint inhibitors, oncolytic virotherapy, cancer vaccines, cytokine therapy, and CAR-T. Such a study might provide more information for clinicians to treat patients with colon cancer in the advanced stages or in recurrence.
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Affiliation(s)
- Arturo G Gutiu
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA, 50266, USA
| | - Lei Zhao
- Department of Respiratory Medicine, The 2nd People's Hospital of Hefei and Hefei Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Austin J Marrah
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Austin J Maher
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Brady B Voss
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Trenton G Mayberry
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Braydon C Cowan
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Mark R Wakefield
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Yujiang Fang
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA, 50266, USA.
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, West Des Moines, IA, 50266, USA.
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Xue C, Chu Q, Shi Q, Zeng Y, Lu J, Li L. Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances. Signal Transduct Target Ther 2025; 10:106. [PMID: 40180907 PMCID: PMC11968978 DOI: 10.1038/s41392-025-02142-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/13/2024] [Accepted: 12/29/2024] [Indexed: 04/05/2025] Open
Abstract
The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling's involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.
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Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Koçak A, Gülle S, Birlik M. Porcupine inhibitors LGK-974 and ETC-159 inhibit Wnt/β-catenin signaling and result in inhibition of the fibrosis. Toxicol In Vitro 2025; 104:105986. [PMID: 39647516 DOI: 10.1016/j.tiv.2024.105986] [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: 09/19/2024] [Revised: 11/22/2024] [Accepted: 11/29/2024] [Indexed: 12/10/2024]
Abstract
OBJECTIVES We evaluated potential therapeutic efficacy of LGK-974 and ETC-159 in fibrotic scleroderma cells. METHODS Primary scleroderma dermal fibroblast cells of mouse origin (SSc fibroblasts) and primary fibrotic lung fibroblast cells of human origin (CCL-191) were used in this study. PORCN inhibitors LGK-974 (S7143, 1 μM; Selleckchem, USA) and ETC-159 (S7143, 10 μM; Selleckchem, USA) were used. The possible therapeutic effects of LGK-974 and ETC-159 on scleroderma cells and fibrosis cells were examined. Cell viability experiments were performed for each substance, and the expression levels of WNT and fibrosis marker genes were determined by qPCR. Western blotting was also used to determine collagen, fibronectin and α-SMA protein markers. RESULTS This study showed that LGK-974 and ETC-159 probable protein-cysteine N-palmitoyltransferase porcupine (PORCN) inhibitors exert potent antifibrotic effects and reduce fibrosis by modulating the TGF-β signaling pathway in scleroderma cells. Using LGK-974 and ETC-159 PORCN inhibitors, either alone or in combination, can affect collagen deposition and fibrosis in patients with SSc. CONCLUSIONS LGK-974 and ETC-159 may be a possible long-term therapeutic target for scleroderma.
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Affiliation(s)
- Ayşe Koçak
- Kutahya Health Sciences University, Faculty of Medicine, Department of Medical Biochemistry, Kutahya, Turkey.
| | - Semih Gülle
- Dokuz Eylul University, Faculty of Medicine, Department of Rheumatology & Immunology, Izmir, Turkey
| | - Merih Birlik
- Dokuz Eylul University, Faculty of Medicine, Department of Rheumatology & Immunology, Izmir, Turkey
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Liu S, Zhou M, Huang X, Chen P, Li Q, Wang Y, Ge X, Wang F, Xu J, Gu J, Miao L, Deng X. A Mechanistic Study of the Feasibility of Ursodeoxycholic Acid in the Treatment of Colon Adenocarcinoma. Drug Des Devel Ther 2025; 19:1839-1852. [PMID: 40093647 PMCID: PMC11910939 DOI: 10.2147/dddt.s500721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 03/01/2025] [Indexed: 03/19/2025] Open
Abstract
Purpose Bile acids promote the progression of colon adenocarcinoma (COAD), and ursodeoxycholic acid (UDCA) is a key drug in promoting bile acid excretion, but its role in COAD unclear. Our study aims to investigate the relationship between COAD and bile acid metabolism and to assess the feasibility of UDCA for the treatment of COAD. Methods Firstly, biological targets closely related to COAD were identified: Based on the cancer genome atlas (TCGA) database, the core genes of COAD were obtained by differential expression analysis and weighted gene-coexpression network analysis (WGCNA), and subjected to gene ontology (GO) function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Secondly, finding a drug by target, after identifying UDCA as a candidate drug, the feasibility of UDCA in treating COAD was verified in reverse: Using databases to collect potential targets for COAD and UDCA, and the intersecting genes were the potential targets for UDCA to exert anti-tumor effects. Then Autodock was used for molecular docking to analyze the interaction between UDCA and core target proteins. Finally, experimental validation was performed: MTT assay, wound healing, transwell migration, and angiogenesis assays were used to detect the effects of UDCA on cell proliferation, migration, invasion, and neovascularization. Results 2064 differential genes were screened from TCGA. WGCNA obtained the module most relevant to CRC, containing 493 genes. KEGG analysis found that overlapping genes were mainly concentrated in bile acid metabolic pathways. A total of 26 UDCA anti-tumor targets were obtained in database, and 5 core targets were selected by STRING database and Cytoscape software: TNF, CYP27B1, MDM2, MMP2, CASP3. Molecular docking results showed that UDCA had good binding activity with the core targets. In vitro experiment showed UDCA effectively inhibited the proliferation, migration, invasion and neovascularization in colon cancer cells. Conclusion The antitumor activity of ursodeoxycholic acid may be related to cell apoptosis, proliferation, migration and vascular neogenesis.
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Affiliation(s)
- Shuyu Liu
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
- Department of Gastroenterology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Mengyue Zhou
- Department of Gastroenterology, Nanjing Pukou Hospital of Traditional Chinese Medicine, Nanjing, People’s Republic of China
| | - Xiaoli Huang
- Department of Gastroenterology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Peng Chen
- Department of Gastroenterology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Quanpeng Li
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Yuting Wang
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Xianxiu Ge
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Fei Wang
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Jianing Xu
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Jiayi Gu
- Department of Neurology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Lin Miao
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Xueting Deng
- Medical Center for Digestive Disease, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
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Maier T, Landwehr LS, Triebig A, Kircher S, Schauer MP, Knösel T, Sbiera S, Schwarzlmueller P, Zimmermann P, Reincke M, Weigand I, Fassnacht M, Kroiss M. Wnt/β-catenin pathway activation is associated with glucocorticoid secretion in adrenocortical carcinoma, but not directly with immune cell infiltration. Front Endocrinol (Lausanne) 2025; 16:1502117. [PMID: 40130164 PMCID: PMC11930824 DOI: 10.3389/fendo.2025.1502117] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 02/12/2025] [Indexed: 03/26/2025] Open
Abstract
Background In advanced adrenocortical carcinoma (ACC), the response rate to immune checkpoint inhibition (ICI) is only ~15%. Glucocorticoid (GC) secretion and the activation of the Wnt/β-catenin pathway have been suggested to contribute to low tumour immune cell infiltration. The transcription factor lymphoid enhancer factor 1 (LEF-1) transduces β-catenin (CTNNB1)-mediated transcriptional activation. Objective To understand the contribution of Wnt/β-catenin pathway activation and glucocorticoid receptor (GR) signalling to the immunologically cold ACC tumour microenvironment. Methods Semi-quantitative immunohistochemistry (IHC) of β-catenin (CTNNB1), LEF-1, GR and T cell markers CD3, CD4, CD8, Fox P3 in 59 ACC samples. Targeted RNA expression analysis of 354 immune-related genes in 58 additional ACC tissue specimens. Correlative analyses with clinical data. Results Nuclear LEF-1 and CTNNB1 protein expression were positively correlated in ACC tissue (Pearson R2 = 0.1283, p=0.0046). High, moderate and low protein expression was detected in 24.1%, 53.2% and 19.3% of samples for LEF-1, and 30.6%, 43.5% and 19.3% for CTNNB1, respectively. We found higher LEF-1 expression in GC-secreting tumours which did not differ from inactive tumours in terms of GR expression. T cell markers, as evaluated by IHC, were not associated with expression of Wnt/β-catenin pathway markers. At RNA level, tumours with high LEF-1 expression showed significant downregulation of 37 transcripts (including 8 involved in antigen presentation). High LEF-1 expression levels correlated with worse overall survival in this cohort. This was not the case for CTNNB1 and GR. Conclusion Lef-1 expression is useful as a biomarker of activated Wnt/β-catenin signalling in ACC. Wnt/β-catenin pathway activation was not associated with reduced immune cell markers in ACC but GC secretion and may be related to tumoural antigen presentation.
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Affiliation(s)
- Tanja Maier
- Department of Medicine IV, Ludwig-Maximilians-Universität (LMU) University Hospital, LMU Munich, Munich, Germany
| | - Laura-Sophie Landwehr
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University Würzburg, Würzburg, Germany
| | - Alexandra Triebig
- Department of Medicine IV, Ludwig-Maximilians-Universität (LMU) University Hospital, LMU Munich, Munich, Germany
| | - Stefan Kircher
- Institute of Pathology, University of Würzburg, Würzburg, Germany
| | - Marc P. Schauer
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University Würzburg, Würzburg, Germany
| | - Thomas Knösel
- Institute of Pathology, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
| | - Silviu Sbiera
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University Würzburg, Würzburg, Germany
| | - Paul Schwarzlmueller
- Department of Medicine IV, Ludwig-Maximilians-Universität (LMU) University Hospital, LMU Munich, Munich, Germany
| | - Petra Zimmermann
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
| | - Martin Reincke
- Department of Medicine IV, Ludwig-Maximilians-Universität (LMU) University Hospital, LMU Munich, Munich, Germany
| | - Isabel Weigand
- Department of Medicine IV, Ludwig-Maximilians-Universität (LMU) University Hospital, LMU Munich, Munich, Germany
| | - Martin Fassnacht
- Department of Medicine IV, Ludwig-Maximilians-Universität (LMU) University Hospital, LMU Munich, Munich, Germany
- Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany
| | - Matthias Kroiss
- Department of Medicine IV, Ludwig-Maximilians-Universität (LMU) University Hospital, LMU Munich, Munich, Germany
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University Würzburg, Würzburg, Germany
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Zeng W, Zhang R, Huang P, Chen M, Chen H, Zeng X, Liu J, Zhang J, Huang D, Lao L. Ferroptotic Neutrophils Induce Immunosuppression and Chemoresistance in Breast Cancer. Cancer Res 2025; 85:477-496. [PMID: 39531510 PMCID: PMC11786957 DOI: 10.1158/0008-5472.can-24-1941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 08/28/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Inducing ferroptosis in tumor cells is emerging as a strategy for treating malignancies that are refractory to traditional treatment modalities. However, the consequences of ferroptosis of immune cells in the tumor microenvironment need to be better understood in order to realize the potential of this approach. In this study, we discovered that neutrophils in chemoresistant breast cancer are highly sensitive to ferroptosis. Reduction of the acyltransferase MOAT1 in chemoresistance-associated neutrophils induced phospholipid reprogramming, switching the preference from monounsaturated fatty acids to polyunsaturated fatty acids, which increased their susceptibility to ferroptosis. Ferroptotic neutrophils secreted PGE2, IDO, and oxidized lipids that suppressed the proliferation and cytotoxicity of antitumor CD8+ T cells. Furthermore, neutrophil ferroptosis was closely related to a distinct subset of IL1β+CXCL3+CD4+ (Fer-CD4) T lymphocytes, which were enriched in chemoresistant tumors. Fer-CD4 T cells orchestrated neutrophil ferroptosis by modulating MOAT1 expression via IL1β/IL1R1/NF-κB signaling. Moreover, Fer-CD4 T cells secreted CXCL3, IL8, and S100A9 to replenish the neutrophil pool in the tumor microenvironment. Ferroptotic neutrophils in turn fostered Fer-CD4 T-cell differentiation. In spontaneous tumorigenesis mouse models, targeting IL1β+ CD4+ T cells or IL1R1+ neutrophils broke the cross-talk, restraining neutrophil ferroptosis, enhancing antitumor immunity, and overcoming chemoresistance. Overall, these findings uncover the role of neutrophil ferroptosis in shaping the immune landscape and propose appealing targets for restoring immunosurveillance and chemosensitivity in breast cancer. Significance: In chemoresistant breast cancer, IL1β+CXCL3+CD4+ T cells mediate neutrophil ferroptosis that suppresses antitumor immunity, indicating that interfering with this intercellular cross-talk could be an attractive strategy to reverse chemoresistance.
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Affiliation(s)
- Wenfeng Zeng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ruihua Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Penghan Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Minxia Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Houying Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xin Zeng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jiang Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jiahui Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Di Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Liyan Lao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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Ni M, Wang Y, Yang J, Ma Q, Pan W, Li Y, Xu Q, Lv H, Wang Y. IL-33 aggravates extranodal NK/T cell lymphoma aggressiveness and angiogenesis by activating the Wnt/β-catenin signaling pathway. Mol Cell Biochem 2025; 480:265-278. [PMID: 38443748 DOI: 10.1007/s11010-024-04944-y] [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: 09/15/2023] [Accepted: 01/16/2024] [Indexed: 03/07/2024]
Abstract
Extranodal NK/T cell lymphoma (ENKTCL) is an extremely aggressive form of lymphoma and lacks of specific diagnostic markers. The study intended to unearth the role of interleukin-33 (IL-33) in ENKTCL. RT-qPCR was conducted to assess mRNA levels of ENKTCL tissues and cells, while western blot assay was performed for evaluating protein levels. Plate cloning experiment and transwell assay were employed to measure aggressiveness of ENKTCL. Tube formation assay was executed to determine the angiogenesis ability. Mice ENKTCL xenograft model was designed to probe the impacts of IL-33 in vivo. IL-33 and suppression of tumorigenicity 2 receptor (ST2, receptor of IL-33) were enhanced in ENKTCL. IL-33 inhibition suppressed viability, migration, and invasion of ENKTCL cells. Moreover, IL-33 knockdown restricted angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, Wnt/β-catenin pathway associated proteins (β-catenin, c-myc, and cyclin D1) were downregulated by loss of IL-33. However, these impacts were overturned by Wnt/β-catenin signaling agonist lithium chloride (LiCl). Additionally, IL-33 silencing exerted anti-tumor effect via Wnt/β-catenin pathway in vivo. Silencing of IL-33 inhibited ENKTCL tumorigenesis and angiogenesis by inactivating Wnt/β-catenin signaling pathway. As such, IL-33 might be a prospective treatment target for ENKTCL.
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Affiliation(s)
- Mingli Ni
- Department of Oncology, The First Affiliated Hospital of Henan University of CM, Zhengzhou, 450099, Henan, China
- Medical Oncology, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471099, Henan, China
| | - Yuhui Wang
- Day Operating Room, Luoyang Central Hospital, Luoyang, 471099, Henan, China
| | - Jiezhi Yang
- Medical Oncology, Luoyang Central Hospital, Luoyang, 471099, Henan, China
| | - Qianwen Ma
- Medical Oncology, Luoyang Central Hospital, Luoyang, 471099, Henan, China
| | - Wei Pan
- Medical Oncology, Luoyang Central Hospital, Luoyang, 471099, Henan, China
| | - Yulin Li
- Medical Oncology, Luoyang Central Hospital, Luoyang, 471099, Henan, China
| | - Qian Xu
- Medical Oncology, Luoyang Central Hospital, Luoyang, 471099, Henan, China
| | - Hongqiong Lv
- Medical Oncology, Luoyang Central Hospital, Luoyang, 471099, Henan, China
| | - Yunlong Wang
- Department of Oncology, The First Affiliated Hospital of Henan University of CM, Zhengzhou, 450099, Henan, China.
- Henan Bioengineering Research Center, No. 81, Zhengshang Road, Zhengzhou, 450066, Henan, China.
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Salesse L, Duval A, Sauvanet P, Da Silva A, Barnich N, Godfraind C, Dalmasso G, Nguyen HTT. ATG16L1 in myeloid cells limits colorectal tumor growth in ApcMin/+ mice infected with colibactin-producing Escherichia coli via decreasing inflammasome activation. Autophagy 2024; 20:2186-2204. [PMID: 38818900 PMCID: PMC11423662 DOI: 10.1080/15548627.2024.2359770] [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: 11/06/2023] [Revised: 05/12/2024] [Accepted: 05/21/2024] [Indexed: 06/01/2024] Open
Abstract
Escherichia coli strains producing the genotoxin colibactin, designated as CoPEC (colibactin-producing E. coli), have emerged as an important player in the etiology of colorectal cancer (CRC). Here, we investigated the role of macroautophagy/autophagy in myeloid cells, an important component of the tumor microenvironment, in the tumorigenesis of a susceptible mouse model infected with CoPEC. For that, a preclinical mouse model of CRC, the ApcMin/+ mice, with Atg16l1 deficiency specifically in myeloid cells (ApcMin/+/Atg16l1[∆MC]) and the corresponding control mice (ApcMin/+), were infected with a clinical CoPEC strain 11G5 or its isogenic mutant 11G5∆clbQ that does not produce colibactin. We showed that myeloid cell-specific Atg16l1 deficiency led to an increase in the volume of colonic tumors in ApcMin/+ mice under infection with 11G5, but not with 11G5∆clbQ. This was accompanied by increased colonocyte proliferation, enhanced inflammasome activation and IL1B/IL-1β secretion, increased neutrophil number and decreased total T cell and cytotoxic CD8+ T cell numbers in the colonic mucosa and tumors. In bone marrow-derived macrophages (BMDMs), compared to uninfected and 11G5∆clbQ-infected conditions, 11G5 infection increased inflammasome activation and IL1B secretion, and this was further enhanced by autophagy deficiency. These data indicate that ATG16L1 in myeloid cells was necessary to inhibit colonic tumor growth in CoPEC-infected ApcMin/+ mice via inhibiting colibactin-induced inflammasome activation and modulating immune cell response in the tumor microenvironment. Abbreviation: AOM, azoxymethane; APC, APC regulator of WNT signaling pathway; ATG, autophagy related; Atg16l1[∆MC] mice, mice deficient for Atg16l1 specifically in myeloid cells; CASP1, caspase 1; BMDM, bone marrow-derived macrophage; CFU, colony-forming unit; CoPEC, colibactin-producing Escherichia coli; CRC, colorectal cancer; CXCL1/KC, C-X-C motif chemokine ligand 1; ELISA, enzyme-linked immunosorbent assay; IL, interleukin; MC, myeloid cell; MOI, multiplicity of infection; PBS, phosphate-buffered saline; pks, polyketide synthase; qRT-PCR, quantitative real-time reverse-transcription polymerase chain reaction; siRNA, small interfering RNA; TME, tumor microenvironment; TNF/TNF-α, tumor necrosis factor.
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Affiliation(s)
- Laurène Salesse
- M2iSH, UMR 1071 Inserm, University of Clermont Auvergne, INRAE USC 1382, CRNH, Clermont-Ferrand, France
| | - Angéline Duval
- M2iSH, UMR 1071 Inserm, University of Clermont Auvergne, INRAE USC 1382, CRNH, Clermont-Ferrand, France
| | - Pierre Sauvanet
- M2iSH, UMR 1071 Inserm, University of Clermont Auvergne, INRAE USC 1382, CRNH, Clermont-Ferrand, France
- Department of Digestive and Hepatobiliary Surgery, CHU, Clermont-Ferrand, France
| | - Alison Da Silva
- M2iSH, UMR 1071 Inserm, University of Clermont Auvergne, INRAE USC 1382, CRNH, Clermont-Ferrand, France
| | - Nicolas Barnich
- M2iSH, UMR 1071 Inserm, University of Clermont Auvergne, INRAE USC 1382, CRNH, Clermont-Ferrand, France
| | - Catherine Godfraind
- M2iSH, UMR 1071 Inserm, University of Clermont Auvergne, INRAE USC 1382, CRNH, Clermont-Ferrand, France
- Department of Pathology, CHU Gabriel Montpied, Clermont-Ferrand, France
| | - Guillaume Dalmasso
- M2iSH, UMR 1071 Inserm, University of Clermont Auvergne, INRAE USC 1382, CRNH, Clermont-Ferrand, France
| | - Hang Thi Thu Nguyen
- M2iSH, UMR 1071 Inserm, University of Clermont Auvergne, INRAE USC 1382, CRNH, Clermont-Ferrand, France
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12
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Ruan C, Zhang Y, Chen D, Zhu M, Yang P, Zhang R, Li Y. Novel Oncogenic Value of C10orf90 in Colon Cancer Identified as a Clinical Diagnostic and Prognostic Marker. Int J Mol Sci 2024; 25:10496. [PMID: 39408824 PMCID: PMC11476934 DOI: 10.3390/ijms251910496] [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: 07/20/2024] [Revised: 09/21/2024] [Accepted: 09/22/2024] [Indexed: 10/20/2024] Open
Abstract
C10orf90, a tumor suppressor, can inhibit the occurrence and development of tumors. Therefore, we investigated the gene function of C10orf90 in various tumors using multiple pan-cancer datasets. Pan-cancer analysis results reveal that the expression levels of C10orf90 vary across different tumors and hold significant value in the clinical diagnosis and prognosis of patients with various tumors. In some cancers, the expression level of C10orf90 is correlated with CNV, DNA methylation, immune subtypes, immune cell infiltration, and drug sensitivity in the tumors. In particular, in COAD, the C10orf90 gene is implicated in multiple processes associated with COAD. Cell experiments demonstrate that C10orf90 suppresses the proliferation and migration of colon cancer cells while promoting apoptosis. In summary, C10orf90 plays a role in the onset and progression of various cancers and could potentially serve as an effective diagnostic and prognostic marker for cancer patients. Notably, in COAD, C10orf90 inhibits the proliferation and migration of colon cancer cells, induces apoptosis, and is linked to the advancement of colon cancer.
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Affiliation(s)
| | | | | | | | | | - Rongxin Zhang
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China; (C.R.); (Y.Z.); (D.C.); (M.Z.); (P.Y.)
| | - Yan Li
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China; (C.R.); (Y.Z.); (D.C.); (M.Z.); (P.Y.)
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13
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Zielinska Z, Oldak L, Guszcz T, Hermanowicz A, Gorodkiewicz E. SPRi Biosensor for Simultaneous Determination of HIF-1α, Angiopoietin-2, and Interleukin-1β in Blood Plasma. SENSORS (BASEL, SWITZERLAND) 2024; 24:5481. [PMID: 39275392 PMCID: PMC11397757 DOI: 10.3390/s24175481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/17/2024] [Accepted: 08/22/2024] [Indexed: 09/16/2024]
Abstract
A new analytical method, based on SPRi biosensors, has been developed for the simultaneous determination of the pro-angiogenic factors HIF-1α, angiopoietin-2 (ANG-2), and interleukin-1β (IL-1β) in biological fluids. These proteins take part in the process of angiogenesis, i.e., the creation of new blood vessels, which is a key stage of cancer development and metastasis. A separate validation process was carried out for each individual compound, indicating that the method can also be used to study one selected protein. Low values of the limit of detection (LOD) and quantification (LOQ) indicate that the developed method enables the determination of very low concentrations, in the order of pg/mL. The LOD values obtained for HIF-1α, ANG-2, and IL-1β were 0.09, 0.01, and 0.01 pg/mL, respectively. The LOQ values were 0.27, 0.039, and 0.02 pg/mL, and the response ranges of the biosensor were 5.00-100.00, 1.00-20.00, and 1.00-15.00 pg/mL. Moreover, determining the appropriate validation parameters confirmed that the design offers high precision, accuracy, and sensitivity. To prove the usefulness of the biosensor in practice, determinations were made in plasma samples from a control group and from a study group consisting of patients with diagnosed bladder cancer. The preliminary results obtained indicate that this biosensor can be used for broader analyses of bladder cancer. Each of the potential biomarkers, HIF-1α, ANG-2, and IL-1β, produced higher concentrations in the study group than in the control group. These are preliminary studies that serve to develop hypotheses, and their confirmation requires the analysis of a larger number of samples. However, the constructed biosensor is characterized by its ease and speed of measurement, and the method does not require special preparation of samples. SPRi biosensors can be used as a sensitive and highly selective method for determining potential blood biomarkers, which in the future may become part of the routine diagnosis of cancers.
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Affiliation(s)
- Zuzanna Zielinska
- Bioanalysis Laboratory, Doctoral School of Exact and Natural Science, Faculty of Chemistry, University of Bialystok, Ciolkowskiego 1K, 15-245 Bialystok, Poland;
| | - Lukasz Oldak
- Bioanalysis Laboratory, Faculty of Chemistry, University of Bialystok, Ciolkowskiego 1K, 15-245 Bialystok, Poland; (L.O.); (E.G.)
| | - Tomasz Guszcz
- Department of Urology, Hospital of Ministry of Interior and Administration in Bialystok, Fabryczna 27, 15-471 Bialystok, Poland;
| | - Adam Hermanowicz
- Pediatric Surgery Department, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Ewa Gorodkiewicz
- Bioanalysis Laboratory, Faculty of Chemistry, University of Bialystok, Ciolkowskiego 1K, 15-245 Bialystok, Poland; (L.O.); (E.G.)
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14
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Zhang Z, Chen Y, Pan X, Li P, Ren Z, Wang X, Chen Y, Shen S, Wang T, Lin A. IL-1β mediates Candida tropicalis-induced immunosuppressive function of MDSCs to foster colorectal cancer. Cell Commun Signal 2024; 22:408. [PMID: 39164774 PMCID: PMC11337875 DOI: 10.1186/s12964-024-01771-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 07/29/2024] [Indexed: 08/22/2024] Open
Abstract
BACKGROUND There is increasing evidence that gut fungi dysbiosis plays a crucial role in the development and progression of colorectal cancer (CRC). It has been reported that gut fungi exacerbate the severity of CRC by regulating tumor immunity. Our previous studies have shown that the opportunistic pathogenic fungal pathogen, Candida tropicalis (C. tropicalis) promotes CRC progression by enhancing the immunosuppressive function of MDSCs and activating the NLRP3 inflammasome of MDSCs. However, the relationship between IL-1β produced by NLRP3 inflammasome activation and the immunosuppressive function of MDSCs enhanced by C. tropicalis in CRC remains unclear. METHODS The TCGA database was used to analyze the relationship between IL-1β and genes related to immunosuppressive function of MDSCs in human CRC. The expression of IL-1β in human CRC tissues was detected by immunofluorescence staining. The proteomic analysis was performed on the culture supernatant of C. tropicalis-stimulated MDSCs. The experiments of supplementing and blocking IL-1β as well as inhibiting the NLRP3 inflammasome activation were conducted. A mouse colon cancer xenograft model was established by using MC38 colon cancer cell line. RESULTS Analysis of CRC clinical samples showed that the high expression of IL-1β was closely related to the immunosuppressive function of tumor-infiltrated MDSCs. The results of in vitro experiments revealed that IL-1β was the most secreted cytokine of MDSCs stimulated by C. tropicalis. In vitro supplementation of IL-1β further enhanced the immunosuppressive function of C. tropicalis-stimulated MDSCs and NLRP3-IL-1β axis mediated the immunosuppressive function of MDSCs enhanced by C. tropicalis. Finally, blockade of IL-1β secreted by MDSCs augmented antitumor immunity and mitigated C. tropicalis-associated colon cancer. CONCLUSIONS C. tropicalis promotes excessive secretion of IL-1β from MDSCs via the NLRP3 inflammasome. IL-1β further enhances the immunosuppressive function of MDSCs to inhibit antitumor immunity, thus promoting the progression of CRC. Therefore, targeting IL-1β secreted by MDSCs may be a potential immunotherapeutic strategy for the treatment of CRC.
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Affiliation(s)
- Zhiyong Zhang
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Ying Chen
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Xinyi Pan
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Pengfei Li
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Zhengqian Ren
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Xiuzhu Wang
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Yuxi Chen
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Sunan Shen
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
| | - Tingting Wang
- The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
| | - Aihua Lin
- Department of Critical Care Medicine, Sucheng District, Suqian Hospital of Nanjing Drum Tower Hospital Group, 138 Huanghe South Road, Suqian City, China.
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15
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Liu H, Huang M, Xin D, Wang H, Yu H, Pu W. Natural products with anti-tumorigenesis potential targeting macrophage. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 131:155794. [PMID: 38875811 DOI: 10.1016/j.phymed.2024.155794] [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: 04/07/2024] [Revised: 05/06/2024] [Accepted: 05/30/2024] [Indexed: 06/16/2024]
Abstract
BACKGROUND Inflammation is a risk factor for tumorigenesis. Macrophage, a subset of immune cells with high plasticity, plays a multifaceted role in this process. Natural products, which are bioactive compounds derived from traditional herbs or foods, have exhibited diverse effects on macrophages and tumorigenesis making them a valuable resource of drug discovery or optimization in tumor prevention. PURPOSE Provide a comprehensive overview of the various roles of macrophages in tumorigenesis, as well as the effects of natural products on tumorigenesis by modulating macrophage function. METHODS A thorough literature search spanning the past two decades was carried out using PubMed, Web of Science, Elsevier, and CNKI following the PRISMA guidelines. The search terms employed included "macrophage and tumorigenesis", "natural products, macrophages and tumorigenesis", "traditional Chinese medicine and tumorigenesis", "natural products and macrophage polarization", "macrophage and tumor related microenvironment", "macrophage and tumor signal pathway", "toxicity of natural products" and combinations thereof. Furthermore, certain articles are identified through the tracking of citations from other publications or by accessing the websites of relevant journals. Studies that meet the following criteria are excluded: (1) Articles not written in English or Chinese; (2) Full texts were not available; (3) Duplicate articles and irrelevant studies. The data collected was organized and summarized based on molecular mechanisms or compound structure. RESULTS This review elucidates the multifaceted effect of macrophages on tumorigenesis, encompassing process such as inflammation, angiogenesis, and tumor cell invasion by regulating metabolism, non-coding RNA, signal transduction and intercellular crosstalk. Natural products, including vitexin, ovatodiolide, ligustilide, and emodin, as well as herbal remedies, have demonstrated efficacy in modulating macrophage function, thereby attenuating tumorigenesis. These interventions mainly focus on mitigating the initial inflammatory response or modifying the inflammatory environment within the precancerous niche. CONCLUSIONS These mechanistic insights of macrophages in tumorigenesis offer valuable ideas for researchers. The identified natural products facilitate the selection of promising candidates for future cancer drug development.
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Affiliation(s)
- Hao Liu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Manru Huang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Dandan Xin
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Hong Wang
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
| | - Haiyang Yu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, PR China.
| | - Weiling Pu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
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16
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Pereira F, Fernández-Barral A, Larriba MJ, Barbáchano A, González-Sancho JM. From molecular basis to clinical insights: a challenging future for the vitamin D endocrine system in colorectal cancer. FEBS J 2024; 291:2485-2518. [PMID: 37699548 DOI: 10.1111/febs.16955] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/03/2023] [Accepted: 09/11/2023] [Indexed: 09/14/2023]
Abstract
Colorectal cancer (CRC) is one of the most life-threatening neoplasias in terms of incidence and mortality worldwide. Vitamin D deficiency has been associated with an increased risk of CRC. 1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the most active vitamin D metabolite, is a pleiotropic hormone that, through its binding to a transcription factor of the nuclear receptor superfamily, is a major regulator of the human genome. 1,25(OH)2D3 acts on colon carcinoma and stromal cells and displays tumor protective actions. Here, we review the variety of molecular mechanisms underlying the effects of 1,25(OH)2D3 in CRC, which affect multiple processes that are dysregulated during tumor initiation and progression. Additionally, we discuss the epidemiological data that associate vitamin D deficiency and CRC, and the most relevant randomized controlled trials of vitamin D3 supplementation conducted in both healthy individuals and CRC patients.
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Affiliation(s)
- Fábio Pereira
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Servicio de Oncología Radioterápica, Complejo Hospitalario Universitario de Ourense, Spain
| | - Asunción Fernández-Barral
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - María Jesús Larriba
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - Antonio Barbáchano
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - José Manuel González-Sancho
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain
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Liang J, Yu M, Li Y, Zhao L, Wei Q. Glycogen synthase kinase-3: A potential immunotherapeutic target in tumor microenvironment. Biomed Pharmacother 2024; 173:116377. [PMID: 38442671 DOI: 10.1016/j.biopha.2024.116377] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 02/23/2024] [Accepted: 02/29/2024] [Indexed: 03/07/2024] Open
Abstract
Glycogen synthase kinase-3(GSK-3) is a protein kinase that can phosphorylate over a hundred substrates and regulate cell differentiation, proliferation, and death. Researchers have acknowledged the pivotal role of abnormal activation of GSK-3 in the progression of various diseases over the past few decades. Recent studies have mostly concentrated on investigating the function of GSK-3 in the tumor microenvironment, specifically examining the interaction between TAM, NK cells, B cells, and T cells. Furthermore, GSK-3 exhibits a strong association with immunological checkpoints, such as programmed cell death protein 1. Novel GSK-3 inhibitors have potential in tumor immunotherapy, exerting beneficial effects on hematologic diseases and solid tumors. Nevertheless, there is a lack of reviews about the correlation between tumor-associated immune cells and GSK-3. This study intends to analyze the function and mechanism of GSK-3 comprehensively and systematically in the tumor microenvironment, with a special focus on its influence on various immune cells. The objective is to present novel perspectives for GSK-3 immunotherapy.
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Affiliation(s)
- Jingyi Liang
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China; Liaoning Province, China Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province 110122, China.
| | - Meng Yu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China.
| | - Yunong Li
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China; Liaoning Province, China Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province 110122, China.
| | - Lin Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China; Liaoning Province, China Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province 110122, China.
| | - Qian Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China; Liaoning Province, China Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, Liaoning Province 110122, China.
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18
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Al lami Z, Kurtca M, Atique MU, Opekun AR, Siam MS, Jalal PK, Najafi B, Devaraj S, Mindikoglu AL. Dawn-to-dusk dry fasting decreases circulating inflammatory cytokines in subjects with increased body mass index. Metabol Open 2024; 21:100274. [PMID: 38455231 PMCID: PMC10918425 DOI: 10.1016/j.metop.2024.100274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 02/04/2024] [Accepted: 02/06/2024] [Indexed: 03/09/2024] Open
Abstract
BACKGROUND The circadian rhythm involves numerous metabolic processes, including sleep/awakening, body temperature regulation, hormone secretion, hepatic function, cellular plasticity, and cytokine release (inflammation), that appear to have a dynamic relationship with all the processes above. Studies have linked various cytokines to the chronic state of low-grade inflammation and oxidative stress in obesity. Dawn-to-dusk dry fasting (DDDF) could alleviate the adverse effects of obesity by decreasing inflammation. This study examined the effects of DDDF on circulating inflammatory cytokines in subjects with increased body mass index (BMI). METHODS The current observational prospective study included adult subjects with a BMI equal to or greater than 25 kg/m2 who practiced the annual religious 30-day DDDF. Individuals with significant underlying medical conditions were excluded to limit confounding factors. All subjects were evaluated within two weeks before 30-day DDDF, within the fourth week of 30-day DDDF, and within two weeks after 30-day DDDF. Multiple cytokines and clinical health indicators were measured at each evaluation. RESULTS Thirteen subjects (10 men and three women) with a mean age of 32.9 years (SD = 9.7 years) and a mean BMI of 32 kg/m2 (SD = 4.6 kg/m2) were included. An overall associated decrease in the levels of multiple cytokines with DDDF was observed. A significant decrease in the mean interleukin 1 beta level was observed within the fourth week of 30-day DDDF (P = 0.045), which persisted even after the fasting period (P = 0.024). There was also a significant decrease in the mean levels of interleukin 15 (IL-15) (P = 0.014), interleukin 1 receptor antagonist (P = 0.041), macrophage-derived chemokine (MDC) (P = 0.013), and monokine induced by interferon gamma/chemokine (C-X-C motif) ligand 9 (P = 0.027) within the fourth week of 30-day DDDF and in the mean levels of fibroblast growth factor 2 (P = 0.010), interleukin 12 p40 subunit (P = 0.038), interleukin 22 (P = 0.025) and tumor necrosis factor alpha (P = 0.046) within two weeks after 30-DDDF. In terms of anthropometric parameters, there was a decrease in mean body weight (P = 0.032), BMI (P = 0.028), and hip circumference (P = 0.007) within the fourth week of 30-day DDDF and a decrease in mean weight (P = 0.026), BMI (P = 0.033) and hip circumference (P = 0.016) within two weeks after 30-day DDDF compared with the levels measured within two weeks before 30-day DDDF. Although there was no significant correlation between changes in weight and changes in circulating inflammatory cytokines, there was a significant positive correlation between changes in waist circumference and changes in specific inflammatory cytokines (e.g., IL-15, MDC, platelet-derived growth factor, soluble CD40L, vascular endothelial growth factor A) within the fourth week of 30-day DDDF and/or two weeks after 30-day DDDF. A significant decrease in mean average resting heart rate within the fourth week of 30-day DDDF was also observed (P = 0.023), and changes between average resting heart rate and changes in interleukin-8 levels within the fourth week of 30-day DDDF compared with baseline levels were positively correlated (r = 0.57, P = 0.042). CONCLUSION DDDF appears to be a unique and potent treatment to reduce low-grade chronic inflammation caused by obesity and visceral adiposity. Further studies with more extended follow-up periods are warranted to investigate the long-term anti-inflammatory benefits of DDDF in individuals with increased BMI.
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Affiliation(s)
- Zahraa Al lami
- Margaret M. and Albert B. Alkek Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
| | - Miray Kurtca
- Clinical Chemistry and Point of Care Technology, Texas Children's Hospital and Health Centers, Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Moin Uddin Atique
- Interdisciplinary Consortium on Advanced Motion Performance (iCAMP), Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Antone R. Opekun
- Margaret M. and Albert B. Alkek Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
- Department of Pediatrics, Division of Gastroenterology, Nutrition and Hepatology, Baylor College of Medicine, Houston, TX, USA
| | - Mohamad S. Siam
- Margaret M. and Albert B. Alkek Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
| | - Prasun K. Jalal
- Margaret M. and Albert B. Alkek Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
- Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA
| | - Bijan Najafi
- Interdisciplinary Consortium on Advanced Motion Performance (iCAMP), Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Sridevi Devaraj
- Clinical Chemistry and Point of Care Technology, Texas Children's Hospital and Health Centers, Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Ayse L. Mindikoglu
- Margaret M. and Albert B. Alkek Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
- Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA
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Shirley CA, Chhabra G, Amiri D, Chang H, Ahmad N. Immune escape and metastasis mechanisms in melanoma: breaking down the dichotomy. Front Immunol 2024; 15:1336023. [PMID: 38426087 PMCID: PMC10902921 DOI: 10.3389/fimmu.2024.1336023] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 01/24/2024] [Indexed: 03/02/2024] Open
Abstract
Melanoma is one of the most lethal neoplasms of the skin. Despite the revolutionary introduction of immune checkpoint inhibitors, metastatic spread, and recurrence remain critical problems in resistant cases. Melanoma employs a multitude of mechanisms to subvert the immune system and successfully metastasize to distant organs. Concerningly, recent research also shows that tumor cells can disseminate early during melanoma progression and enter dormant states, eventually leading to metastases at a future time. Immune escape and metastasis have previously been viewed as separate phenomena; however, accumulating evidence is breaking down this dichotomy. Recent research into the progressive mechanisms of melanoma provides evidence that dedifferentiation similar to classical epithelial to mesenchymal transition (EMT), genes involved in neural crest stem cell maintenance, and hypoxia/acidosis, are important factors simultaneously involved in immune escape and metastasis. The likeness between EMT and early dissemination, and differences, also become apparent in these contexts. Detailed knowledge of the mechanisms behind "dual drivers" simultaneously promoting metastatically inclined and immunosuppressive environments can yield novel strategies effective in disabling multiple facets of melanoma progression. Furthermore, understanding progression through these drivers may provide insight towards novel treatments capable of preventing recurrence arising from dormant dissemination or improving immunotherapy outcomes.
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Affiliation(s)
- Carl A. Shirley
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Gagan Chhabra
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Deeba Amiri
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Hao Chang
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
- William S. Middleton Memorial Veterans Hospital, Madison, WI, United States
| | - Nihal Ahmad
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
- William S. Middleton Memorial Veterans Hospital, Madison, WI, United States
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20
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Bird RP. Vitamin D and cancer. ADVANCES IN FOOD AND NUTRITION RESEARCH 2024; 109:92-159. [PMID: 38777419 DOI: 10.1016/bs.afnr.2023.12.002] [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: 05/25/2024]
Abstract
The role of vitamin D in the prevention of chronic diseases including cancer, has received a great deal of attention during the past few decades. The term "Cancer" represents multiple disease states with varying biological complexities. The strongest link between vitamin D and cancer is provided by ecological and studies like observational, in preclinical models. It is apparent that vitamin D exerts diverse biological responses in a tissue specific manner. Moreover, several human factors could affect bioactivity of vitamin D. The mechanism(s) underlying vitamin D initiated anti-carcinogenic effects are diverse and includes changes at the muti-system levels. The oncogenic environment could easily corrupt the traditional role of vitamin D or could ensure resistance to vitamin D mediated responses. Several researchers have identified gaps in our knowledge pertaining to the role of vitamin D in cancer. Further areas are identified to solidify the role of vitamin D in cancer control strategies.
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Affiliation(s)
- Ranjana P Bird
- School of Health Sciences, University of Northern British Columbia, Prince George, BC, Canada.
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21
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Che N, Li M, Liu X, Cui CA, Gong J, Xuan Y. Macelignan prevents colorectal cancer metastasis by inhibiting M2 macrophage polarization. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 122:155144. [PMID: 37925889 DOI: 10.1016/j.phymed.2023.155144] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 09/23/2023] [Accepted: 10/12/2023] [Indexed: 11/07/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) metastasis is a complicated process that not only involves tumor cells but also the effects of M2 type tumor-associated macrophages, a key component of the tumor microenvironment (TME), act a crucial role in cancer metastasis. Macelignan, an orally active lignan isolated from Myristica fragrans, possesses various beneficial biological activities, including anti-cancer effects, but its effect on macrophage polarization in the TME remains unknown. PURPOSE To evaluate the inhibitory potency and prospective mechanism of macelignan on M2 polarization of macrophages and CRC metastasis. METHODS The polarization and specific mechanism of M1 and M2 macrophage regulated by macelignan were determined by western blot, flow cytometry, immunofluorescence and network pharmacology. In vitro and in vivo function assays were performed to investigate the roles of macelignan in CRC metastasis. RESULTS Macelignan efficiently inhibited IL-4/13-induced polarization of M2 macrophages by suppressing the PI3K/AKT pathway in a reactive oxygen species (ROS)-dependent manner. The proportion of CD206+ M2 macrophages was elevated in patients with CRC liver metastasis. Furthermore, macelignan inhibited M2 macrophage-mediated metastasis of CRC cells in vitro and in vivo. Mechanistically, macelignan reduced secretion of IL-1β from M2 macrophages, which in turn blocked NF-κB p65 nuclear translocation and inhibited metastasis. CONCLUSION Macelignan suppressed macrophage M2 polarization via ROS-mediated PI3K/AKT signaling pathway, thus preventing IL-1β/NF-κB-dependent CRC metastasis. In the present study, we reveal a previously unrecognized mechanism of macelignan in the prevention of CRC metastasis and demonstrate its effectively and safely therapeutic potential in CRC treatment.
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Affiliation(s)
- Nan Che
- Institute of Regenerative Medicine, Yanbian University College of Medicine, Yanji, China
| | - Mengxuan Li
- Institute of Regenerative Medicine, Yanbian University College of Medicine, Yanji, China
| | - Xingzhe Liu
- Institute of Regenerative Medicine, Yanbian University College of Medicine, Yanji, China; Department of Pathology, Yanbian University College of Medicine, Yanji, China
| | - Chun-Ai Cui
- Department of Pathology, Yanbian University College of Medicine, Yanji, China
| | - Jie Gong
- Institute of Regenerative Medicine, Yanbian University College of Medicine, Yanji, China; Department of Pathology, Yanbian University College of Medicine, Yanji, China
| | - Yanhua Xuan
- Institute of Regenerative Medicine, Yanbian University College of Medicine, Yanji, China; Department of Pathology, Yanbian University College of Medicine, Yanji, China.
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22
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Ferrer-Mayorga G, Muñoz A, González-Sancho JM. Vitamin D and colorectal cancer. FELDMAN AND PIKE'S VITAMIN D 2024:859-899. [DOI: 10.1016/b978-0-323-91338-6.00039-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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23
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Kaczmarek K, Więckiewicz J, Que I, Gałuszka-Bulaga A, Chan A, Siedlar M, Baran J. Human Soluble TRAIL Secreted by Modified Lactococcus lactis Bacteria Promotes Tumor Growth in the Orthotopic Mouse Model of Colorectal Cancer. Arch Immunol Ther Exp (Warsz) 2024; 72:aite-2024-0002. [PMID: 38299562 DOI: 10.2478/aite-2024-0002] [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: 07/05/2023] [Accepted: 11/30/2023] [Indexed: 02/02/2024]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of sensitive cancer cells, including colorectal cancer (CRC). Due to its short biological half-life after intravenous administration and related clinical ineffectiveness, novel formulations of TRAIL need to be developed. Here we propose Lactococcus lactis bacteria as a vehicle for local delivery of human soluble TRAIL (hsTRAIL) in CRC. The use of common probiotics targeting guts as carriers for TRAIL could ensure its sustained release at the tumor site and extend the duration of its activity. We have already engineered hsTRAIL-secreting L.lactis bacteria and showed their effectiveness in elimination of human CRC cells in vitro and in vivo in a mouse subcutaneous model. Here, L.lactis(hsTRAIL+) were administered by gastric gavage to SCID mice with orthotopically developed HCT116 tumor in cecum, in monotherapy or in combination with metformin (MetF), already shown to enhance the hsTRAIL anti-tumor activity in subcutaneous CRC model. Oral administration of L.lactis(hsTRAIL+) resulted in significant progression of HCT116 tumors and shortening of the colon crypts. Secretion of hsTRAIL in the colon was accompanied by infiltration of the primary tumor with M2-macrophages, while MetF promoted transient colonization of the gut by L.lactis. Our study indicates that L.lactis bacteria after oral administration enable delivery of biologically active hsTRAIL to colon, however its potential therapeutic effect in CRC treatment is abolished by its pro-tumorigenic signalling, leading to the recruitment of M2-macrophages and tumor growth promotion.
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Affiliation(s)
- Katarzyna Kaczmarek
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Kraków, Poland
| | - Jerzy Więckiewicz
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Kraków, Poland
| | - Ivo Que
- Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands
- Currently: Department of Radiology and Nuclear Medicine, Department of Molecular Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
| | - Adrianna Gałuszka-Bulaga
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Kraków, Poland
| | - Alan Chan
- Percuros B.V., Zernikedreef 8, 2333 CL Leiden, The Netherlands
| | - Maciej Siedlar
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Kraków, Poland
| | - Jarek Baran
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Kraków, Poland
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24
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Su JY, Wang Y, Wu SS, Li WK, Wang CY, Ma JY, Qiu YT, Zhou MS, Wang Z, Li P, Liu CT, Wu J. Association between new plasma inflammatory markers and risk of colorectal neoplasms in individuals over 50 years old. Carcinogenesis 2023; 44:824-836. [PMID: 37713476 DOI: 10.1093/carcin/bgad064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 07/02/2023] [Accepted: 09/14/2023] [Indexed: 09/17/2023] Open
Abstract
OBJECTIVE(S) The prognostic value of systemic cytokine profiles and inflammatory markers in colorectal cancer were explored by several studies. We want to know more about inflammatory biomarkers in colorectal adenoma and early cancer. METHOD The level of 38 inflammatory markers in the plasma of 112 adenoma patients, 72 Tis-T1 staging of colorectal carcinoma patients, 34 T2-T4 staging of colorectal carcinoma patients and 53 normal subjects were detected and compared. RESULT(S) Eight inflammatory biomarkers (Eotaxin, GCSF, IL-4, IL-5, IL-17E, MCP-1, TNF-α and VEGF-A) have higher plasma concentrations in colorectal adenoma and cancer patients compared with normal participants over 50 years old. CONCLUSION(S) Inflammatory markers may have the prognostic value for colorectal adenoma and early-stage carcinoma.
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Affiliation(s)
- Jia-Yi Su
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
- Beijing Digestive Disease Center, Beijing 100050, China
| | - Yun Wang
- Department of Presbyatrics, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Shang-Shang Wu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
- Beijing Digestive Disease Center, Beijing 100050, China
- Department of Clinical Epidemiology and Evidence-based Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Wen-Kun Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
- Beijing Digestive Disease Center, Beijing 100050, China
| | - Cheng-Yao Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
- Beijing Digestive Disease Center, Beijing 100050, China
| | - Jiu-Yue Ma
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
- Beijing Digestive Disease Center, Beijing 100050, China
| | - Yu-Ting Qiu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
- Beijing Digestive Disease Center, Beijing 100050, China
| | - Min-Si Zhou
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
- Beijing Digestive Disease Center, Beijing 100050, China
| | - Zhan Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
- Beijing Digestive Disease Center, Beijing 100050, China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
- Beijing Digestive Disease Center, Beijing 100050, China
| | - Chun-Tao Liu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
- Beijing Digestive Disease Center, Beijing 100050, China
| | - Jing Wu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
- Beijing Digestive Disease Center, Beijing 100050, China
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Florescu DN, Boldeanu MV, Șerban RE, Florescu LM, Serbanescu MS, Ionescu M, Streba L, Constantin C, Vere CC. Correlation of the Pro-Inflammatory Cytokines IL-1β, IL-6, and TNF-α, Inflammatory Markers, and Tumor Markers with the Diagnosis and Prognosis of Colorectal Cancer. Life (Basel) 2023; 13:2261. [PMID: 38137862 PMCID: PMC10744550 DOI: 10.3390/life13122261] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/19/2023] [Accepted: 11/25/2023] [Indexed: 12/24/2023] Open
Abstract
Colorectal cancer (CRC) remains one of the most important global health problems, being in the top 3 neoplasms in terms of the number of cases worldwide. Although CRC develops predominantly from the adenoma-adenocarcinoma sequence through APC gene mutations, in recent years, studies have demonstrated the role of chronic inflammation in this neoplasia pathogenesis. Cytokines are important components of chronic inflammation, being some of the host regulators in response to inflammation. The pro-inflammatory cytokines IL-1β, IL-6, and TNF-α are involved in tumor cell proliferation, angiogenesis, and metastasis and seem to strengthen each other's mode of action, these being stimulated by the same mediators. In our study, we collected data on 68 patients with CRC and 20 healthy patients from the Gastroenterology Department of Craiova County Emergency Clinical Hospital, who were assessed between January 2022 and February 2023. The main purpose of this study was to investigate the correlation between increased plasma levels of the cytokines and the extent of the tumor, lymph nodes, and metastasis-(TNM stage), as well as the patients' prognoses. We also compared the plasma levels of cytokines and acute inflammatory markers, namely, the erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), and fibrinogen, along with the tumor markers, carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA 19.9), in CRC patients. We showed that all the pro-inflammatory cytokines studied had higher levels in patients with CRC in comparison with the control group. We also showed that the acute inflammatory markers of erythrocyte sedimentation rate, C-reactive protein, and fibrinogen, and the tumor markers of CEA and CA 19.9 can be useful in diagnosis and prognosis in patients with CRC. Considering the association between pro-inflammatory cytokines and CRC, the development of new targeted therapies against IL-1β, IL-6, and TNF-α can improve patient care and the CRC survival rate.
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Affiliation(s)
- Dan Nicolae Florescu
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.N.F.); (C.C.V.)
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania
| | - Mihail-Virgil Boldeanu
- Department of Immunology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Robert-Emmanuel Șerban
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.N.F.); (C.C.V.)
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania
| | - Lucian Mihai Florescu
- Department of Radiology and Medical Imaging, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (L.M.F.); (C.C.)
| | - Mircea-Sebastian Serbanescu
- Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Mihaela Ionescu
- Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Liliana Streba
- Department of Oncology, University of Medicine and Pharmacy Craiova, 2 Petru Rares Str., 200349 Craiova, Romania;
| | - Cristian Constantin
- Department of Radiology and Medical Imaging, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (L.M.F.); (C.C.)
| | - Cristin Constantin Vere
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.N.F.); (C.C.V.)
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania
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Ballarò C, Quaranta V, Giannelli G. Colorectal Liver Metastasis: Can Cytokines Make the Difference? Cancers (Basel) 2023; 15:5359. [PMID: 38001618 PMCID: PMC10670198 DOI: 10.3390/cancers15225359] [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: 09/08/2023] [Revised: 10/20/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. Metastasis is the prime driver of CRC-related mortality, and the liver is the organ most frequently involved. Despite the overall success of current treatments, colorectal liver metastasis (CRLM) is associated with poor prognoses and a survival rate of only 14%. Recent studies have highlighted the importance of the tumor microenvironment (TME) and the crosstalk within it in determining the invasion of distant organs by circulating cancer cells. In the TME, cellular communication is mediated via soluble molecules, among which cytokines have recently emerged as key regulators, involved in every aspect of tumor progression and the metastatic cascade. Indeed, in the serum of CRC patients elevated levels of several cytokines are associated with cancer development and progression. The current review evaluates the role of different cytokines during CRLM development. Additionally, considering the increasing amount of data concerning the importance of cytokine complex networks, we outline the potential of combination treatments using targeted cytokines together with other well-established therapies, such as immune checkpoint blockades, chemotherapy, or gene therapy, to improve therapeutic outcomes.
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Affiliation(s)
- Costanza Ballarò
- Laboratory of Molecular Medicine, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
| | - Valeria Quaranta
- Laboratory of Personalized Medicine, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy;
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy;
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Kubera M, Arteta B, Grygier B, Curzytek K, Malicki S, Maes M. Stimulatory effect of fluoxetine and desipramine, but not mirtazapine on C26 colon carcinoma hepatic metastases formation: association with cytokines. Front Immunol 2023; 14:1160977. [PMID: 37409130 PMCID: PMC10318584 DOI: 10.3389/fimmu.2023.1160977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/30/2023] [Indexed: 07/07/2023] Open
Abstract
Due to the high prevalence of depression among cancer patients, antidepressant medications are frequently administered as adjuvant treatment. However, the safety of such medications in the development of metastasis is unclear. In this study, we investigated the effects of fluoxetine, desipramine, and mirtazapine on the liver metastasis of murine C26 colon carcinoma (cc). Balb/c male mice were administered these antidepressants intraperitoneally (i.p.) for 14 days following intrasplenic injections of C26 colon carcinoma cells. Desipramine and fluoxetine, but not mirtazapine, significantly increased the number of tumor foci and total volume of the tumor in liver tissue. This effect was associated with a decrease in the ability of splenocytes to produce interleukin (IL)-1β and interferon (IFN)-γ and an increase in their ability to produce interleukin (IL)-10. Similar changes were observed in plasma IL-1β, IFN-γ, and IL-10 levels. The current study demonstrates that the stimulatory effect of desipramine and fluoxetine, but not mirtazapine, on experimental colon cancer liver metastasis is associated with a suppression of immune defenses against the tumor.
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Affiliation(s)
- Marta Kubera
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland
| | - Beatriz Arteta
- Department of Cell Biology and Histology, School of Medicine and Nursing, Tumor Microenvironment Group, Basque Country University, Leioa, Spain
| | - Beata Grygier
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland
| | - Katarzyna Curzytek
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland
| | - Stanisław Malicki
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
- IMPACT Strategic Research Centre, Deakin University, Geelong, VIC, Australia
- Kyung Hee University, Seoul, Republic of Korea
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Wilton J, de Mendonça FL, Pereira-Castro I, Tellier M, Nojima T, Costa AM, Freitas J, Murphy S, Oliveira MJ, Proudfoot NJ, Moreira A. Pro-inflammatory polarization and colorectal cancer modulate alternative and intronic polyadenylation in primary human macrophages. Front Immunol 2023; 14:1182525. [PMID: 37359548 PMCID: PMC10286830 DOI: 10.3389/fimmu.2023.1182525] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 05/09/2023] [Indexed: 06/28/2023] Open
Abstract
Introduction Macrophages are essential cells of the immune system that alter their inflammatory profile depending on their microenvironment. Alternative polyadenylation in the 3'UTR (3'UTR-APA) and intronic polyadenylation (IPA) are mechanisms that modulate gene expression, particularly in cancer and activated immune cells. Yet, how polarization and colorectal cancer (CRC) cells affect 3'UTR-APA and IPA in primary human macrophages was unclear. Methods In this study, we isolated primary human monocytes from healthy donors, differentiated and polarized them into a pro-inflammatory state and performed indirect co-cultures with CRC cells. ChrRNA-Seq and 3'RNA-Seq was performed to quantify gene expression and characterize new 3'UTR-APA and IPA mRNA isoforms. Results Our results show that polarization of human macrophages from naïve to a pro-inflammatory state causes a marked increase of proximal polyA site selection in the 3'UTR and IPA events in genes relevant to macrophage functions. Additionally, we found a negative correlation between differential gene expression and IPA during pro-inflammatory polarization of primary human macrophages. As macrophages are abundant immune cells in the CRC microenvironment that either promote or abrogate cancer progression, we investigated how indirect exposure to CRC cells affects macrophage gene expression and 3'UTR-APA and IPA events. Co-culture with CRC cells alters the inflammatory phenotype of macrophages, increases the expression of pro-tumoral genes and induces 3'UTR-APA alterations. Notably, some of these gene expression differences were also found in tumor-associated macrophages of CRC patients, indicating that they are physiologically relevant. Upon macrophage pro-inflammatory polarization, SRSF12 is the pre-mRNA processing gene that is most upregulated. After SRSF12 knockdown in M1 macrophages there is a global downregulation of gene expression, in particular in genes involved in gene expression regulation and in immune responses. Discussion Our results reveal new 3'UTR-APA and IPA mRNA isoforms produced during pro-inflammatory polarization of primary human macrophages and CRC co-culture that may be used in the future as diagnostic or therapeutic tools. Furthermore, our results highlight a function for SRSF12 in pro-inflammatory macrophages, key cells in the tumor response.
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Affiliation(s)
- Joana Wilton
- Graduate Program in Areas of Basic and Applied Biology (GABBA) PhD Program, ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
- Gene Regulation - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- IBMC-Instituto de Biologia Molecular e Celular Universidade do Porto, Porto, Portugal
| | - Filipa Lopes de Mendonça
- Gene Regulation - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- IBMC-Instituto de Biologia Molecular e Celular Universidade do Porto, Porto, Portugal
| | - Isabel Pereira-Castro
- Gene Regulation - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- IBMC-Instituto de Biologia Molecular e Celular Universidade do Porto, Porto, Portugal
| | - Michael Tellier
- Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
| | - Takayuki Nojima
- Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
| | - Angela M. Costa
- Tumour and Microenvironment Interactions Group – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB-Instituto Nacional de Engenharia Biomédica Universidade do Porto, Porto, Portugal
| | - Jaime Freitas
- Gene Regulation - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Shona Murphy
- Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
| | - Maria Jose Oliveira
- Tumour and Microenvironment Interactions Group – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB-Instituto Nacional de Engenharia Biomédica Universidade do Porto, Porto, Portugal
- Faculdade de Medicina, Universidade do Porto, Porto, Portugal
- ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | | | - Alexandra Moreira
- Gene Regulation - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- IBMC-Instituto de Biologia Molecular e Celular Universidade do Porto, Porto, Portugal
- ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
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Wu T, Zhang X, Liu X, Cai X, Shen T, Pan D, Liang R, Ding R, Hu R, Dong J, Li F, Li J, Xie L, Wang C, Geng S, Yang Z, Xing L, Li Y. Single-cell sequencing reveals the immune microenvironment landscape related to anti-PD-1 resistance in metastatic colorectal cancer with high microsatellite instability. BMC Med 2023; 21:161. [PMID: 37106440 PMCID: PMC10142806 DOI: 10.1186/s12916-023-02866-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND The objective response rate of microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) patients with first-line anti-programmed cell death protein-1 (PD-1) monotherapy is only 40-45%. Single-cell RNA sequencing (scRNA-seq) enables unbiased analysis of the full variety of cells comprising the tumor microenvironment. Thus, we used scRNA-seq to assess differences among microenvironment components between therapy-resistant and therapy-sensitive groups in MSI-H/mismatch repair-deficient (dMMR) mCRC. Resistance-related cell types and genes identified by this analysis were subsequently verified in clinical samples and mouse models to further reveal the molecular mechanism of anti-PD-1 resistance in MSI-H or dMMR mCRC. METHODS The response of primary and metastatic lesions to first-line anti-PD-1 monotherapy was evaluated by radiology. Cells from primary lesions of patients with MSI-H/dMMR mCRC were analyzed using scRNA-seq. To identify the marker genes in each cluster, distinct cell clusters were identified and subjected to subcluster analysis. Then, a protein‒protein interaction network was constructed to identify key genes. Immunohistochemistry and immunofluorescence were applied to verify key genes and cell marker molecules in clinical samples. Immunohistochemistry, quantitative real-time PCR, and western blotting were performed to examine the expression of IL-1β and MMP9. Moreover, quantitative analysis and sorting of myeloid-derived suppressor cells (MDSCs) and CD8+ T cells were performed using flow cytometry. RESULTS Tumor responses in 23 patients with MSI-H/dMMR mCRC were evaluated by radiology. The objective response rate was 43.48%, and the disease control rate was 69.57%. ScRNA-seq analysis showed that, compared with the treatment-resistant group, the treatment-sensitive group accumulated more CD8+ T cells. Experiments with both clinical samples and mice indicated that infiltration of IL-1β-driven MDSCs and inactivation of CD8+ T cells contribute to anti-PD-1 resistance in MSI-H/dMMR CRC. CONCLUSIONS CD8+ T cells and IL-1β were identified as the cell type and gene, respectively, with the highest correlation with anti-PD-1 resistance. Infiltration of IL-1β-driven MDSCs was a significant factor in anti-PD-1 resistance in CRC. IL-1β antagonists are expected to be developed as a new treatment for anti-PD-1 inhibitor resistance.
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Affiliation(s)
- Tao Wu
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, No. 519, Kunzhou Road, Xishan District, Kunming, 650118, China
| | - Xuan Zhang
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, No. 519, Kunzhou Road, Xishan District, Kunming, 650118, China
| | - Xinxing Liu
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, No. 519, Kunzhou Road, Xishan District, Kunming, 650118, China
| | - Xinyi Cai
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, No. 519, Kunzhou Road, Xishan District, Kunming, 650118, China
| | - Tao Shen
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, No. 519, Kunzhou Road, Xishan District, Kunming, 650118, China
| | - Dingguo Pan
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, No. 519, Kunzhou Road, Xishan District, Kunming, 650118, China
| | - Rui Liang
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Rong Ding
- Department of Minimally Invasive Intervention, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ruixi Hu
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, No. 519, Kunzhou Road, Xishan District, Kunming, 650118, China
| | - Jianhua Dong
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, No. 519, Kunzhou Road, Xishan District, Kunming, 650118, China
| | - Furong Li
- Department of Gastroenteroscopy, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jinsha Li
- Department of Gastroenteroscopy, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lin Xie
- Department of Oncology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chunlong Wang
- Department of Radiology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Shilei Geng
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, No. 519, Kunzhou Road, Xishan District, Kunming, 650118, China
| | - Zhaoyu Yang
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, No. 519, Kunzhou Road, Xishan District, Kunming, 650118, China
| | - Lu Xing
- Department of Dermatology, Kunming Children's Hospital, Kunming, China.
| | - YunFeng Li
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, No. 519, Kunzhou Road, Xishan District, Kunming, 650118, China.
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Wang D, Cheng C, Chen X, Wang J, Liu K, Jing N, Xu P, Xi X, Sun Y, Ji Z, Zhao H, He Y, Zhang K, Du X, Dong B, Fang Y, Zhang P, Qian X, Xue W, Gao WQ, Zhu HH. IL-1β Is an Androgen-Responsive Target in Macrophages for Immunotherapy of Prostate Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023:e2206889. [PMID: 37092583 DOI: 10.1002/advs.202206889] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 03/03/2023] [Indexed: 05/03/2023]
Abstract
Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells. However, the understanding of the role of androgen in PCa-infiltrated immune cells and the impact of androgen deprivation therapy (ADT), the first-line treatment for advanced PCa, on the PCa immune microenvironment remains limited. On the other hand, immune checkpoint blockade has revolutionized the treatment of certain cancer types, but fails to achieve any benefit in advanced PCa, due to an immune suppressive environment. In this study, it is reported that AR signaling pathway is evidently activated in tumor-associated macrophages (TAMs) of PCa both in mice and humans. AR acts as a transcriptional repressor for IL1B in TAMs. ADT releases the restraint of AR on IL1B and therefore leads to an excessive expression and secretion of IL-1β in TAMs. IL-1β induces myeloid-derived suppressor cells (MDSCs) accumulation that inhibits the activation of cytotoxic T cells, leading to the immune suppressive microenvironment. Critically, anti-IL-1β antibody coupled with ADT and the immune checkpoint inhibitor anti-PD-1 antibody exerts a stronger anticancer effect on PCa following castration. Together, IL-1β is an important androgen-responsive immunotherapeutic target for advanced PCa.
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Affiliation(s)
- Deng Wang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China
| | - Chaping Cheng
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Xinyu Chen
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Jinming Wang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Kaiyuan Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Na Jing
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China
| | - Penghui Xu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China
| | - Xialian Xi
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Yujiao Sun
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Zhongzhong Ji
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Huifang Zhao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Yuman He
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Kai Zhang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Xinxing Du
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, P. R. China
| | - Baijun Dong
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, P. R. China
| | - Yuxiang Fang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
| | - Pengcheng Zhang
- School of Biomedical Engineering, ShanghaiTech University, Shanghai, 201210, P. R. China
| | - Xueming Qian
- Mabspace Biosciences (Suzhou) Co. Limited, Suzhou, 215123, P. R. China
| | - Wei Xue
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, P. R. China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China
| | - Helen He Zhu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China
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Habanjar O, Bingula R, Decombat C, Diab-Assaf M, Caldefie-Chezet F, Delort L. Crosstalk of Inflammatory Cytokines within the Breast Tumor Microenvironment. Int J Mol Sci 2023; 24:4002. [PMID: 36835413 PMCID: PMC9964711 DOI: 10.3390/ijms24044002] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/10/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023] Open
Abstract
Several immune and immunocompetent cells, including dendritic cells, macrophages, adipocytes, natural killer cells, T cells, and B cells, are significantly correlated with the complex discipline of oncology. Cytotoxic innate and adaptive immune cells can block tumor proliferation, and others can prevent the immune system from rejecting malignant cells and provide a favorable environment for tumor progression. These cells communicate with the microenvironment through cytokines, a chemical messenger, in an endocrine, paracrine, or autocrine manner. These cytokines play an important role in health and disease, particularly in host immune responses to infection and inflammation. They include chemokines, interleukins (ILs), adipokines, interferons, colony-stimulating factors (CSFs), and tumor necrosis factor (TNF), which are produced by a wide range of cells, including immune cells, such as macrophages, B-cells, T-cells, and mast cells, as well as endothelial cells, fibroblasts, a variety of stromal cells, and some cancer cells. Cytokines play a crucial role in cancer and cancer-related inflammation, with direct and indirect effects on tumor antagonistic or tumor promoting functions. They have been extensively researched as immunostimulatory mediators to promote the generation, migration and recruitment of immune cells that contribute to an effective antitumor immune response or pro-tumor microenvironment. Thus, in many cancers such as breast cancer, cytokines including leptin, IL-1B, IL-6, IL-8, IL-23, IL-17, and IL-10 stimulate while others including IL-2, IL-12, and IFN-γ, inhibit cancer proliferation and/or invasion and enhance the body's anti-tumor defense. Indeed, the multifactorial functions of cytokines in tumorigenesis will advance our understanding of cytokine crosstalk pathways in the tumor microenvironment, such as JAK/STAT, PI3K, AKT, Rac, MAPK, NF-κB, JunB, cFos, and mTOR, which are involved in angiogenesis, cancer proliferation and metastasis. Accordingly, targeting and blocking tumor-promoting cytokines or activating and amplifying tumor-inhibiting cytokines are considered cancer-directed therapies. Here, we focus on the role of the inflammatory cytokine system in pro- and anti-tumor immune responses, discuss cytokine pathways involved in immune responses to cancer and some anti-cancer therapeutic applications.
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Affiliation(s)
- Ola Habanjar
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Rea Bingula
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Caroline Decombat
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Mona Diab-Assaf
- Equipe Tumorigénèse Pharmacologie Moléculaire et Anticancéreuse, Faculté des Sciences II, Université Libanaise Fanar, Beyrouth 1500, Lebanon
| | - Florence Caldefie-Chezet
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Laetitia Delort
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
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Muto S, Enta A, Maruya Y, Inomata S, Yamaguchi H, Mine H, Takagi H, Ozaki Y, Watanabe M, Inoue T, Yamaura T, Fukuhara M, Okabe N, Matsumura Y, Hasegawa T, Osugi J, Hoshino M, Higuchi M, Shio Y, Hamada K, Suzuki H. Wnt/β-Catenin Signaling and Resistance to Immune Checkpoint Inhibitors: From Non-Small-Cell Lung Cancer to Other Cancers. Biomedicines 2023; 11:biomedicines11010190. [PMID: 36672698 PMCID: PMC9855612 DOI: 10.3390/biomedicines11010190] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 01/06/2023] [Indexed: 01/13/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. The standard of care for advanced non-small-cell lung cancer (NSCLC) without driver-gene mutations is a combination of an anti-PD-1/PD-L1 antibody and chemotherapy, or an anti-PD-1/PD-L1 antibody and an anti-CTLA-4 antibody with or without chemotherapy. Although there were fewer cases of disease progression in the early stages of combination treatment than with anti-PD-1/PD-L1 antibodies alone, only approximately half of the patients had a long-term response. Therefore, it is necessary to elucidate the mechanisms of resistance to immune checkpoint inhibitors. Recent reports of such mechanisms include reduced cancer-cell immunogenicity, loss of major histocompatibility complex, dysfunctional tumor-intrinsic interferon-γ signaling, and oncogenic signaling leading to immunoediting. Among these, the Wnt/β-catenin pathway is a notable potential mechanism of immune escape and resistance to immune checkpoint inhibitors. In this review, we will summarize findings on these resistance mechanisms in NSCLC and other cancers, focusing on Wnt/β-catenin signaling. First, we will review the molecular biology of Wnt/β-catenin signaling, then discuss how it can induce immunoediting and resistance to immune checkpoint inhibitors. We will also describe other various mechanisms of immune-checkpoint-inhibitor resistance. Finally, we will propose therapeutic approaches to overcome these mechanisms.
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Affiliation(s)
- Satoshi Muto
- Correspondence: ; Tel.: +81-24-547-1252; Fax: +81-24-548-2735
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Zhang YG, Xia Y, Zhang J, Deb S, Garrett S, Sun J. Intestinal vitamin D receptor protects against extraintestinal breast cancer tumorigenesis. Gut Microbes 2023; 15:2202593. [PMID: 37074210 PMCID: PMC10120454 DOI: 10.1080/19490976.2023.2202593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 03/17/2023] [Accepted: 04/03/2023] [Indexed: 04/20/2023] Open
Abstract
The microbiota plays critical roles in regulating the function and health of the intestine and extraintestinal organs. A fundamental question is whether an intestinal-microbiome-breast axis exists during the development of breast cancer. If so, what are the roles of host factors? Vitamin D receptor (VDR) involves host factors and the human microbiome. Vdr gene variation shapes the human microbiome, and VDR deficiency leads to dysbiosis. We hypothesized that intestinal VDR protects hosts against tumorigenesis in the breast. We examined a 7,12-dimethylbenzanthracene (DMBA)-induced breast cancer model in intestinal epithelial VDR knockout (VDRΔIEC) mice with dysbiosis. We reported that VDRΔIEC mice with dysbiosis are more susceptible to breast cancer induced by DMBA. Intestinal and breast microbiota analysis showed that VDR deficiency leads to a bacterial profile shift from normal to susceptible to carcinogenesis. We found enhanced bacterial staining within breast tumors. At the molecular and cellular levels, we identified the mechanisms by which intestinal epithelial VDR deficiency led to increased gut permeability, disrupted tight junctions, microbial translocation, and enhanced inflammation, thus increasing tumor size and number in the breast. Furthermore, treatment with the beneficial bacterial metabolite butyrate or the probiotic Lactobacillus plantarum reduced breast tumors, enhanced tight junctions, inhibited inflammation, increased butyryl-CoA transferase, and decreased levels of breast Streptococcus bacteria in VDRΔIEC mice. The gut microbiome contributes to the pathogenesis of diseases not only in the intestine but also in the breast. Our study provides insights into the mechanism by which intestinal VDR dysfunction and gut dysbiosis lead to a high risk of extraintestinal tumorigenesis. Gut-tumor-microbiome interactions represent a new target in the prevention and treatment of breast cancer.
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Affiliation(s)
- Yong-Guo Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Yinglin Xia
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Jilei Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Shreya Deb
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Shari Garrett
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Jun Sun
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, IL, USA
- UIC Cancer Center, University of Illinois Chicago, Chicago, IL, USA
- Jesse Brown VA Medical Center Chicago, Chicago, IL, USA
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Xu W, Nie C, Lv H, Chen B, Wang J, Wang S, Zhao J, He Y, Chen X. Molecular subtypes based on Wnt-signaling gene expression predict prognosis and tumor microenvironment in hepatocellular carcinoma. Front Immunol 2022; 13:1010554. [PMID: 36275697 PMCID: PMC9582750 DOI: 10.3389/fimmu.2022.1010554] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/26/2022] [Indexed: 11/16/2022] Open
Abstract
Based on increasing research evidence, hepatocellular carcinoma (HCC) is heterogeneous, and genetic profiling has led to the identification of multiple subtypes of this disease. To advance our knowledge and the ability to use individualized medicine in the treatment of HCC, it is essential to perform a complete and methodical characterization of various molecular subtypes. The canonical Wnt/β-catenin pathway is an evolutionarily conserved complicated signaling mechanism that plays a role in carcinogenesis and progression of HCC. In this study, we acquired RNA sequencing, somatic mutation, and clinical data from 701 patients from The Cancer Genome Atlas and Gene Expression Omnibus databases and stratified patients into two subgroups: WNT-high and WNT-low. In general, the WNT-high subtype is associated with an immunosuppressive microenvironment, poor prognosis, cancer-related pathways, and a low response to immune checkpoint therapy. We also found that WNT3 is negatively linked to CD8+ T-cell infiltration using multiple immunofluorescence assays. Finally, we developed a WNT-related prognostic model to predict the survival time of patients with HCC. In summary, we developed a new classification scheme for HCC based on Wnt signaling signatures. This classification produced substantial clinical effects, both in terms of assessing patient prognosis and immunotherapy administered to patients with HCC.
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Affiliation(s)
- Weifeng Xu
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, China
| | - Caiyun Nie
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huifang Lv
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - BeiBei Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jianzheng Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Saiqi Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jing Zhao
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yunduan He
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Xiaobing Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, China
- *Correspondence: Xiaobing Chen,
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Mego M, Vlkova B, Minarik G, Cierna Z, Karaba M, Benca J, Sedlackova T, Cholujova D, Gronesova P, Kalavska K, Pindak D, Mardiak J, Celec P. Vitamin D and circulating tumor cells in primary breast cancer. Front Oncol 2022; 12:950451. [PMID: 36158648 PMCID: PMC9489852 DOI: 10.3389/fonc.2022.950451] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 08/09/2022] [Indexed: 11/13/2022] Open
Abstract
Background Circulating tumor cells (CTCs) contribute to the metastatic cascade and represent an independent survival predictor in breast cancer (BC) patients. Vitamin D has pleiotropic effects, and its low concentrations are associated with breast cancer and metastasis. The aim of this study was to assess plasma vitamin D in primary BC patients in relation to CTCs. Methods This study included 91 non-metastatic BC patients (stage I–III) and 24 healthy donors. Blood samples for the analyses were drawn at the time of surgery. CTCs were assessed using a quantitative RT-PCR assay for expression of epithelial (CK19) or epithelial-to-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, and ZEB1). Total 25-OH vitamin D was measured in plasma using ELISA. Plasma cytokines and angiogenic factors were measured by enzyme-linked immunoassay. Results CTCs were detected in 30 (33%) patients. Patients with detectable CTCs in peripheral blood had significantly lower vitamin D concentrations in comparison to patients without detectable CTCs ((mean ± SD) 8.50 ± 3.89 µg/L for CTC-positive vs 9.69 ± 3.49 µg/L for CTC-negative patients, p = 0.03). The mean ( ± SD) vitamin D plasma level was 9.3 ± 3.65 µg/L for breast cancer patients compared to 18.6 ± 6.8 for healthy donors (p < 0.000001). There was no association between plasma vitamin D and other patient/tumor characteristics. Plasma vitamin D levels are inversely correlated with plasma TGF-β1, TGF-β2, IL β, IL-5, and eotaxin (all p < 0.05). Patients with vitamin D above the median had a better overall survival (hazard ratio (HR) = 0.36, 95% CI 0.16–0.80, p = 0.017), and combined analysis showed the best survival for CTC-negative patients with vitamin D levels above the median as compared to patients with opposite characteristics (HR = 0.18, 95% CI 0.05–0.63, p = 0.004). Conclusions Low vitamin D could be a consequence and hence a biomarker of a more invasive disease. Alternatively, vitamin D could be associated with survival because of its role in tumor dissemination. Whether its supplementation affects the metastatic cascade should be tested in animal experiments and interventional studies.
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Affiliation(s)
- Michal Mego
- 2Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
- Translational Research Unit, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
- *Correspondence: Michal Mego,
| | - Barbora Vlkova
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Gabriel Minarik
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Zuzana Cierna
- Department of Pathology, Faculty of Medicine, Comenius University, Bratislava, Slovakia
- Department of Pathology, Faculty Hospital, Trnava, Slovakia
| | - Marian Karaba
- Department of Oncosurgery, National Cancer Institute, Bratislava, Slovakia
| | - Juraj Benca
- Department of Oncosurgery, National Cancer Institute, Bratislava, Slovakia
- Department of Medicine, St. Elizabeth University, Bratislava, Slovakia
| | - Tatiana Sedlackova
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Dana Cholujova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Paulina Gronesova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Katarina Kalavska
- Translational Research Unit, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Daniel Pindak
- Department of Oncosurgery, National Cancer Institute, Bratislava, Slovakia
- Department of Oncosurgery, Slovak Medical University, Bratislava, Slovakia
| | - Jozef Mardiak
- 2Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Peter Celec
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
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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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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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Novoa Díaz MB, Martín MJ, Gentili C. Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway: Providing understanding of the complex mechanisms of chemoresistance. World J Gastroenterol 2022; 28:3027-3046. [PMID: 36051330 PMCID: PMC9331520 DOI: 10.3748/wjg.v28.i26.3027] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 04/29/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current therapies. Dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer, including CRC. In many subtypes of CRC, hyperactivation of the β-catenin pathway is associated with mutations of the adenomatous polyposis coli gene. However, it can also be associated with other causes. In recent years, studies of the tumor microenvironment (TME) have demonstrated its importance in the development and progression of CRC. In this tumor nest, several cell types, structures, and biomolecules interact with neoplastic cells to pave the way for the spread of the disease. Cross-communications between tumor cells and the TME are then established primarily through paracrine factors, which trigger the activation of numerous signaling pathways. Crucial advances in the field of oncology have been made in the last decade. This Minireview aims to actualize what is known about the central role of the Wnt/β-catenin pathway in CRC chemoresistance and aggressiveness, focusing on cross-communication between CRC cells and the TME. Through this analysis, our main objective was to increase the understanding of this complex disease considering a more global context. Since many treatments for advanced CRC fail due to mechanisms involving chemoresistance, the data here exposed and analyzed are of great interest for the development of novel and effective therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - María Julia Martín
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
- Departamento de Química, Universidad Nacional del Sur (UNS)-INQUISUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
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Zhao L, Lu W, Mao Z, Mou D, Huang L, Yang M, Ding D, Yan H, Fang Z, Che L, Zhuo Y, Jiang X, Xu S, Lin Y, Li J, Huang C, Zou Y, Li L, Wu D, Feng B. Maternal VD 3 supplementation during gestation improves intestinal health and microbial composition of weaning piglets. Food Funct 2022; 13:6830-6842. [PMID: 35687102 DOI: 10.1039/d1fo04303j] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Vitamin D3 (VD3) has been reported to improve the reproductive performance of sows. This study was conducted to investigate the long-term effect of maternal VD3 supplementation during gestation on the intestinal health of piglets. Twenty-three Landrace × Yorkshire gilts were randomly allocated into two groups to receive one of the following two diets during gestation: basal diet (CON group, 800 IU VD3 per kg diet, n = 12) and VD3 supplemented diet (VD3 group, 2000 IU VD3 per kg diet, n = 11). All sows were then fed with the same diet during lactation. Results showed that maternal VD3 supplementation during lactation tended to decrease (p = 0.08) the body weight loss of sows during lactation compared to the CON group. Besides, the relative length and weight of the small intestine (SI) and the villus height of the duodenum and ileum in weaning piglets were much higher (p < 0.05) in the VD3 group than those in the CON group, though their body weight was not changed. Meanwhile, maternal VD3 supplementation significantly upregulated the expression levels of IGF-1, IGF-2R, VDR, GLUT-2 and CAT1 in the duodenum (p < 0.05), and increased the expression levels of IGF-1, IGF-1R, IGF-2R, VDR, Occludin, ZO-1, MUC2, PEPT1 and CAT1 (p < 0.05) in the jejunum of suckling piglets compared with the CON group. Besides, the concentration of SigA in the jejunum of suckling piglets was higher (p < 0.05) in the VD3 group than that in the CON group. In addition, maternal VD3 supplementation significantly increased the contents of short chain fatty acids and the relative abundance of Lactobacillus and Faecalibacterium (p < 0.05) in the feces of weaning piglets compared to the CON group. Moreover, the relative abundance of unidentified_Lachnospiraceae in the feces of weaning piglets tended to be higher (p = 0.05), while that of unidentified_Spirochaetaceae was lower (p < 0.05) in the VD3 group than those in the CON group. Taken together, maternal VD3 supplementation during gestation could improve the intestinal function and microbiota in suckling piglets.
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Affiliation(s)
- Lianpeng Zhao
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Wei Lu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Zhengyu Mao
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Daolin Mou
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Long Huang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Min Yang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Dajiang Ding
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Hui Yan
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Zhengfeng Fang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Lianqiang Che
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Yong Zhuo
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Xuemei Jiang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Shengyu Xu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Yan Lin
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Jian Li
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Chao Huang
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Yuanfeng Zou
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Lixia Li
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - De Wu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
| | - Bin Feng
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, 211 Huimin Road, No. 6 Teaching Building, Room 604, Wenjiang District, Chengdu, Sichuan 611130, China.
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The Breast Cancer Protooncogenes HER2, BRCA1 and BRCA2 and Their Regulation by the iNOS/NOS2 Axis. Antioxidants (Basel) 2022; 11:antiox11061195. [PMID: 35740092 PMCID: PMC9227079 DOI: 10.3390/antiox11061195] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 02/04/2023] Open
Abstract
The expression of inducible nitric oxide synthase (iNOS; NOS2) and derived NO in various cancers was reported to exert pro- and anti-tumorigenic effects depending on the levels of expression and the tumor types. In humans, the breast cancer level of iNOS was reported to be overexpressed, to exhibit pro-tumorigenic activities, and to be of prognostic significance. Likewise, the expression of the oncogenes HER2, BRCA1, and BRCA2 has been associated with malignancy. The interrelationship between the expression of these protooncogenes and oncogenes and the expression of iNOS is not clear. We have hypothesized that there exist cross-talk signaling pathways between the breast cancer protooncogenes, the iNOS axis, and iNOS-mediated NO mutations of these protooncogenes into oncogenes. We review the molecular regulation of the expression of the protooncogenes in breast cancer and their interrelationships with iNOS expression and activities. In addition, we discuss the roles of iNOS, HER2, BRCA1/2, and NO metabolism in the pathophysiology of cancer stem cells. Bioinformatic analyses have been performed and have found suggested molecular alterations responsible for breast cancer aggressiveness. These include the association of BRCA1/2 mutations and HER2 amplifications with the dysregulation of the NOS pathway. We propose that future studies should be undertaken to investigate the regulatory mechanisms underlying the expression of iNOS and various breast cancer oncogenes, with the aim of identifying new therapeutic targets for the treatment of breast cancers that are refractory to current treatments.
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A Comprehensive Cancer-Associated MicroRNA Expression Profiling and Proteomic Analysis of Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes. Tissue Eng Regen Med 2022; 19:1013-1031. [PMID: 35511336 PMCID: PMC9478013 DOI: 10.1007/s13770-022-00450-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/23/2022] [Accepted: 03/04/2022] [Indexed: 12/12/2022] Open
Abstract
Background: The mesenchymal stem cells (MSCs) have enormous therapeutic potential owing to their multi-lineage differentiation and self-renewal properties. MSCs express growth factors, cytokines, chemokines, and non-coding regulatory RNAs with immunosuppressive, anti-tumor, and migratory properties. MSCs also release several anti-cancer molecules via extracellular vesicles, that act as pro-apoptotic/tumor suppressor factors. This study aimed to identify the stem cell-derived secretome that could exhibit anti-cancer properties through molecular profiling of cargos in MSC-derived exosomes.
Methods: Human umbilical cord mesenchymal stem cells (hUCMSCs) were isolated from umbilical cord tissues and culture expanded. Subsequently, exosomes were isolated from hUCMSC conditioned medium and characterized by DLS, electron microscopy. Western blot for exosome surface marker protein CD63 expression was performed. The miRNA profiling of hUCMSCs and hUCMSC-derived exosomes was performed, followed by functional enrichment analysis. Results: The tri-lineage differentiation potential, fibroblastic morphology, and strong expression of pluripotency genes indicated that isolated fibroblasts are MSCs. The isolated extracellular vesicles were 133.8 ± 42.49 nm in diameter, monodispersed, and strongly expressed the exosome surface marker protein CD63. The miRNA expression profile and gene ontology (GO) depicted the differential expression patterns of high and less-expressed miRNAs that are crucial to be involved in the regulation of apoptosis. The LCMS/MS data and GO analysis indicate that hUCMSC secretomes are involved in several oncogenic and inflammatory signaling cascades. Conclusion: Primary human MSCs released miRNAs and growth factors via exosomes that are increasingly implicated in intercellular communications, and hUCMSC-exosomal miRNAs have a critical influence in regulating cell death and apoptosis of cancer cells. Graphical abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1007/s13770-022-00450-8.
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Matusiewicz M, Marczak K, Kwiecińska B, Kupis J, Zglińska K, Niemiec T, Kosieradzka I. Effect of extracts from eggs of Helix aspersa maxima and Helix aspersa aspersa snails on Caco-2 colon cancer cells. PeerJ 2022; 10:e13217. [PMID: 35433131 PMCID: PMC9012176 DOI: 10.7717/peerj.13217] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 03/14/2022] [Indexed: 01/12/2023] Open
Abstract
Background Colorectal cancer is the third most commonly diagnosed cancer. Natural compounds, administered together with conventional chemotherapeutic agent(s) and/or radiotherapy, may be a novel element in the combination therapy of this cancer. Considering the anticancer properties of compounds derived from different tissues of various snail species confirmed earlier, the purpose of the present research was to evaluate the effect of extracts from eggs of Helix aspera maxima and Helix aspersa aspersa snails, and fractions of extracts containing particles of different molecular weights on Caco-2 human epithelial colorectal adenocarcinoma cells. Methods The extracts and fractions were analyzed for antioxidant activity, phenols and total carbohydrates using colorimetric methods. Lipid peroxidation products and glutathione in eggs were also examined using these methods. Crude protein and fat in eggs were determined. Molecular weights of egg proteins and glycoproteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Astaxanthin, selected vitamins and amino acids in eggs were measured using liquid chromatography methods, and minerals by emission spectroscopy, mass spectrometry or X-ray fluorescence. The action of extracts on the cell viability was determined by the MTT (methylthiazolyldiphenyl-tetrazolium bromide) test, based on the mitochondrial oxidative activity, after 24 and 72 h of treatment. The influence of fractions on the cell viability was assayed after 24 h. The effect of extracts on the percentage of live and dead cells was evaluated by the trypan blue assay, in which live cells exclude trypan blue, while dead cells take up this dye, after 12, 24, 48 and 72 h of treatment. Their influence on the integrity of cell membranes was determined based on the activity of LDH (lactate dehydrogenase), released from damaged cells, after 24 and 72 h of treatment. Then, the effect of extracts on the content of lipid peroxidation products in cells was examined using colorimetric method, after 24 h of treatment. Their influence on types of cell death was determined by flow cytometry, after this time. Results The extracts and their fractions containing molecules <3 kDa decreased the cell viability, after 24 h of treatment. The extracts reduced the percentage of live cells (also after 48 h), increased the degree of cell membrane damage and the amount of lipid peroxidation products, induced apoptosis and reduced necrosis. Conclusions Antioxidants, phenols, lipid peroxidation products, anticancer peptides, restriction of methionine, appropriate ratio of essential amino acids to non-essential amino acids, vitamin D3, Ca, Mg, S, Cu, Mn, Zn, Se and other bioactive compounds comprised in the extracts and their additive and synergistic effects may have influenced Caco-2 cells. Natural extracts or the chemical compounds contained in them might be used in the combination therapy of colorectal cancer, which requires further research.
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Affiliation(s)
- Magdalena Matusiewicz
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Karolina Marczak
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Barbara Kwiecińska
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Julia Kupis
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Klara Zglińska
- Department of Animal Nutrition, Institute of Animal Sciences, Warsaw University of Life Sciences, Warsaw, Poland
| | - Tomasz Niemiec
- Department of Animal Nutrition, Institute of Animal Sciences, Warsaw University of Life Sciences, Warsaw, Poland
| | - Iwona Kosieradzka
- Department of Animal Nutrition, Institute of Animal Sciences, Warsaw University of Life Sciences, Warsaw, Poland
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43
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Muñoz A, Grant WB. Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms. Nutrients 2022; 14:1448. [PMID: 35406059 PMCID: PMC9003337 DOI: 10.3390/nu14071448] [Citation(s) in RCA: 140] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/28/2022] [Accepted: 03/28/2022] [Indexed: 02/07/2023] Open
Abstract
This is a narrative review of the evidence supporting vitamin D's anticancer actions. The first section reviews the findings from ecological studies of cancer with respect to indices of solar radiation, which found a reduced risk of incidence and mortality for approximately 23 types of cancer. Meta-analyses of observational studies reported the inverse correlations of serum 25-hydroxyvitamin D [25(OH)D] with the incidence of 12 types of cancer. Case-control studies with a 25(OH)D concentration measured near the time of cancer diagnosis are stronger than nested case-control and cohort studies as long follow-up times reduce the correlations due to changes in 25(OH)D with time. There is no evidence that undiagnosed cancer reduces 25(OH)D concentrations unless the cancer is at a very advanced stage. Meta-analyses of cancer incidence with respect to dietary intake have had limited success due to the low amount of vitamin D in most diets. An analysis of 25(OH)D-cancer incidence rates suggests that achieving 80 ng/mL vs. 10 ng/mL would reduce cancer incidence rates by 70 ± 10%. Clinical trials have provided limited support for the UVB-vitamin D-cancer hypothesis due to poor design and execution. In recent decades, many experimental studies in cultured cells and animal models have described a wide range of anticancer effects of vitamin D compounds. This paper will review studies showing the inhibition of tumor cell proliferation, dedifferentiation, and invasion together with the sensitization to proapoptotic agents. Moreover, 1,25-(OH)2D3 and other vitamin D receptor agonists modulate the biology of several types of stromal cells such as fibroblasts, endothelial and immune cells in a way that interferes the apparition of metastases. In sum, the available mechanistic data support the global protective action of vitamin D against several important types of cancer.
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Affiliation(s)
- Alberto Muñoz
- Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, CIBERONC and IdiPAZ, 28029 Madrid, Spain;
| | - William B. Grant
- Sunlight, Nutrition and Health Research Center, P.O. Box 641603, San Francisco, CA 94164-1603, USA
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Rinninella E, Mele MC, Raoul P, Cintoni M, Gasbarrini A. Vitamin D and colorectal cancer: Chemopreventive perspectives through the gut microbiota and the immune system. Biofactors 2022; 48:285-293. [PMID: 34559412 PMCID: PMC9293134 DOI: 10.1002/biof.1786] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 09/13/2021] [Indexed: 12/14/2022]
Abstract
Vitamin D and its receptor are involved in health and diseases through multiple mechanisms including the immune system and gut microbiota modulations. Gut microbiota variations have huge implications in intestinal and extra-intestinal disorders such as colorectal cancer (CRC). This review highlights the preventive role of vitamin D in colorectal tumorigenesis through the effects on the immune system and gut microbiota modulation. The different associations between vitamin D, gut microbial homeostasis, immune system, and CRC, are dissected. Vitamin D is supposed to exert several chemopreventive effects on CRC including direct antineoplastic mechanisms, the effects on the immune system, and gut microbiota modulation. Large clinical studies with a randomized design, are required to confirm the role of vitamin D in CRC, confirming its key role in the complex interplay between the gut immune system and microbiota.
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Affiliation(s)
- Emanuele Rinninella
- UOC di Nutrizione Clinica, Dipartimento di Scienze Mediche e ChirurgicheFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
| | - Maria Cristina Mele
- Dipartimento di Medicina e Chirurgia TraslazionaleUniversità Cattolica Del Sacro CuoreRomeItaly
- UOSD di Nutrizione Avanzata in Oncologia, Dipartimento di Scienze Mediche e ChirurgicheFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
| | - Pauline Raoul
- Dipartimento di Medicina e Chirurgia TraslazionaleUniversità Cattolica Del Sacro CuoreRomeItaly
- UOSD di Nutrizione Avanzata in Oncologia, Dipartimento di Scienze Mediche e ChirurgicheFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
| | - Marco Cintoni
- Scuola di Specializzazione in Scienza dell'AlimentazioneUniversità di Roma Tor VergataRomeItaly
| | - Antonio Gasbarrini
- Dipartimento di Medicina e Chirurgia TraslazionaleUniversità Cattolica Del Sacro CuoreRomeItaly
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e ChirurgicheFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
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Safarzadeh Kozani P, Safarzadeh Kozani P, Rahbarizadeh F. Addressing the obstacles of CAR T cell migration in solid tumors: wishing a heavy traffic. Crit Rev Biotechnol 2021; 42:1079-1098. [PMID: 34957875 DOI: 10.1080/07388551.2021.1988509] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy has been recognized as one of the most prosperous treatment options against certain blood-based malignancies. However, the same clinical and commercial success have been out of range in the case of solid tumors. The main contributing factor in this regard is the hostile environment the tumor cells impose that results in the exhaustion of immune effector cells alongside the abrogation of their infiltration capacity. The discovery of the underlying mechanisms and the development of reliable counterstrategies to overcome the inaccessibility of CAR-Ts to their target cells might correlate with encouraging clinical outcomes in advanced solid tumors. Here, we highlight the successive physical and metabolic barriers that systemically administered CAR-Ts face on their journey toward their target cells. Moreover, we propose meticulously-devised countertactics and combination therapies that can be applied to maximize the therapeutic benefits of CAR-T therapies against solid tumors.
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Affiliation(s)
- Pooria Safarzadeh Kozani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Pouya Safarzadeh Kozani
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran.,Student Research Committee, Medical Biotechnology Research Center, School of Nursing, Midwifery, and Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Fatemeh Rahbarizadeh
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.,Research and Development Center of Biotechnology, Tarbiat Modares University, Tehran, Iran
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Czajka-Francuz P, Cisoń-Jurek S, Czajka A, Kozaczka M, Wojnar J, Chudek J, Francuz T. Systemic Interleukins' Profile in Early and Advanced Colorectal Cancer. Int J Mol Sci 2021; 23:124. [PMID: 35008550 PMCID: PMC8745135 DOI: 10.3390/ijms23010124] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 12/18/2021] [Accepted: 12/20/2021] [Indexed: 02/05/2023] Open
Abstract
Tumor microenvironment (TME) is characterized by mutual interactions of the tumor, stromal and immune cells. Early and advanced colorectal tumors differ in structure and present altered serum cytokine levels. Mutual crosstalk among TME infiltrating cells may shift the balance into immune suppressive or pro-inflammatory, antitumor response this way influencing patients' prognosis. Cancer-related inflammation affects all the body and this way, the systemic level of cytokines could reflect TME processes. Despite numerous studies, it is still not known how systemic cytokines levels change during colorectal cancer (CRC) tumor development. Better understanding tumor microenvironment processes could help in planning therapeutic interventions and more accurate patient prognosis. To contribute to the comprehension of these processes within TME, we reviewed cytokines levels from clinical trials in early and advanced colorectal cancer. Presented data were analyzed in the context of experimental studies and studies analyzing tumor infiltration with immune cells. The review summarizes clinical data of cytokines secreted by tumor microenvironment cells: lymphocytes T helper 1 (Th1), lymphocytes T helper 2 (Th2), lymphocytes T helper 17 (Th17), regulatory T cells (Treg cells), regulatory T cells (Breg cells), M1/M2 macrophages, N1/N2 neutrophils, myeloid-derived suppressor cells (MDSC), dendritic cells (DC), innate lymphoid cells (ILC) natural killer (NK) cells and tumor cells.
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Affiliation(s)
- Paulina Czajka-Francuz
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
| | - Sylwia Cisoń-Jurek
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
| | - Aleksander Czajka
- Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-635 Katowice, Poland;
| | - Maciej Kozaczka
- Department of Radiotherapy and Chemotherapy, National Institute of Oncology, Public Research Institute in Gliwice, 44-101 Gliwice, Poland;
| | - Jerzy Wojnar
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
| | - Jerzy Chudek
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
| | - Tomasz Francuz
- Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-027 Katowice, Poland; (S.C.-J.); (J.W.); (J.C.); (T.F.)
- Department of Biochemistry, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland
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Guo Y, Jiang F, Yang W, Shi W, Wan J, Li J, Pan J, Wang P, Qiu J, Zhang Z, Li B. Effect of 1α,25(OH) 2D 3-Treated M1 and M2 Macrophages on Cell Proliferation and Migration Ability in Ovarian Cancer. Nutr Cancer 2021; 74:2632-2643. [PMID: 34894920 DOI: 10.1080/01635581.2021.2014903] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The biological active form of vitamin D3, 1α,25-dehydroxyvitamin D3 [1α,25(OH)2D3], exerts pleiotropic effects including bone mineralization, anti-tumor, as well as immunomodulator. This study aimed to explore the potential impact of 1α,25(OH)2D3 on tumor-associated macrophages (TAMs) infiltration in ovarian cancer. Firstly, human monocytic THP-1 cells were differentiated into macrophages (M0) in the presence of phorbol 12-myristate 13-acetate (PMA). In Vivo, 1α,25(OH)2D3 not only reversed the polarization of M2 macrophages, but also decreased the proliferation and migration abilities of ovarian cancer cells induced by M2 macrophages supernatant. Furthermore, 1α,25(OH)2D3 dramatically decreased the secretion of TGF-β1 and MMP-9 in M2 macrophages. However, no significant effect was observed in 1α,25(OH)2D3 treated M1 macrophages. In Vivo, vitamin D3 had an inhibitive effect of 1α,25(OH)2D3-treated M2 macrophages on tumorigenesis. In addition, we conducted the association of TAMs with the poor prognosis of patients with ovarian cancer by meta-analysis, which suggested the higher proportion of M2 macrophages was related to the poorer prognosis in ovarian cancer. Collectively, these results identified distinct roles of 1α,25(OH)2D3 treated M1 and M2 macrophages on cell proliferation and migration abilities in ovarian cancer.
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Affiliation(s)
- Yi Guo
- Medical College of Soochow University, Suzhou, China.,Jiangpu Community Healthcare Service, Suzhou, Kunshan, China
| | - Fei Jiang
- Medical College of Soochow University, Suzhou, China
| | - Wenqing Yang
- Medical College of Soochow University, Suzhou, China
| | - Weiqiang Shi
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jianmei Wan
- Medical College of Soochow University, Suzhou, China
| | - Jie Li
- Medical College of Soochow University, Suzhou, China
| | - Jinjing Pan
- Medical College of Soochow University, Suzhou, China
| | - Ping Wang
- Medical College of Soochow University, Suzhou, China
| | - Junlan Qiu
- Medical College of Soochow University, Suzhou, China.,Department of Oncology and Hematology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, China
| | - Zengli Zhang
- Medical College of Soochow University, Suzhou, China
| | - Bingyan Li
- Medical College of Soochow University, Suzhou, China
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The Complex Network between Inflammation and Colorectal Cancer: A Systematic Review of the Literature. Cancers (Basel) 2021; 13:cancers13246237. [PMID: 34944856 PMCID: PMC8699209 DOI: 10.3390/cancers13246237] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Colorectal cancer is one of the most diffuse malignant pathologies, and many factors are involved in its genesis. Among these factors, inflammation plays an important role. Many molecules are involved in inflammation processes and are linked in different pathways, either in the sense of pro-tumorigenesis or anti-tumorigenic action. This review was conducted with the aim to review in a single paper the majority of actual knowledge in the literature and to comprehend inflammation patterns for better clinical and surgical management of patients. Abstract Background: colorectal cancer (CRC) has a multifactorial etiology which comprises microbiota, genetic predisposition, diet, environmental factors, and last but not least, a substantial contribution by inflammation. The aim of this study is to conduct a systematic review of the literature regarding the strong link between inflammation and colorectal cancer. Methods: A systematic review of the literature on PubMed (Medline), Scopus, Cochrane and EMBase databases was performed, following the PRISMA 2020 guidelines. Each paper was reviewed by two groups of researchers in a single-blind format by using a pre-planned Microsoft© Excel® grid. Results: Using automated research filters, 14,566 studies were included, but 1% was found significant by the reviewers. Seventy pathways of inflammation were described in the sequence of inflammation-carcinogenesis, and anti-tumorigenic molecules were also found. Conclusion: several studies suggest a strong role of inflammation in the tumorigenesis of colorectal cancer through different pathways: this may have a diagnostic and clinical role and also therapeutic purpose in preventing carcinogenesis by treating inflammation. In vitro tests support this theory, even if many other clinical trials are necessary. The present paper was registered in the OpenScience Framework registry (Identifier: DOI 10.17605/OSF.IO/2KG7T).
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The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis. Cancers (Basel) 2021; 13:cancers13246206. [PMID: 34944826 PMCID: PMC8699466 DOI: 10.3390/cancers13246206] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is the third most common cancer worldwide. Metastasis to secondary organs, such as the liver and lungs, is a key driver of CRC-related mortality. The tumor microenvironment, which consists of the primary cancer cells, as well as associated support and immune cells, significantly affects the behavior of CRC cells at the primary tumor site, as well as in metastatic lesions. In this paper, we review the role of the individual components of the tumor microenvironment on tumor progression, immune evasion, and metastasis, and we discuss the implications of these components on antitumor therapies. Abstract Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastases, most frequently to the liver and lung. In the primary tumor, as well as at each metastatic site, the cellular components of the tumor microenvironment (TME) contribute to tumor engraftment and metastasis. These include immune cells (macrophages, neutrophils, T lymphocytes, and dendritic cells) and stromal cells (cancer-associated fibroblasts and endothelial cells). In this review, we highlight how the TME influences tumor progression and invasion at the primary site and its function in fostering metastatic niches in the liver and lungs. We also discuss emerging clinical strategies to target the CRC TME.
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Hou J, Hsu JM, Hung MC. Molecular mechanisms and functions of pyroptosis in inflammation and antitumor immunity. Mol Cell 2021; 81:4579-4590. [PMID: 34562371 DOI: 10.1016/j.molcel.2021.09.003] [Citation(s) in RCA: 183] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 07/17/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022]
Abstract
Canonically, gasdermin D (GSDMD) cleavage by caspase-1 through inflammasome signaling triggers immune cell pyroptosis (ICP) as a host defense against pathogen infection. However, cancer cell pyroptosis (CCP) was recently discovered to be activated by distinct molecular mechanisms in which GSDMB, GSDMC, and GSDME, rather than GSDMD, are the executioners. Moreover, instead of inflammatory caspases, apoptotic caspases and granzymes are required for gasdermin protein cleavage to induce CCP. Sufficient accumulation of protease-cleaved gasdermin proteins is the prerequisite for CCP. Inflammation induced by ICP or CCP results in diametrically opposite effects on antitumor immunity because of the differential duration and released cellular contents, leading to contrary effects on therapeutic outcomes. Here, we focus on the distinct mechanisms of ICP and CCP and discuss the roles of ICP and CCP in inflammation and antitumor immunity, representing actionable targets.
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Affiliation(s)
- Junwei Hou
- Xiangya Cancer Center, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, Hunan, China; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Xiangya Road 87, Changsha 410008, Hunan, China; Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, Hunan, China; Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Jung-Mao Hsu
- Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan
| | - Mien-Chie Hung
- Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan; Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Biotechnology, Asia University, Taichung, Taiwan.
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