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Silinskaite U, Valciukiene J, Jakubauskas M, Poskus T. The Immune Environment in Colorectal Adenoma: A Systematic Review. Biomedicines 2025; 13:699. [PMID: 40149674 PMCID: PMC11940254 DOI: 10.3390/biomedicines13030699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 02/28/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Research on colorectal adenoma is significantly less comprehensive compared to studies on colorectal carcinoma. Although colorectal adenoma is a precursor of the majority of sporadic colorectal cancers, not all adenomas develop into carcinomas. The complex interaction of immune responses in the premalignant tumor microenvironment might be a factor for that. Methods: In this systematic review, we aim to provide a thorough analysis of the current research examining the immune infiltration patterns in sporadic colorectal adenoma tissues in the context of immune cell-based, cytokine-based, and other immunological factor-related changes along the conventional adenoma-carcinoma sequence. The articles included in the review extend up to December 2024 in PubMed and Web of Science databases. Results: Most included studies have shown significant differences in immune cell counts, densities, and cytokine expression levels associated with premalignant colorectal lesions (and/or colorectal cancer). No consensus on the immune-related tendencies concerning CD4+T cells and CD8+T cells was reached. Decreasing expression of mDCs and plasma and naïve B cells were detected along the ACS. The increased density of tissue eosinophils in the adenoma tissue dramatically diminishes after the transition to carcinoma. As the adenoma progresses, the increasing expression of IL-1α, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-21, IL-23, IL-33, and TGF-β and decreasing levels of IL-12A, IL-18, IFN-γ, and TNFα cytokines in the invasive carcinoma stage is being detected. The over-expression of COX-2, PD-1/PD-L1, CTLA-4, and ICOS/ICOSLG in the colorectal adenomatous and cancerous tissues was also observed. Conclusions: Further studies are needed for a better understanding of the whole picture of colorectal adenoma-associated immunity and its impact on precancerous lesion's potential to progress.
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Dias IHK, Shokr H. Oxysterols as Biomarkers of Aging and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1440:307-336. [PMID: 38036887 DOI: 10.1007/978-3-031-43883-7_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
Oxysterols derive from either enzymatic or non-enzymatic oxidation of cholesterol. Even though they are produced as intermediates of bile acid synthesis pathway, they are recognised as bioactive compounds in cellular processes. Therefore, their absence or accumulation have been shown to be associated with disease phenotypes. This chapter discusses the contribution of oxysterol to ageing, age-related diseases such as neurodegeneration and various disorders such as cancer, cardiovascular disease, diabetes, metabolic and ocular disorders. It is clear that oxysterols play a significant role in development and progression of these diseases. As a result, oxysterols are being investigated as suitable markers for disease diagnosis purposes and some drug targets are in development targeting oxysterol pathways. However, further research will be needed to confirm the suitability of these potentials.
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Affiliation(s)
- Irundika H K Dias
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham, UK.
| | - Hala Shokr
- Manchester Pharmacy School, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
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Vigne S, Pot C. Implication of Oxysterols and Phytosterols in Aging and Human Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1440:231-260. [PMID: 38036883 DOI: 10.1007/978-3-031-43883-7_12] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
Cholesterol is easily oxidized and can be transformed into numerous oxidation products, among which oxysterols. Phytosterols are plant sterols related to cholesterol. Both oxysterols and phytosterols can have an impact on human health and diseases.Cholesterol is a member of the sterol family that plays essential roles in biological processes, including cell membrane stability and myelin formation. Cholesterol can be metabolized into several molecules including bile acids, hormones, and oxysterols. On the other hand, phytosterols are plant-derived compounds structurally related to cholesterol, which can also have an impact on human health. Here, we review the current knowledge about the role of oxysterols and phytosterols on human health and focus on the impact of their pathways on diseases of the central nervous system (CNS), autoimmune diseases, including inflammatory bowel diseases (IBD), vascular diseases, and cancer in both experimental models and human studies. We will first discuss the implications of oxysterols and then of phytosterols in different human diseases.
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Affiliation(s)
- Solenne Vigne
- Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Epalinges, Lausanne, Switzerland
| | - Caroline Pot
- Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Epalinges, Lausanne, Switzerland.
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Zhao C, Wang D, Li Z, Zhang Z, Xu Y, Liu J, Lei Q, Han D, Huo Y, Liu S, Li L, Zhang Y. IL8 derived from macrophages inhibits CD8 + T-cell function by downregulating TIM3 expression through IL8-CXCR2 axis in patients with advanced colorectal cancer. Int Immunopharmacol 2023; 121:110457. [PMID: 37331296 DOI: 10.1016/j.intimp.2023.110457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/14/2023] [Accepted: 06/02/2023] [Indexed: 06/20/2023]
Abstract
BACKGROUND T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is a vital immune checkpoint that regulates the immune response. However, the specific role of TIM3 in patients with colorectal cancer (CRC) have rarely been studied. In this study, we investigated the effect of TIM3 on CD8+ T cells in CRC and explored the mechanism of TIM3 regulation in tumor microenvironment (TME). METHODS Peripheral blood and tumor tissues of patients with CRC were collected to evaluate TIM3 expression using flow cytometry. Cytokines in the serum of healthy donors and patients with early- and advanced-stage CRC were screened using a multiplex assay. The effects of interleukin-8 (IL8) on TIM3 expression on CD8+ T cells were analyzed using cell incubation experiments in vitro. The correlation between TIM3 or IL8 and prognosis was verified using bioinformatics analysis. RESULTS TIM3 expression on CD8+ T cells was obviously reduced in patients with advanced-stage CRC, whereas a lower TIM3 expression level was associated with poorer prognosis. Macrophage-derived IL8, which could inhibit TIM3 expression on CD8+ T cells, was significantly increased in the serum of patients with advanced CRC. In addition, the function and proliferation of CD8+ and TIM3+CD8+ T cells were inhibited by IL8, which was partly depending on TIM3 expression. The inhibitory effects of IL8 were reversed by anti-IL8 and anti-CXCR2 antibodies. CONCLUSIONS In summary, macrophages-derived IL8 suppresses TIM3 expression on CD8+ T cells through CXCR2. Targeting the IL8/CXCR2 axis may be an effective strategy for treating patients with advanced CRC.
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Affiliation(s)
- Chenhui Zhao
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Dan Wang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Zhen Li
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Zhen Zhang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yujie Xu
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China
| | - Jinbo Liu
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Qingyang Lei
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Dong Han
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yachang Huo
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Shasha Liu
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ling Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Lymphoma Diagnosis and Treatment Centre of Henan Province, Zhengzhou, Henan 450052, China.
| | - Yi Zhang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450052, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan 450052, China.
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Belhabib I, Zaghdoudi S, Lac C, Bousquet C, Jean C. Extracellular Matrices and Cancer-Associated Fibroblasts: Targets for Cancer Diagnosis and Therapy? Cancers (Basel) 2021; 13:3466. [PMID: 34298680 PMCID: PMC8303391 DOI: 10.3390/cancers13143466] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/25/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Solid cancer progression is dictated by neoplastic cell features and pro-tumoral crosstalks with their microenvironment. Stroma modifications, such as fibroblast activation into cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling, are now recognized as critical events for cancer progression and as potential therapeutic or diagnostic targets. The recent appreciation of the key, complex and multiple roles of the ECM in cancer and of the CAF diversity, has revolutionized the field and raised innovative but challenging questions. Here, we rapidly present CAF heterogeneity in link with their specific ECM remodeling features observed in cancer, before developing each of the impacts of such ECM modifications on tumor progression (survival, angiogenesis, pre-metastatic niche, chemoresistance, etc.), and on patient prognosis. Finally, based on preclinical studies and recent results obtained from clinical trials, we highlight key mechanisms or proteins that are, or may be, used as potential therapeutic or diagnostic targets, and we report and discuss benefits, disappointments, or even failures, of recently reported stroma-targeting strategies.
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Affiliation(s)
| | | | | | | | - Christine Jean
- Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, 31037 Toulouse, France; (I.B.); (S.Z.); (C.L.); (C.B.)
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Kasprzak A. The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia. Int J Mol Sci 2021; 22:ijms22041565. [PMID: 33557173 PMCID: PMC7913937 DOI: 10.3390/ijms22041565] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/27/2021] [Accepted: 02/01/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer cachexia (CC) is a multifactorial syndrome in patients with advanced cancer characterized by weight loss via skeletal-muscle and adipose-tissue atrophy, catabolic activity, and systemic inflammation. CC is correlated with functional impairment, reduced therapeutic responsiveness, and poor prognosis, and is a major cause of death in cancer patients. In colorectal cancer (CRC), cachexia affects around 50–61% of patients, but remains overlooked, understudied, and uncured. The mechanisms driving CC are not fully understood but are related, at least in part, to the local and systemic immune response to the tumor. Accumulating evidence demonstrates a significant role of tumor microenvironment (TME) cells (e.g., macrophages, neutrophils, and fibroblasts) in both cancer progression and tumor-induced cachexia, through the production of multiple procachectic factors. The most important role in CRC-associated cachexia is played by pro-inflammatory cytokines, including the tumor necrosis factor α (TNFα), originally known as cachectin, Interleukin (IL)-1, IL-6, and certain chemokines (e.g., IL-8). Heterogeneous CRC cells themselves also produce numerous cytokines (including chemokines), as well as novel factors called “cachexokines”. The tumor microenvironment (TME) contributes to systemic inflammation and increased oxidative stress and fibrosis. This review summarizes the current knowledge on the role of TME cellular components in CRC-associated cachexia, as well as discusses the potential role of selected mediators secreted by colorectal cancer cells in cooperation with tumor-associated immune and non-immune cells of tumor microenvironment in inducing or potentiating cancer cachexia. This knowledge serves to aid the understanding of the mechanisms of this process, as well as prevent its consequences.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Święcicki Street 6, 60-781 Poznań, Poland
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7
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Czajka-Francuz P, Francuz T, Cisoń-Jurek S, Czajka A, Fajkis M, Szymczak B, Kozaczka M, Malinowski KP, Zasada W, Wojnar J, Chudek J. Serum cytokine profile as a potential prognostic tool in colorectal cancer patients - one center study. Rep Pract Oncol Radiother 2020; 25:867-875. [PMID: 32982592 PMCID: PMC7498852 DOI: 10.1016/j.rpor.2020.08.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023] Open
Abstract
AIM Comparison of 14 cytokines levels between a control group and prospectively enrolled CRC patients to confirm their significance in CRC development. We tested if a model based on 14 cytokines levels could predict prognosis in Caucasian CRC patients treated with 5-FU based chemotherapy. BACKGROUND Novel prognostic tools in colorectal cancer (CRC) are necessary to optimize treatment, reduce toxicity and chemotherapy (CHT) costs. MATERIALS AND METHODS We assessed prognostic significance of 14 cytokines: IL-1 beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL12p70, IL-13, IL-17A in 75 prospectively enrolled CRC patients before initiation of palliative or adjuvant CHT and in 22 control subjects. Readings were taken using the Bio-Plex 200 System. Response to treatment was assessed after 6 months from initiation of CHT. The treated group was divided depending on the response into a progressors (death, progression of disease) and non-progressors group (stable disease, partial response, complete response). RESULTS We found that increased concentration of IL-8 was a negative prognostic factor in the whole group and palliative subgroup, whereas increased level of IL-10, IL-7, and IL-12p70 was a negative predictor in the adjuvant group CHT. CONCLUSIONS We proposed a statistical model based on circulating cytokine levels, showing a good prognostic value in prediction of the response to CHT (AUC = 0.956). The model, including combined IL-2, IL-8, IL-10 and IL-13 levels, established in the whole treated group, should be validated in larger trials.
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Affiliation(s)
- Paulina Czajka-Francuz
- Department of Internal Medicine and Oncology, Silesian Medical University, ul. Reymonta 8, 40-027 Katowice, Poland
| | - Tomasz Francuz
- Department of Biochemistry, Silesian Medical University, ul. Medyków 18, 40-752 Katowice, Poland
| | - Sylwia Cisoń-Jurek
- Department of Internal Medicine and Oncology, Silesian Medical University, ul. Reymonta 8, 40-027 Katowice, Poland
| | - Aleksander Czajka
- Department of General and Vascular Surgery, Silesian Medical University, Ziołowa 45/47, 40-635 Katowice, Poland
| | - Marcin Fajkis
- Department of Internal Medicine and Oncology, Silesian Medical University, ul. Reymonta 8, 40-027 Katowice, Poland
| | - Bożena Szymczak
- Department of Internal Medicine and Oncology, Silesian Medical University, ul. Reymonta 8, 40-027 Katowice, Poland
| | - Maciej Kozaczka
- National Institute of Oncology, Public Research Institute in Gliwice, Department of Radiotherapy and Chemotherapy, 44-101 Gliwice, Wybrzeże Armii Krajowej 15, Poland
| | - Krzysztof Piotr Malinowski
- Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland
| | - Wojciech Zasada
- 2nd Department of Cardiology, University Hospital in Krakow, Poland
| | - Jerzy Wojnar
- Department of Internal Medicine and Oncology, Silesian Medical University, ul. Reymonta 8, 40-027 Katowice, Poland
| | - Jerzy Chudek
- Department of Internal Medicine and Oncology, Silesian Medical University, ul. Reymonta 8, 40-027 Katowice, Poland
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Steinway SN, Saleh J, Koo BK, Delacour D, Kim DH. Human Microphysiological Models of Intestinal Tissue and Gut Microbiome. Front Bioeng Biotechnol 2020; 8:725. [PMID: 32850690 PMCID: PMC7411353 DOI: 10.3389/fbioe.2020.00725] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 06/09/2020] [Indexed: 12/11/2022] Open
Abstract
The gastrointestinal (GI) tract is a complex system responsible for nutrient absorption, digestion, secretion, and elimination of waste products that also hosts immune surveillance, the intestinal microbiome, and interfaces with the nervous system. Traditional in vitro systems cannot harness the architectural and functional complexity of the GI tract. Recent advances in organoid engineering, microfluidic organs-on-a-chip technology, and microfabrication allows us to create better in vitro models of human organs/tissues. These micro-physiological systems could integrate the numerous cell types involved in GI development and physiology, including intestinal epithelium, endothelium (vascular), nerve cells, immune cells, and their interplay/cooperativity with the microbiome. In this review, we report recent progress in developing micro-physiological models of the GI systems. We also discuss how these models could be used to study normal intestinal physiology such as nutrient absorption, digestion, and secretion as well as GI infection, inflammation, cancer, and metabolism.
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Affiliation(s)
- Steven N. Steinway
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jad Saleh
- Cell Adhesion and Mechanics, Institut Jacques Monod, CNRS UMR 7592, Paris Diderot University, Paris, France
| | - Bon-Kyoung Koo
- Institute of Molecular Biotechnology, Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria
| | - Delphine Delacour
- Cell Adhesion and Mechanics, Institut Jacques Monod, CNRS UMR 7592, Paris Diderot University, Paris, France
| | - Deok-Ho Kim
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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9
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Rossin D, Dias IHK, Solej M, Milic I, Pitt AR, Iaia N, Scoppapietra L, Devitt A, Nano M, Degiuli M, Volante M, Caccia C, Leoni V, Griffiths HR, Spickett CM, Poli G, Biasi F. Increased production of 27-hydroxycholesterol in human colorectal cancer advanced stage: Possible contribution to cancer cell survival and infiltration. Free Radic Biol Med 2019; 136:35-44. [PMID: 30910555 DOI: 10.1016/j.freeradbiomed.2019.03.020] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 02/08/2023]
Abstract
So far, the investigation in cancer cell lines of the modulation of cancer growth and progression by oxysterols, in particular 27-hydroxycholesterol (27HC), has yielded controversial results. The primary aim of this study was the quantitative evaluation of possible changes in 27HC levels during the different steps of colorectal cancer (CRC) progression in humans. A consistent increase in this oxysterol in CRC mass compared to the tumor-adjacent tissue was indeed observed, but only in advanced stages of progression (TNM stage III), a phase in which cancer has spread to nearby sites. To investigate possible pro-tumor properties of 27HC, its effects were studied in vitro in differentiated CaCo-2 cells. Relatively high concentrations of this oxysterol markedly increased the release of pro-inflammatory interleukins 6 and 8, monocyte chemoattractant protein-1, vascular endothelial growth factor, as well as matrix metalloproteinases 2 and 9. The up-regulation of all these molecules, which are potentially able to favor cancer progression, appeared to be dependent upon a net stimulation of Akt signaling exerted by supra-physiological amounts of 27HC.
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Affiliation(s)
- D Rossin
- Dept. of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
| | - I H K Dias
- Aston Research Centre for Healthy Ageing, School of Life and Health Sciences, Aston University, Birmingham, UK.
| | - M Solej
- Dept. of Oncology, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
| | - I Milic
- Aston Research Centre for Healthy Ageing, School of Life and Health Sciences, Aston University, Birmingham, UK.
| | - A R Pitt
- Aston Research Centre for Healthy Ageing, School of Life and Health Sciences, Aston University, Birmingham, UK.
| | - N Iaia
- Dept. of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
| | - L Scoppapietra
- Dept. of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
| | - A Devitt
- Aston Research Centre for Healthy Ageing, School of Life and Health Sciences, Aston University, Birmingham, UK.
| | - M Nano
- Dept. of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
| | - M Degiuli
- Dept. of Oncology, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
| | - M Volante
- Dept. of Oncology, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
| | - C Caccia
- Genetics of Neurodegenerative and Metabolic Diseases, Dept. of Applied Diagnostic, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
| | - V Leoni
- Department of Laboratory Medicine, University of Milano-Bicocca, School of Medicine, Hospital of Desio, Desio, Milan, Italy.
| | - H R Griffiths
- Health and Medical Sciences, University of Surrey, Guildford, UK.
| | - C M Spickett
- Aston Research Centre for Healthy Ageing, School of Life and Health Sciences, Aston University, Birmingham, UK.
| | - G Poli
- Dept. of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
| | - F Biasi
- Dept. of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
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Tumor Extracellular Matrix Remodeling: New Perspectives as a Circulating Tool in the Diagnosis and Prognosis of Solid Tumors. Cells 2019; 8:cells8020081. [PMID: 30678058 PMCID: PMC6406979 DOI: 10.3390/cells8020081] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 01/18/2019] [Accepted: 01/21/2019] [Indexed: 12/12/2022] Open
Abstract
In recent years, it has become increasingly evident that cancer cells and the local microenvironment are crucial in the development and progression of tumors. One of the major components of the tumor microenvironment is the extracellular matrix (ECM), which comprises a complex mixture of components, including proteins, glycoproteins, proteoglycans, and polysaccharides. In addition to providing structural and biochemical support to tumor tissue, the ECM undergoes remodeling that alters the biochemical and mechanical properties of the tumor microenvironment and contributes to tumor progression and resistance to therapy. A novel concept has emerged, in which tumor-driven ECM remodeling affects the release of ECM components into peripheral blood, the levels of which are potential diagnostic or prognostic markers for tumors. This review discusses the most recent evidence on ECM remodeling-derived signals that are detectable in the bloodstream, as new early diagnostic and risk prediction tools for the most frequent solid cancers.
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11
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Kovač U, Skubic C, Bohinc L, Rozman D, Režen T. Oxysterols and Gastrointestinal Cancers Around the Clock. Front Endocrinol (Lausanne) 2019; 10:483. [PMID: 31379749 PMCID: PMC6653998 DOI: 10.3389/fendo.2019.00483] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 07/03/2019] [Indexed: 12/24/2022] Open
Abstract
This review focuses on the role of oxidized sterols in three major gastrointestinal cancers (hepatocellular carcinoma, pancreatic, and colon cancer) and how the circadian clock affects the carcinogenesis by regulating the lipid metabolism and beyond. While each field of research (cancer, oxysterols, and circadian clock) is well-studied within their specialty, little is known about the intertwining mechanisms and how these influence the disease etiology in each cancer type. Oxysterols are involved in pathology of these cancers, but final conclusions about their protective or damaging effects are elusive, since the effect depends on the type of oxysterol, concentration, and the cell type. Oxysterol concentrations, the expression of key regulators liver X receptors (LXR), farnesoid X receptor (FXR), and oxysterol-binding proteins (OSBP) family are modulated in tumors and plasma of cancer patients, exposing these proteins and selected oxysterols as new potential biomarkers and drug targets. Evidence about how cholesterol/oxysterol pathways are intertwined with circadian clock is building. Identified key contact points are different forms of retinoic acid receptor related orphan receptors (ROR) and LXRs. RORs and LXRs are both regulated by sterols/oxysterols and the circadian clock and in return also regulate the same pathways, representing a complex interplay between sterol metabolism and the clock. With this in mind, in addition to classical therapies to modulate cholesterol in gastrointestinal cancers, such as the statin therapy, the time is ripe also for therapies where time and duration of the drug application is taken as an important factor for successful therapies. The final goal is the personalized approach with chronotherapy for disease management and treatment in order to increase the positive drug effects.
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12
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Testa G, Rossin D, Poli G, Biasi F, Leonarduzzi G. Implication of oxysterols in chronic inflammatory human diseases. Biochimie 2018; 153:220-231. [DOI: 10.1016/j.biochi.2018.06.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 06/07/2018] [Indexed: 12/18/2022]
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13
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The Association of Simultaneous Increase in Interleukin-6, C Reactive Protein, and Matrix Metalloproteinase-9 Serum Levels with Increasing Stages of Colorectal Cancer. JOURNAL OF ONCOLOGY 2018; 2018:2830503. [PMID: 30154846 PMCID: PMC6091449 DOI: 10.1155/2018/2830503] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Revised: 06/23/2018] [Accepted: 06/28/2018] [Indexed: 12/14/2022]
Abstract
Background Tumor development and growth are driven in many cases by inflammatory cells, which can produce cytokines and other factors that can stimulate the development of the malignant process. The aim of this study was to evaluate interleukin-6 (IL-6), C-reactive protein (CRP), matrix metalloproteinase-9 (MMP-9), serum levels in patients with colorectal cancer (CRC), and their association with the stage of CRC. Methods IL-6, MMP-9, and CRP serum levels were measured in 75 patients with CRC just before surgical treatment, as well as in 20 healthy individuals as controls. Surgically obtained tissue material was subjected to pathological analysis. Results Significant increase in CRP and IL-6 serum concentration is associated with increasing stage of CRC (p <0.05), where MMP-9 serum level was significantly higher in stages III and IV compared to the stage II CRC. Significant correlation was found between IL-6 and MMP-9 serum levels (rho=0.478; p <0.001) as well as between IL-6 and CRP serum levels (rho=0.720; p <0.001) and between MMP-9 and CRP serum levels (rho=0.379; p <0.001). Serum levels of MMP-9 and CRP have been shown to be independent predictors of the CRC stage. Conclusion Combined quantification of IL-6, MMP-9, and CRP serum levels seems to be a reliable index of inflammation-related processes during colorectal carcinogenesis.
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Böckelman C, Beilmann-Lehtonen I, Kaprio T, Koskensalo S, Tervahartiala T, Mustonen H, Stenman UH, Sorsa T, Haglund C. Serum MMP-8 and TIMP-1 predict prognosis in colorectal cancer. BMC Cancer 2018; 18:679. [PMID: 29929486 PMCID: PMC6013876 DOI: 10.1186/s12885-018-4589-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 06/13/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Almost all of the extracellular matrix (ECM) components can be degraded by the endoproteinases matrix metalloproteinases (MMPs). Important regulators of MMPs, and thereby of the extracellular environment, are tissue inhibitors of metalloproteinases (TIMPs), and especially TIMP-1. Early tumor development, as well as distant metastasis, may be results of an MMP/TIMP ratio imbalance altering the ECM. MMPs are elevated in several inflammatory conditions. Our aim is to investigate the prognostic role of MMP-8, - 9, and TIMP-1 in colorectal cancer (CRC) and their relationship to inflammation. METHODS We included 337 colorectal cancer patients and 47 controls undergoing surgery at Helsinki University Hospital in Finland, 1998-2011. Serum levels of MMP-8 and plasma levels of C-reactive protein (CRP) were determined with a time-resolved immunofluorometric assay (IFMA), and MMP-9 and TIMP-1 with commercial enzyme-linked immunosorbent assay (ELISA) kits. Association and correlation analyses were performed with the Mann-Whitney U, Kruskal-Wallis, and Spearman rank correlation tests. Survival curves were constructed according to the Kaplan-Meier method and compared with the log-rank test. RESULTS Among patients with advanced disease, serum levels of MMP-8 and TIMP-1 were elevated. CRC patients with high MMP-8 (HR (hazard ratio) 1.72, 95% confidence interval (CI) 1.17-2.52, P = 0.005) and those with high TIMP-1 (HR 1.80, 95% CI 1.23-2.64, P = 0.002) had worse prognoses. MMP-9 level failed to serve as a prognostic factor. In multivariable survival analysis, Dukes stage, and low MMP-9/TIMP-1 molar ratio (HR 0.46, 95% CI 0.33-0.98, P = 0.042) were independently predicted prognosis. A weak correlation between CRP and MMP-8 (rS = 0.229, P < 0.001), and TIMP-1 (rS = 0.280, P < 0.001) was noted. Among patients showing no systemic inflammatory response, MMP-8 (HR 1.66, 95% CI 1.10-2.53, P = 0.017) and TIMP-1 (HR 1.59, 95% CI 1.05-2.42, P = 0.029) were prognostic factors. CONCLUSIONS MMP-8 and TIMP-1 in serum, but not MMP-9, identified CRC patients with bad prognosis. Among patients showing no systemic inflammatory response, MMP-8 and TIMP-1 may associate with poor prognosis.
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Affiliation(s)
- Camilla Böckelman
- Department of Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland. .,Research Programs Unit, Translational Cancer Biology, University of Helsinki, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland.
| | - Ines Beilmann-Lehtonen
- Department of Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland
| | - Tuomas Kaprio
- Department of Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland.,Research Programs Unit, Translational Cancer Biology, University of Helsinki, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland
| | - Selja Koskensalo
- Department of Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland
| | - Taina Tervahartiala
- Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and Biomedicum Helsinki, P.O. Box 63, Haartmaninkatu 8, 2nd floor, FIN-00014, Helsinki, Finland
| | - Harri Mustonen
- Department of Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland
| | - Ulf-Håkan Stenman
- Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital, P.O. Box 700, FIN-00029 HUS, Helsinki, Finland
| | - Timo Sorsa
- Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and Biomedicum Helsinki, P.O. Box 63, Haartmaninkatu 8, 2nd floor, FIN-00014, Helsinki, Finland.,Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Caj Haglund
- Department of Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland.,Research Programs Unit, Translational Cancer Biology, University of Helsinki, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland
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15
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Liang S, Chang L. Serum matrix metalloproteinase-9 level as a biomarker for colorectal cancer: a diagnostic meta-analysis. Biomark Med 2018; 12:393-402. [PMID: 29575908 DOI: 10.2217/bmm-2017-0206] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
AIM To comprehensively evaluate the diagnostic value of serum matrix metalloproteinase-9 (MMP-9) level for colorectal cancer (CRC). METHODS Both of the relationships between MMP-9 level and CRC and the diagnostic value were evaluated from 12 eligible papers. RESULTS The high MMP-9 level increased CRC risk. The estimated sensitivity and specificity were 69 and 68%, respectively, which signified that the diagnostic value was medium. Diagnostic odds ratio and the area under the receiver operating characteristic curve suggested MMP-9 level has a moderate diagnostic value in CRC. Additionally, the likelihood matrix indicated MMP-9 levels could be considered as a biomarker for the diagnosis of CRC. CONCLUSION Patients with CRC have elevated MMP-9 levels, which is a potential biomarker for CRC diagnosis.
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Affiliation(s)
- Shucai Liang
- Luohe Medical College, Luohe 462002, Henan Province, PR China
| | - Lulin Chang
- Luohe Medical College, Luohe 462002, Henan Province, PR China
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16
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Deiana M, Calfapietra S, Incani A, Atzeri A, Rossin D, Loi R, Sottero B, Iaia N, Poli G, Biasi F. Derangement of intestinal epithelial cell monolayer by dietary cholesterol oxidation products. Free Radic Biol Med 2017; 113:539-550. [PMID: 29102636 DOI: 10.1016/j.freeradbiomed.2017.10.390] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/23/2017] [Accepted: 10/31/2017] [Indexed: 12/22/2022]
Abstract
The emerging role of the diet in the incidence of intestinal inflammatory diseases has stimulated research on the influence of eating habits with pro-inflammatory properties in inducing epithelial barrier disturbance. Cholesterol oxidation products, namely oxysterols, have been shown to promote and sustain oxidative/inflammatory reactions in human digestive tract. This work investigated in an in vitro model the potential ability of a combination of dietary oxysterols representative of a hyper-cholesterol diet to induce the loss of intestinal epithelial layer integrity. The components of the experimental mixture were the main oxysterols stemming from heat-induced cholesterol auto-oxidation, namely 7-ketocholesterol, 5α,6α-and 5β,6β-epoxycholesterol, 7α- and 7β-hydroxycholesterol. These compounds added to monolayers of differentiated CaCo-2 cells in combination or singularly, caused a time-dependent induction of matrix metalloproteinases (MMP)-2 and -9, also known as gelatinases. The hyperactivation of MMP-2 and -9 was found to be associated with decreased levels of the tight junctions zonula occludens-1 (ZO-1), occludin and Junction Adhesion Molecule-A (JAM-A). Together with such a protein loss, particularly evident for ZO-1, a net perturbation of spatial localization of the three tight junctions was observed. Cell monolayer pre-treatment with the selective inhibitor of MMPs ARP100 or polyphenol (-)-epicathechin, previously shown to inhibit NADPH oxidase in the same model system, demonstrated that the decrease of the three tight junction proteins was mainly a consequence of MMPs induction, which was in turn dependent on the pro-oxidant property of the oxysterols investigated. Although further investigation on oxysterols intestinal layer damage mechanism is to be carried on, the consequent - but incomplete - prevention of oxysterols-dependent TJs alteration due to MMPs inhibition, avoided the loss of scaffold protein ZO-1, with possible significant recovery of intestinal monolayer integrity.
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Affiliation(s)
- Monica Deiana
- Dept. of Biomedical Sciences, Pathology Section, University of Cagliari, 09124 Cagliari, Italy.
| | - Simone Calfapietra
- Dept. of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Turin, Italy.
| | - Alessandra Incani
- Dept. of Biomedical Sciences, Pathology Section, University of Cagliari, 09124 Cagliari, Italy.
| | - Angela Atzeri
- Dept. of Biomedical Sciences, Pathology Section, University of Cagliari, 09124 Cagliari, Italy.
| | - Daniela Rossin
- Dept. of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Turin, Italy.
| | - Roberto Loi
- Dept. of Biomedical Sciences, Pathology Section, University of Cagliari, 09124 Cagliari, Italy.
| | - Barbara Sottero
- Dept. of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Turin, Italy.
| | - Noemi Iaia
- Dept. of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Turin, Italy.
| | - Giuseppe Poli
- Dept. of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Turin, Italy.
| | - Fiorella Biasi
- Dept. of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Turin, Italy.
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17
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Rossin D, Calfapietra S, Sottero B, Poli G, Biasi F. HNE and cholesterol oxidation products in colorectal inflammation and carcinogenesis. Free Radic Biol Med 2017; 111:186-195. [PMID: 28089726 DOI: 10.1016/j.freeradbiomed.2017.01.017] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 01/09/2017] [Accepted: 01/10/2017] [Indexed: 12/23/2022]
Abstract
Consistent experimental data suggest the importance of inflammation-associated oxidative stress in colorectal cancer (CRC) pathogenesis. Inflammatory bowel disease with chronic intestinal inflammation is now considered a precancerous condition. Oxidative stress is an essential feature of inflammation. Activation of redox-sensitive pro-inflammatory cell signals and inflammatory mediators concur to establish a pro-tumoral environment. In this frame, lipid oxidation products, namely 4-hydroxynonenal and oxysterols, can be produced in big quantity so as to be able to exert their function as inducers of cell signaling pathways of proliferation and survival. Notably, an important source of these two compounds is represented by a high fat diet, which is undoubtedly a risk factor for inflammation and CRC development. Current evidence for the emerging implication of these two oxidized lipids in inflammation and CRC development is discussed in this review.
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Affiliation(s)
- Daniela Rossin
- Department of Clinical and Biological Sciences, University of Turin at San Luigi Gonzaga Hospital, Orbassano, Turin, Italy.
| | - Simone Calfapietra
- Department of Clinical and Biological Sciences, University of Turin at San Luigi Gonzaga Hospital, Orbassano, Turin, Italy.
| | - Barbara Sottero
- Department of Clinical and Biological Sciences, University of Turin at San Luigi Gonzaga Hospital, Orbassano, Turin, Italy.
| | - Giuseppe Poli
- Department of Clinical and Biological Sciences, University of Turin at San Luigi Gonzaga Hospital, Orbassano, Turin, Italy.
| | - Fiorella Biasi
- Department of Clinical and Biological Sciences, University of Turin at San Luigi Gonzaga Hospital, Orbassano, Turin, Italy.
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18
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Metformin Suppressed CXCL8 Expression and Cell Migration in HEK293/TLR4 Cell Line. Mediators Inflamm 2017; 2017:6589423. [PMID: 29147073 PMCID: PMC5632916 DOI: 10.1155/2017/6589423] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 06/22/2017] [Accepted: 08/24/2017] [Indexed: 01/28/2023] Open
Abstract
Chronic inflammation is associated with cancer. CXCL8 promotes tumor microenvironment construction through recruiting leukocytes and endothelial progenitor cells that are involved in angiogenesis. It also enhances tumor cell proliferation and migration. Metformin, type II diabetes medication, demonstrates anticancer properties via suppressing inflammation, tumor cell proliferation, angiogenesis, and metastasis. This study intended to address the role of metformin in regulation of CXCL8 expression and cell proliferation and migration. Our data indicated that metformin suppressed LPS-induced CXCL8 expression in a dose-dependent manner through inhibiting NF-κB, but not AP-1 and C/EBP, activities under the conditions we used. This inhibitory effect of metformin is achieved through dampening LPS-induced NF-κB nuclear translocation. Cell migration was inhibited by metformin under high dose (10 mM), but not cell proliferation.
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19
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Milovanovic J, Todorovic-Rakovic N, Vujasinovic T, Abu Rabi Z. Interleukin 8 in progression of hormone-dependent early breast cancer. J Biosci 2017; 42:265-274. [PMID: 28569250 DOI: 10.1007/s12038-017-9679-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Jelena Milovanovic
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
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20
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Okada R, Naito M, Hattori Y, Seiki T, Wakai K, Nanri H, Watanabe M, Suzuki S, Kairupan TS, Takashima N, Mikami H, Ohnaka K, Watanabe Y, Katsuura-Kamano S, Kubo M, Hamajima N, Tanaka H. Matrix metalloproteinase 9 gene polymorphisms are associated with a multiple family history of gastric cancer. Gastric Cancer 2017; 20:246-253. [PMID: 27053167 DOI: 10.1007/s10120-016-0608-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 03/30/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND A family history of gastric cancer (GC) is a well-known risk factor of GC. Genetic variations in genes of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been related to the risk of GC, but their association with familial background is not clear. We investigated whether individuals with a multiple family history of GC have more risk genotypes of MMP/TIMP genes. METHODS We genotyped ten common functional polymorphisms of MMP/TIMP genes in 4427 individuals aged 35-69 years without a history of GC who were enrolled in the Japan Multi-institutional Collaborative Cohort Study. Individuals who have two or more first-degree relatives (parents and siblings) with GC were categorized as having a multiple family history. Odds ratios (ORs) for multiple family history compared with no family history were calculated. RESULTS MMP9 279QQ (rs17576) was more frequently observed in individuals whose both parents had a history of GC (n = 23) and in individuals for whom one parent and their sibling(s) had a history of GC (n = 36) compared with those with no family history (n = 3816) [30.4 % vs 11.6 %, OR 4.34, 95 % confidence interval (CI) 1.45-13.03 and 16.7 % vs 11.6 %, OR 2.26, 95 % CI 0.81-6.27 after adjustment for age, sex, and current smoking]. The population attributable fraction was 38.1 %. The haplotype MMP9-1562C/279Q/668Q was more frequently observed in individuals whose both parents had a history of GC and in individuals for whom one parent and their sibling(s) had a history of GC compared with those with no family history (OR 3.35, 95 % CI 0.75-14.96 and OR 3.51, 95 % CI 1.35-9.15 respectively). CONCLUSIONS MMP9 polymorphisms were associated with a multiple family history of GC. Screening for these genotypes together with familial background may help us to identify individuals at an increased risk of GC.
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Affiliation(s)
- Rieko Okada
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan.
| | - Mariko Naito
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Yuta Hattori
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Toshio Seiki
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Hinako Nanri
- Department of Public Health, Showa University School of Medicine, Tokyo, Japan
| | - Miki Watanabe
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.,Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Sadao Suzuki
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tara Sefanya Kairupan
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Naoyuki Takashima
- Department of Health Science, Shiga University of Medical Science, Otsu, Japan
| | - Haruo Mikami
- Division of Cancer Prevention and Epidemiology, Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Keizo Ohnaka
- Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshiyuki Watanabe
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Sakurako Katsuura-Kamano
- Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Michiaki Kubo
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Nobuyuki Hamajima
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideo Tanaka
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.,Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Rasic I, Radovic S, Aksamija G. Relationship Between Chronic Inflammation and the Stage and Histopathological Size of Colorectal Carcinoma. Med Arch 2016; 70:104-7. [PMID: 27147782 PMCID: PMC4851510 DOI: 10.5455/medarh.2016.70.104-107] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 03/18/2016] [Indexed: 01/05/2023] Open
Abstract
Objectives: The association of inflammatory reactions with almost all types of cancer supports the concept that inflammation is a critical component of tumor progression. The present study aimed to evaluate the relationship of serum markers of chronic inflammation with the stage of and histopathological size of colorectal carcinoma (CRC). Methods: This cross-sectional study included 90 patients of both sexes, mean age 66.2 (range 47-78) years, with clinically and histologically confirmed CRC, who were admitted to the Clinic for abdominal surgery UCCS for surgical treatment of CRC. The patients according to the stage of disease were divided into three groups (stage II–IV). The control group consisted of 30 subjects with no signs of malignancy and acute inflammatory diseases. Staging of CRC was done according to the TNM classification. In each patient, the preoperative blood samples were taken for determination of the parameters of inflammation: the erythrocyte sedimentation rate, white blood cells, C-reactive protein (CRP), fibrinogen and alpha 2 globulins. Results: It was confirmed that increasing markers of inflammation followed increasing stages of colorectal cancer, depth of tumor invasion and the occurrence of metastatic disease. CRP is a biomarker that consistently and significantly increases from the second to the fourth stage of colorectal cancer (7.2 (2.3-14.6) mg/L vs. 21.85 (12.3-41) mg/L vs. 38.6 (21.5-79) mg/L; p<0.01) and significantly correlates positively with the stage of CRC (r= 0.783, p<0.001), and the tumor size (r=0.249, p<0.05). Conclusion: The study results point to an increase in the degree of chronic inflammation throughout the progression of colorectal cancer. The most consistent marker of chronic inflammation that accompanies the progression of colorectal carcinoma is CRP.
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Affiliation(s)
- Ismar Rasic
- Clinic for Abdominal Surgery, Clinical Center of the University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Svjetlana Radovic
- Department of Pathology, Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Goran Aksamija
- Clinic for Abdominal Surgery, Clinical Center of the University of Sarajevo, Sarajevo, Bosnia and Herzegovina
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Plasma matrix metalloproteinase 9 as an early surrogate biomarker of advanced colorectal neoplasia. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 39:433-41. [PMID: 26601990 DOI: 10.1016/j.gastrohep.2015.10.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2015] [Revised: 09/23/2015] [Accepted: 10/01/2015] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Matrix metalloproteinases (MMPs) are overexpressed at different stages of colorectal carcinogenesis and could serve as early surrogate biomarkers of colorectal neoplasia. OBJECTIVE To assess the utility of plasma MMP2 and MMP9 levels in the detection of advanced colorectal neoplasia and their correlation with tissue levels. METHODS We analysed blood and tissue samples from patients with non-advanced adenomas (n=25), advanced adenomas (n=25), colorectal cancer (n=25) and healthy controls (n=75). Plasma and tissue gelatinase levels were determined by Luminex XMAP technology and gelatin zymography. Receiver operating characteristic (ROC) curve analysis was used to calculate the optimum cut-off for the detection of advanced colorectal neoplasia. RESULTS Plasma MMP2 levels were similar between groups whatever the type of lesion. Plasma MMP9 levels were significantly higher in patients with neoplastic lesions than in healthy controls (median 292.3ng/ml vs. 139.08ng/ml, P<0.001). MMP9 levels were also higher in colorectal cancer than in non-advanced adenomas (median 314.6ng/ml vs. 274.3ng/ml, P=0.03). There was a significant correlation between plasma and tissue levels of MMP9 (r=0.5, P<0.001). The plasma MMP9 cut-off range with the highest diagnostic accuracy was between 173ng/ml and 204ng/ml (AUC=0.80 [95% CI: 0.72-0.86], P<0.001; sensitivity, 80-86% and specificity, 57-67%). CONCLUSION Plasma MMP9 could be a surrogate biomarker for the early detection of advanced colorectal neoplasia, although its diagnostic performance could be increased by combination with other biomarkers.
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23
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Serum matrix metalloproteinase-9 in colorectal cancer family-risk population screening. Sci Rep 2015; 5:13030. [PMID: 26264519 PMCID: PMC4532998 DOI: 10.1038/srep13030] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 07/15/2015] [Indexed: 12/15/2022] Open
Abstract
Matrix metalloproteinase-9 (MMP-9) is related to tumour development and progression in colorectal cancer (CRC) and its utility as biomarker has been suggested. The aim of our study was to measure serum MMP-9 in asymptomatic first-degree relatives of CRC patients, and to analyse its diagnostic accuracy for the detection of advanced neoplasia (AN: advanced adenomas and CRC). Additionally, we compared its diagnostic capability with the most used non-invasive faecal immunochemical test (FIT). Serum MMP-9 was quantified by ELISA in 516 asymptomatic individuals that underwent a colonoscopy and a FIT. MMP-9 levels were significantly related to age and gender and therefore the concentration was corrected by these confounders. Corrected MMP-9 (cMMP-9) levels were higher in individuals with advanced adenomas (AA; p-value = 0.029) and AN (p-value = 0.056) compared to individuals with no neoplasia. Moreover, elevated cMMP-9 concentration was associated with more severe characteristics of adenomas (number of lesions, size and histology). Nevertheless, the diagnostic accuracy of cMMP-9 was considerably lower than that of FIT for identifying AA (22.64% vs. 47.17% sensitivity, 90% specificity) or AN (19.30% vs. 52.63% sensitivity, 90% specificity). According to our results, serum MMP-9 cannot be considered of utility for the diagnosis of AN in CRC family-risk population screening.
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Guina T, Biasi F, Calfapietra S, Nano M, Poli G. Inflammatory and redox reactions in colorectal carcinogenesis. Ann N Y Acad Sci 2015; 1340:95-103. [PMID: 25727454 DOI: 10.1111/nyas.12734] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
It has been established that there is a relationship between chronic inflammation and cancer development. The constant colonic inflammation typical of inflammatory bowel diseases is now considered a risk factor for colorectal carcinoma (CRC) development. The inflammatory network of signaling molecules is also required during the late phases of carcinogenesis, to enable cancer cells to survive and to metastasize. Oxidative reactions are an integral part of the inflammatory response, and are generally associated with CRC development. However, when the malignant phenotype is acquired, increased oxidative status induces antioxidant defenses in cancer cells, favoring their aggressiveness. This contradictory behavior of cancer cells toward redox status is of great significance for potential anticancer therapies. This paper summarizes the essential background information relating to the molecules involved in regulating oxidative stress and inflammation during carcinogenesis. Understanding more of their function in CRC stages might provide the foundation for future developments in CRC treatment.
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Affiliation(s)
- Tina Guina
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
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Herszényi L, Barabás L, Hritz I, István G, Tulassay Z. Impact of proteolytic enzymes in colorectal cancer development and progression. World J Gastroenterol 2014; 20:13246-13257. [PMID: 25309062 PMCID: PMC4188883 DOI: 10.3748/wjg.v20.i37.13246] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 01/26/2014] [Accepted: 05/23/2014] [Indexed: 02/06/2023] Open
Abstract
Tumor invasion and metastasis is a highly complicated, multi-step phenomenon. In the complex event of tumor progression, tumor cells interact with basement membrane and extracellular matrix components. Proteolytic enzymes (proteinases) are involved in the degradation of extracellular matrix, but also in cancer invasion and metastasis. The four categories of proteinases (cysteine-, serine-, aspartic-, and metalloproteinases) are named and classified according to the essential catalytic component in their active site. We and others have shown that proteolytic enzymes play a major role not only in colorectal cancer (CRC) invasion and metastasis, but also in malignant transformation of precancerous lesions into cancer. Tissue and serum-plasma antigen concentrations of proteinases might be of great value in identifying patients with poor prognosis in CRC. Our results, in concordance with others indicate the potential tumor marker impact of proteinases for the early diagnosis of CRC. In addition, proteinases may also serve as potential target molecules for therapeutic agents.
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The Chemokine CXCL8 in Carcinogenesis and Drug Response. ISRN ONCOLOGY 2013; 2013:859154. [PMID: 24224100 PMCID: PMC3810054 DOI: 10.1155/2013/859154] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Accepted: 09/08/2013] [Indexed: 02/08/2023]
Abstract
Although the functions of chemokines in the regulation of immune processes have been studied in some detail, the role of these biomolecules in cancer is not fully understood. Chemokines mediate migration of immune cells and other functions related to immunity. They are also involved in oncogenesis and in tumor progression, invasion, and metastasis through mechanisms similar to their roles in immune functions. Various chemokines also promote cell proliferation and resistance to apoptosis of stressed cells. Consequently, chemokines and their receptors present potential therapeutic targets for anticancer drugs. The chemokine CXCL8, also known as interleukin-8 (IL8), is a proinflammatory molecule that has functions within the tumor microenvironment. Due to its potent angiogenic effects and the activity of the chemokine and its receptors in the promotion of invasion and metastasis, CXCL8 and its receptors are now considered as attractive targets for cancer therapy. This review relates the current understanding of the regulation, signaling, and functions of CXCL8 that contribute to tumor growth and metastasis, and of its role in drug response.
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Assessing the value of matrix metalloproteinase 9 (MMP9) in improving the appropriateness of referrals for colorectal cancer. Br J Cancer 2013; 108:1149-56. [PMID: 23392084 PMCID: PMC3619067 DOI: 10.1038/bjc.2013.49] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND A blood test may be an effective means of improving the appropriateness of referrals for symptomatic patients referred to specialist colorectal clinics. We evaluated the accuracy of a serum matrix metalloproteinase (MMP9) test in indicating colorectal cancer or its precursor conditions in a symptomatic population. METHODS Patients aged over 18, referred urgently or routinely to secondary care following primary care presentation with colorectal symptoms completed a questionnaire and provided a blood sample for serum MMP9 estimation. Univariate analysis and logistic regression modelling investigated the association between presenting symptoms, MMP9 measurements and the diagnostic outcome of patient investigations, in order to derive the combination of factors which best predicted a high risk of malignancy. RESULTS Data were analysed for 1002 patients. Forty-seven cases of neoplasia were identified. Age, male gender, absence of anal pain, diabetes, blood in stools, urgent referral, previous bowel polyps and previous bowel cancer were significantly associated with neoplasia. Matrix metalloproteinase 9 measurements were not found to be associated with significant colorectal pathology. CONCLUSION This study, despite robust sampling protocols, showed no clear association between MMP9 and colorectal neoplasia. Matrix metalloproteinase 9 therefore appears to have little value as a tool to aid referral decisions in the symptomatic population.
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