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Lyon-Colbert AD, Basson MD, Klug MG, Schwartz GG. Well water contaminants and colorectal cancer in North Dakota. World J Clin Oncol 2024; 15:1454-1458. [PMID: 39582609 PMCID: PMC11514423 DOI: 10.5306/wjco.v15.i11.1454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 09/16/2024] [Accepted: 09/25/2024] [Indexed: 10/14/2024] Open
Abstract
This study aims to identify common contaminants in well water linked to an increase in colorectal cancer (CRC) incidence rates in North Dakota (ND) counties. County-specific incidence rates for CRC were obtained from the ND Statewide Cancer Registry. Corresponding demographic, agricultural, and geophysical data were obtained from population-based sources. Associations between well water contaminants and CRC incidence were examined for 16 counties in ND with complete well water profiles between 1997-2019. Data were analyzed by multiple linear regression. Iron in well water exhibited a significant positive association with CRC incidence (4.75, P = 0.001), and barium exhibited a small, but significant negative association (-0.06907, P = 0.01). Residents in counties in ND with prevalent well water usage contaminated with iron may be at higher risk for CRC.
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Affiliation(s)
- Amber D Lyon-Colbert
- Department of Population Health, University of North Dakota, Grand Forks, ND 58202, United States
| | - Marc D Basson
- College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, United States
- College of Medicine, University Hospitals, Cleveland, OH 44106, United States
| | - Marilyn G Klug
- Department of Population Health, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202, United States
| | - Gary G Schwartz
- Department of Population Health, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202, United States
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2
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Canonical Wnt Signaling in the Pathology of Iron Overload-Induced Oxidative Stress and Age-Related Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7163326. [PMID: 35116092 PMCID: PMC8807048 DOI: 10.1155/2022/7163326] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/04/2022] [Indexed: 12/26/2022]
Abstract
Iron accumulates in the vital organs with aging. This is associated with oxidative stress, inflammation, and mitochondrial dysfunction leading to age-related disorders. Abnormal iron levels are linked to neurodegenerative diseases, liver injury, cancer, and ocular diseases. Canonical Wnt signaling is an evolutionarily conserved signaling pathway that regulates many cellular functions including cell proliferation, apoptosis, cell migration, and stem cell renewal. Recent evidences indicate that iron regulates Wnt signaling, and iron chelators like deferoxamine and deferasirox can inhibit Wnt signaling and cell growth. Canonical Wnt signaling is implicated in the pathogenesis of many diseases, and there are significant efforts ongoing to develop innovative therapies targeting the aberrant Wnt signaling. This review examines how intracellular iron accumulation regulates Wnt signaling in various tissues and their potential contribution in the progression of age-related diseases.
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3
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Stokowa-Soltys K, Kierpiec K, Wieczorek R. May Cu(II) binding, DNA cleavage and radicals production by YadA fragments be involved in the promotion of F. nucleatum related cancers? Dalton Trans 2022; 51:7040-7052. [DOI: 10.1039/d2dt00328g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
In many cases, human microbiota is associated with cancer progression. It was concluded that Fusobacterium nucleatum increases neoplastic changes. This bacterium is naturally present in the human dental plaque. However,...
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4
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Mertens C, Marques O, Horvat NK, Simonetti M, Muckenthaler MU, Jung M. The Macrophage Iron Signature in Health and Disease. Int J Mol Sci 2021; 22:ijms22168457. [PMID: 34445160 PMCID: PMC8395084 DOI: 10.3390/ijms22168457] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 12/13/2022] Open
Abstract
Throughout life, macrophages are located in every tissue of the body, where their main roles are to phagocytose cellular debris and recycle aging red blood cells. In the tissue niche, they promote homeostasis through trophic, regulatory, and repair functions by responding to internal and external stimuli. This in turn polarizes macrophages into a broad spectrum of functional activation states, also reflected in their iron-regulated gene profile. The fast adaptation to the environment in which they are located helps to maintain tissue homeostasis under physiological conditions.
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Affiliation(s)
- Christina Mertens
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany; (O.M.); (N.K.H.); (M.U.M.)
- Correspondence: (C.M.); (M.J.); Tel.: +(49)-622-156-4582 (C.M.); +(49)-696-301-6931 (M.J.)
| | - Oriana Marques
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany; (O.M.); (N.K.H.); (M.U.M.)
- Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
| | - Natalie K. Horvat
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany; (O.M.); (N.K.H.); (M.U.M.)
- Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), Collaboration for Joint PhD Degree between EMBL and the Faculty of Biosciences, University of Heidelberg, 69117 Heidelberg, Germany
| | - Manuela Simonetti
- Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University, INF 366, 69120 Heidelberg, Germany;
| | - Martina U. Muckenthaler
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany; (O.M.); (N.K.H.); (M.U.M.)
- Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
| | - Michaela Jung
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
- Correspondence: (C.M.); (M.J.); Tel.: +(49)-622-156-4582 (C.M.); +(49)-696-301-6931 (M.J.)
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Al-Hassi HO, Ng O, Evstatiev R, Mangalika M, Worton N, Jambrich M, Khare V, Phipps O, Keeler B, Gasche C, Acheson AG, Brookes MJ. Intravenous iron is non-inferior to oral iron regarding cell growth and iron metabolism in colorectal cancer associated with iron-deficiency anaemia. Sci Rep 2021; 11:13699. [PMID: 34211054 PMCID: PMC8249613 DOI: 10.1038/s41598-021-93155-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 06/10/2021] [Indexed: 01/25/2023] Open
Abstract
Oral iron promotes intestinal tumourigenesis in animal models. In humans, expression of iron transport proteins are altered in colorectal cancer. This study examined whether the route of iron therapy alters iron transport and tumour growth. Colorectal adenocarcinoma patients with pre-operative iron deficiency anaemia received oral ferrous sulphate (n = 15), or intravenous ferric carboxymaltose (n = 15). Paired (normal and tumour tissues) samples were compared for expression of iron loading, iron transporters, proliferation, apoptosis and Wnt signalling using immunohistochemistry and RT-PCR. Iron loading was increased in tumour and distributed to the stroma in intravenous treatment and to the epithelium in oral treatment. Protein and mRNA expression of proliferation and iron transporters were increased in tumours compared to normal tissues but there were no significant differences between the treatment groups. However, intravenous iron treatment reduced ferritin mRNA levels in tumours and replenished body iron stores. Iron distribution to non-epithelial cells in intravenous iron suggests that iron is less bioavailable to tumour cells. Therefore, intravenous iron may be a better option in the treatment of colorectal cancer patients with iron deficiency anaemia due to its efficiency in replenishing iron levels while its effect on proliferation and iron metabolism is similar to that of oral iron treatment.
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Affiliation(s)
- Hafid O Al-Hassi
- Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK
| | - Oliver Ng
- NIHR Nottingham Biomedical Research Centre and the University of Nottingham, Nottingham, UK
| | - Rayko Evstatiev
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | | | | | - Manuela Jambrich
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Vineeta Khare
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Oliver Phipps
- Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK
| | - Barrie Keeler
- NIHR Nottingham Biomedical Research Centre and the University of Nottingham, Nottingham, UK
| | - Christoph Gasche
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Austin G Acheson
- NIHR Nottingham Biomedical Research Centre and the University of Nottingham, Nottingham, UK
| | - Matthew J Brookes
- Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK. .,The Royal Wolverhampton NHS Trust, Wolverhampton, UK.
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Aksan A, Farrag K, Aksan S, Schroeder O, Stein J. Flipside of the Coin: Iron Deficiency and Colorectal Cancer. Front Immunol 2021; 12:635899. [PMID: 33777027 PMCID: PMC7991591 DOI: 10.3389/fimmu.2021.635899] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/18/2021] [Indexed: 12/12/2022] Open
Abstract
Iron deficiency, with or without anemia, is the most frequent hematological manifestation in individuals with cancer, and is especially common in patients with colorectal cancer. Iron is a vital micronutrient that plays an essential role in many biological functions, in the context of which it has been found to be intimately linked to cancer biology. To date, however, whereas a large number of studies have comprehensively investigated and reviewed the effects of excess iron on cancer initiation and progression, potential interrelations of iron deficiency with cancer have been largely neglected and are not well-defined. Emerging evidence indicates that reduced iron intake and low systemic iron levels are associated with the pathogenesis of colorectal cancer, suggesting that optimal iron intake must be carefully balanced to avoid both iron deficiency and iron excess. Since iron is vital in the maintenance of immunological functions, insufficient iron availability may enhance oncogenicity by impairing immunosurveillance for neoplastic changes and potentially altering the tumor immune microenvironment. Data from clinical studies support these concepts, showing that iron deficiency is associated with inferior outcomes and reduced response to therapy in patients with colorectal cancer. Here, we elucidate cancer-related effects of iron deficiency, examine preclinical and clinical evidence of its role in tumorigenesis, cancer progression and treatment response. and highlight the importance of adequate iron supplementation to limit these outcomes.
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Affiliation(s)
- Aysegül Aksan
- Institute of Nutritional Science, Justus-Liebig University, Giessen, Germany
- Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany
- Interdisziplinäres Crohn Colitis Centrum, Rhein-Main, Frankfurt, Germany
| | - Karima Farrag
- Interdisziplinäres Crohn Colitis Centrum, Rhein-Main, Frankfurt, Germany
- DGD Kliniken Sachsenhausen, Frankfurt, Germany
| | - Sami Aksan
- Interdisziplinäres Crohn Colitis Centrum, Rhein-Main, Frankfurt, Germany
- DGD Kliniken Sachsenhausen, Frankfurt, Germany
| | - Oliver Schroeder
- Interdisziplinäres Crohn Colitis Centrum, Rhein-Main, Frankfurt, Germany
- DGD Kliniken Sachsenhausen, Frankfurt, Germany
| | - Jürgen Stein
- Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany
- Interdisziplinäres Crohn Colitis Centrum, Rhein-Main, Frankfurt, Germany
- DGD Kliniken Sachsenhausen, Frankfurt, Germany
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7
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Wilson MJ, Koopman-van Gemert AW, Harlaar JJ, Jeekel J, Zwaginga JJ, Schipperus M. Patient blood management in colorectal cancer patients: a survey among Dutch gastroenterologists, surgeons, and anesthesiologists. Transfusion 2018; 58:2345-2351. [DOI: 10.1111/trf.14807] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 04/25/2018] [Accepted: 04/27/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Michael J. Wilson
- TRIP Hemovigilance and Biovigilance Office; Leiden The Netherlands
- Department of Surgery, Erasmus University Medical Center; Rotterdam The Netherlands
| | | | - Joris J. Harlaar
- Department of Surgery; VU Medical Center; Amsterdam The Netherlands
- Department of Surgery; Westfries Gasthuis; Hoorn The Netherlands
| | - Johannes Jeekel
- Department of Neuroscience; Erasmus University Medical Center; Rotterdam The Netherlands
| | - Jaap Jan Zwaginga
- Center for Clinical Transfusion Research; Sanquin Research
- Department of Immunohematology and Blood Transfusion; Leiden University Medical Center; Leiden The Netherlands
| | - Martin Schipperus
- TRIP Hemovigilance and Biovigilance Office; Leiden The Netherlands
- Department of Hematology; Haga Teaching Hospital; The Hague The Netherlands
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8
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The effect of intravenous iron therapy on long-term survival in anaemic colorectal cancer patients: Results from a matched cohort study. Surg Oncol 2018; 27:192-199. [DOI: 10.1016/j.suronc.2018.03.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 03/02/2018] [Accepted: 03/26/2018] [Indexed: 12/27/2022]
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9
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Wilson MJ, Dekker JW, Bruns E, Borstlap W, Jeekel J, Zwaginga JJ, Schipperus M. Short-term effect of preoperative intravenous iron therapy in colorectal cancer patients with anemia: results of a cohort study. Transfusion 2017; 58:795-803. [PMID: 29250797 DOI: 10.1111/trf.14456] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 09/18/2017] [Accepted: 11/06/2017] [Indexed: 01/28/2023]
Abstract
BACKGROUND In the treatment of preoperative anemia, which is associated with increased postoperative morbidity, iron supplementation can replace blood transfusion and erythropoiesis-stimulating agents. The aim of this study was to assess the efficacy of preoperative intravenous (IV) iron infusion in optimizing hemoglobin (Hb) levels in anemic colorectal cancer patients. STUDY DESIGN AND METHODS A retrospective cohort study was performed on patients who underwent surgery for colorectal cancer between 2010 and 2016 in a single teaching hospital. The primary outcome measure, the change in Hb level, was assessed by comparing anemic patients receiving usual care (UC; i.e. no iron therapy and no blood transfusion) with anemic patients receiving IV iron therapy (no blood transfusion). RESULTS A total of 758 patients with colorectal cancer were eligible, of whom 318 (41.9%) had anemia. The IV and the UC groups included 52 and 153 patients with mean Hb levels at diagnosis of 6.3 and 6.9 mmol/L, respectively. In the IV group, preoperative Hb level was significantly increased compared to the UC group (0.65 mmol/L vs. 0.10 mmol/L, p < 0.001). High increase in Hb level after iron infusion was associated with initial higher transferrin and lower ferritin levels (high vs. poor responders: median transferrin 2.9 g/L vs. 2.7 g/L, median ferritin 12 µg/L vs. 27 µg/L). CONCLUSION Implementation of IV iron therapy in anemic colorectal cancer patients leads to a distinct increase of preoperative Hb level. IV iron therapy is most effective in patients presenting with more severe anemia, and with higher transferrin and lower ferritin levels, markers for an absolute iron deficiency (ID), compared to functional ID.
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Affiliation(s)
- Michael Jordi Wilson
- TRIP Hemovigilance and Biovigilance Office, Leiden, the Netherlands.,Department of Surgery, Rotterdam, the Netherlands
| | - Jan Willem Dekker
- Department of Surgery, Reinier de Graaf Hospital, Delft, the Netherlands
| | - Emma Bruns
- Department of Surgery, Academic Medical Center, Amsterdam, the Netherlands
| | - Wernard Borstlap
- Department of Surgery, Academic Medical Center, Amsterdam, the Netherlands
| | - Johannes Jeekel
- Department of Neuroscience, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Jaap Jan Zwaginga
- Center for Clinical Transfusion Research, Sanquin Research, Leiden.,Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
| | - Martin Schipperus
- TRIP Hemovigilance and Biovigilance Office, Leiden, the Netherlands.,Department of Hematology, Haga Teaching Hospital, the Hague, the Netherlands
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10
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Wilson MJ, Harlaar JJ, Jeekel J, Schipperus M, Zwaginga JJ. Iron therapy as treatment of anemia: A potentially detrimental and hazardous strategy in colorectal cancer patients. Med Hypotheses 2017; 110:110-113. [PMID: 29317052 DOI: 10.1016/j.mehy.2017.12.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 11/21/2017] [Accepted: 12/03/2017] [Indexed: 01/22/2023]
Abstract
In colorectal cancer patients, iron therapy, and especially intravenous iron therapy, is increasingly used to treat anemia and reduce the use of blood transfusions. However, iron has also been shown to be an essential nutrient for rapidly proliferating tissues and cells. In this respect, anemia of inflammation, characterized by limited duodenal iron uptake and sequestration of iron into the reticuloendothelial system, might be regarded as a potentially effective defense strategy of the human body against tumor growth. We therefore hypothesize that iron therapy, by supporting colorectal tumor growth and increasing the metastatic potential, may worsen tumor prognosis in colorectal cancer patients. This hypothesis is particularly supported for colorectal cancer by laboratory, epidemiological and animal studies, demonstrating the role of iron in all aspects of tumor development growth. Compared to non-malignant colon cells, tumor cells differ in the levels and activity of many iron import and export proteins, resulting in an increase in intracellular iron level and enhanced proliferation. In addition, it is demonstrated that iron is able to amplify Wnt signaling in tumors with Apc mutation, a critical mutation in the development of colorectal cancer. If our hypothesis is to be confirmed, current practice of iron administration, as treatment for anemia and as replacement of blood transfusions, can be hazardous and should be completely reconsidered.
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Affiliation(s)
- M J Wilson
- TRIP Hemovigilance and Biovigilance Office, Leiden, The Netherlands; Erasmus University Medical Center Rotterdam, Department of Surgery, The Netherlands.
| | - J J Harlaar
- VU Medical Center Amsterdam, Department of Surgery, The Netherlands
| | - J Jeekel
- Erasmus University Medical Center Rotterdam, Department of Neuroscience, The Netherlands
| | - M Schipperus
- TRIP Hemovigilance and Biovigilance Office, Leiden, The Netherlands; Haga Teaching Hospital the Hague, Department of Hematology, The Netherlands
| | - J J Zwaginga
- Center for Clinical Transfusion Research, Sanquin Research, Leiden, The Netherlands; Leiden University Medical Center, Department of Immunohematology and Blood Transfusion, The Netherlands
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11
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Zhang LJ, Chen B, Zhang JJ, Li J, Yang Q, Zhong QS, Zhan S, Liu H, Cai C. Serum polyunsaturated fatty acid metabolites as useful tool for screening potential biomarker of colorectal cancer. Prostaglandins Leukot Essent Fatty Acids 2017; 120:25-31. [PMID: 28515019 DOI: 10.1016/j.plefa.2017.04.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 02/14/2017] [Accepted: 04/04/2017] [Indexed: 02/08/2023]
Abstract
The biomarker identification of cancer is benefit for early detection and less invasion. Polyunsaturated fatty acid (PUFA) metabolite as inflammatory mediators can affect progression and treatment of cancer. In this work, the serum was collected from colorectal cancer patients and healthy volunteers, and then we tested the change of serum PUFA metabolites in both of them by ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Of the 158 PUFA and their metabolites, we found that abnormal change of 2, 3-dinor-8-iso-PGF2α, 19-HETE and 12-keto-LTB4 from arachidonic acid were observed in colorectal cancer patients. Meanwhile, 9-HODE and 13-HODE from linoleic acid were significant lower in colorectal cancer patients. Our data suggested that some PUFA metabolites might be used as a potential biomarker of colorectal cancer, which might provide assistance in clinical diagnosis and treatment.
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Affiliation(s)
- Li-Jian Zhang
- Guangdong key laboratory for research and development of nature drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, China
| | - Bin Chen
- Guangdong key laboratory for research and development of nature drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, China
| | - Jun-Jie Zhang
- Guangdong key laboratory for research and development of nature drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, China
| | - Jian Li
- Guangdong key laboratory for research and development of nature drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, China
| | - Qingjing Yang
- Guangdong key laboratory for research and development of nature drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, China
| | - Qi-Sheng Zhong
- Shimadzu Global COE for Application& Technical Development, Guangzhou, Guangdong, 510010, China
| | - Song Zhan
- Shimadzu Global COE for Application& Technical Development, Guangzhou, Guangdong, 510010, China
| | - Huwei Liu
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Institute of Analytical Chemistry, College of Chemistry and Molecular Engineering Peking University Beijing, 100871, China.
| | - Chun Cai
- Guangdong key laboratory for research and development of nature drugs, Guangdong Medical University, Zhanjiang, Guangdong 524023, China.
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12
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Wilson MJ, van Haaren M, Harlaar JJ, Park HC, Bonjer HJ, Jeekel J, Zwaginga JJ, Schipperus M. Long-term prognostic value of preoperative anemia in patients with colorectal cancer: A systematic review and meta-analysis. Surg Oncol 2017; 26:96-104. [PMID: 28317592 DOI: 10.1016/j.suronc.2017.01.005] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 01/12/2017] [Accepted: 01/31/2017] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To evaluate the long-term prognostic factor of preoperative anemia in colorectal cancer patients. BACKGROUND Anemia is frequently observed in colorectal cancer patients, with a case incidence of 30 to 67 percent. Besides an indicator of tumor-induced blood loss and inflammation, anemia in cancer is also suggested to be a cause of inferior outcome, possibly via worsening of tumor hypoxia. As surgery is likely to enhance anemia, the long-term prognostic value of preoperative anemia seems most interesting. METHODS Comprehensive searches were carried out in all relevant databases, including MEDLINE, Embase and Web-of-Science. To include studies addressing overall survival, follow-up had to be at least 24 months or till death. For pooling of survival results, a mixed-linear (fixed-effects) model was fit to the reported hazard ratios (HRs) to calculate a pooled estimate and confidence interval. RESULTS We included 12 studies comprising 3588 patients to estimate the association between preoperative anemia and overall survival (OS) and disease-free survival (DFS). In a fixed-effects meta-analysis of eight studies, including both colon and rectal cancer, preoperative anemia was significantly associated with poor OS (HR 1.56; 95% CI 1.30 to 1.88; p < 0.001). A meta-analysis of seven studies also showed that preoperative anemia was significantly associated with poor DFS (HR 1.34; 95% CI 1.11 to 1.61; p = 0.002). Restricted to studies exclusively on colon cancer or rectal cancer, HRs for OS were 1.25 (95% CI 1.00 to 1.55; p = 0.05) and 2.59 (95% CI 1.68 to 4.01; p < 0.001), respectively, while HRs for DFS were 1.21 (95% CI 0.96 to 1.52; p = 0.11) and 1.61 (95% CI 1.18 to 2.21; p = 0.003). CONCLUSION The present meta-analysis reveals that preoperative anemia is significantly associated with decreased long-term OS and DFS in rectal cancer, but not in colon cancer patients, although this meta-analysis is mainly based on retrospective studies with high heterogeneity. These results justify raised awareness about the impact of preoperative anemia on long-term survival.
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Affiliation(s)
- M J Wilson
- TRIP Hemovigilance and Biovigilance Office, Leiden, The Netherlands; Erasmus University Medical Center Rotterdam, Department of Surgery, The Netherlands.
| | - M van Haaren
- OLVG Amsterdam, Department of Internal Medicine, The Netherlands
| | - J J Harlaar
- Westfriesgasthuis Hoorn, Department of Surgery, The Netherlands; VU Medical Center Amsterdam, Department of Surgery, The Netherlands
| | - Hee Chul Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Department of Radiation Oncology, Seoul, South Korea
| | - H J Bonjer
- VU Medical Center Amsterdam, Department of Surgery, The Netherlands
| | - J Jeekel
- Erasmus University Medical Center Rotterdam, Department of Neuroscience, The Netherlands
| | - J J Zwaginga
- Center for Clinical Transfusion Research, Sanquin Research, Leiden, The Netherlands; Leiden University Medical Center, Department of Immunohematology and Blood Transfusion, The Netherlands
| | - M Schipperus
- Haga Ziekenhuis Den Haag, Department of Hematology, The Netherlands; TRIP Hemovigilance and Biovigilance Office, Leiden, The Netherlands
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13
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Wilson MJ, Dekker JWT, Harlaar JJ, Jeekel J, Schipperus M, Zwaginga JJ. The role of preoperative iron deficiency in colorectal cancer patients: prevalence and treatment. Int J Colorectal Dis 2017; 32:1617-1624. [PMID: 28889320 PMCID: PMC5635103 DOI: 10.1007/s00384-017-2898-1] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/30/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND In preoperative blood management of colorectal cancer patients, intravenous iron therapy is increasingly used to treat anaemia and prevent red blood cell transfusions. However, while iron deficiency is the most common cause of anaemia, little is known about the prevalence and namely type of iron deficiency in this population, whereas both types of iron deficiency (i.e. absolute and functional iron deficiency) are recommended to be treated differently by international cancer guidelines. OBJECTIVE The aim of present study is to investigate the prevalence and namely type of iron deficiency in colorectal cancer patients, and to assess its clinical relevance. METHODS Preoperative iron status, clinical parameters (i.e. age, ASA classification, tumour location, tumour stage) and postoperative complications were retrospectively collected for all newly diagnosed colorectal cancer patients in our institution over a 3-year period. RESULTS Iron deficiency was observed in 163 (48.1%) of 339 patients. Of these iron-deficient patients, 3.7% had an isolated absolute iron deficiency (AID) and 15.3% a functional iron deficiency (FID), while the rest had a combination of AID and FID. Anaemia was present in 66.1% of iron-deficient patients. Iron deficiency was significantly associated with an increased postoperative complication rate (univariable OR 1.94, p = 0.03, multivariable OR 1.84, p = 0.07), with right-sided tumours (p < 0.001), high ASA classification (p = 0.002), advanced tumour stage (p = 0.01) and advanced age (p = 0.04). In comparing clinical parameters between patients with AID and FID, advanced age was significantly associated with FID (p = 0.03), and the presence of anaemia with AID (p = 0.02). CONCLUSION In preoperative colorectal cancer patients, there is a high prevalence of iron deficiency, including a high percentage of patients with-a component of-functional iron deficiency, associated with the increased postoperative complication rate. As both types of iron deficiency require a different treatment strategy, our results illustrate the therapeutic potential of especially intravenous iron supplementation in patients with severe iron deficiency and stress the urgency of routinely monitoring preoperative iron status and differentiation between types of iron deficiency. As iron therapy may also be potentially harmful in respect to stimulation of tumour growth, future clinical trials assessing the long-term effect of iron therapy are necessary.
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Affiliation(s)
- M J Wilson
- TRIP Hemovigilance and Biovigilance Office, Leiden, the Netherlands.
- Department of Surgery, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
| | - J W T Dekker
- Department of Surgery, Reinier de Graaf Hospital, Delft, the Netherlands
| | - J J Harlaar
- Department of Surgery, Westfriesgasthuis Hoorn, Hoorn, the Netherlands
- Department of Surgery, VU Medical Center Amsterdam, Amsterdam, the Netherlands
| | - J Jeekel
- Department of Neuroscience, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - M Schipperus
- TRIP Hemovigilance and Biovigilance Office, Leiden, the Netherlands
- Department of Hematology, Haga Teaching Hospital, The Hague, the Netherlands
| | - J J Zwaginga
- Sanquin Research, Center for Clinical Transfusion Research, Leiden, the Netherlands
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
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Hossein Davoodi S, Jamshidi-Naeini Y, Esmaeili S, Sohrabvandi S, Mortazavian AM. The Dual Nature of Iron in Relation to Cancer: A Review. IRANIAN JOURNAL OF CANCER PREVENTION 2016. [DOI: 10.17795/ijcp-5494] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Chua AC, Knuiman MW, Trinder D, Divitini ML, Olynyk JK. Higher concentrations of serum iron and transferrin saturation but not serum ferritin are associated with cancer outcomes. Am J Clin Nutr 2016; 104:736-42. [PMID: 27488234 DOI: 10.3945/ajcn.115.129411] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Accepted: 06/16/2016] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Although the carcinogenic potential of iron has been shown, evidence from observational studies that have linked serum iron variables and cancer outcomes has been inconsistent. OBJECTIVE We investigated whether higher iron concentrations increased risk of cancer outcomes. DESIGN A prospective examination of iron biomarkers as independent risk factors for cancer was assessed in 1597 men and 1795 women aged 25-79 y who participated in the 1994/1995 Busselton Health Survey and had relevant data, no history of cancer before the survey, and serum ferritin concentrations ≥20 μg/L. Follow-up for incident cancers and death from cancer was available to 2010. Proportional hazards regression modeling was performed to investigate if iron status predicted cancer incidence and mortality. RESULTS After adjustments for age, smoking, drinking, anthropometric and biochemical variables, or menopausal status (breast cancer), higher serum iron concentrations and transferrin saturation were associated with increased risks of incident nonskin cancer [HR for iron: 1.83 (95% CI: 1.21, 2.76; P < 0.01); HR for transferrin saturation: 1.68 (95% CI: 1.18, 2.38; P < 0.01)] including breast cancer [HR for iron: 2.45 (95% CI:1.12, 5.34; P < 0.05); HR for transferrin saturation: 1.90 (95% CI:1.02, 3.56; P < 0.05)] in women. Transferrin saturation was also associated with a greater risk of cancer death (HR: 2.48; 95% CI: 1.28, 4.82; P < 0.01). In men, higher iron concentrations were associated with reduced risks of incident nonskin cancer (HR: 0.65; 95% CI: 0.42, 0.99; P < 0.05) including colorectal cancer (HR: 0.34; 95% CI: 0.12, 0.95; P < 0.05). There was no association between serum iron and colorectal cancer risk in women. Serum ferritin was not associated with cancer risk or cancer death. CONCLUSIONS Higher transferrin saturation or serum iron concentrations were associated with increased nonskin cancer risk and increased risk of cancer death. Conversely, in men, higher serum iron concentrations were associated with decreased risk of nonskin cancer. The molecular basis for the observed differences in the association between serum iron and nonskin cancer risk is unclear.
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Affiliation(s)
- Anita Cg Chua
- School of Medicine and Pharmacology, The University of Western Australia, Fiona Stanley Hospital, Murdoch, Australia; Harry Perkins Institute of Medical Research, Murdoch, Australia;
| | - Matthew W Knuiman
- School of Population Health, The University of Western Australia, Crawley, Australia
| | - Debbie Trinder
- School of Medicine and Pharmacology, The University of Western Australia, Fiona Stanley Hospital, Murdoch, Australia; Harry Perkins Institute of Medical Research, Murdoch, Australia
| | - Mark L Divitini
- School of Population Health, The University of Western Australia, Crawley, Australia
| | - John K Olynyk
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch, Australia; Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, Australia; Faculty of Health Sciences, Curtin University, Bentley, Australia; and School of Veterinary and Life Sciences, Murdoch University, Murdoch, Australia
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16
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Reddivari L, Charepalli V, Radhakrishnan S, Vadde R, Elias RJ, Lambert JD, Vanamala JKP. Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 16:278. [PMID: 27506388 PMCID: PMC4977641 DOI: 10.1186/s12906-016-1254-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 07/29/2016] [Indexed: 12/22/2022]
Abstract
Background We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known. Methods We tested the anti-cancer efficacy of the RSV-GSE against colon CSCs using isolated human colon CSCs in vitro and an azoxymethane-induced mouse model of colon carcinogenesis in vivo. Results RSV-GSE suppressed tumor incidence similar to sulindac, without any gastrointestinal toxicity. Additionally, RSV-GSE treatment reduced the number of crypts containing cells with nuclear β-catenin (an indicator of colon CSCs) via induction of apoptosis. In vitro, RSV-GSE suppressed - proliferation, sphere formation, nuclear translocation of β-catenin (a critical regulator of CSC proliferation) similar to sulindac in isolated human colon CSCs. RSV-GSE, but not sulindac, suppressed downstream protein levels of Wnt/β-catenin pathway, c-Myc and cyclin D1. RSV-GSE also induced mitochondrial-mediated apoptosis in colon CSCs characterized by elevated p53, Bax/Bcl-2 ratio and cleaved PARP. Furthermore, shRNA-mediated knockdown of p53, a tumor suppressor gene, in colon CSCs did not alter efficacy of RSV-GSE. Conclusion The suppression of Wnt/β-catenin signaling and elevated mitochondrial-mediated apoptosis in colon CSCs support potential clinical testing/application of grape bioactives for colon cancer prevention and/or therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12906-016-1254-2) contains supplementary material, which is available to authorized users.
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Cuyamendous C, de la Torre A, Lee YY, Leung KS, Guy A, Bultel-Poncé V, Galano JM, Lee JCY, Oger C, Durand T. The novelty of phytofurans, isofurans, dihomo-isofurans and neurofurans: Discovery, synthesis and potential application. Biochimie 2016; 130:49-62. [PMID: 27519299 DOI: 10.1016/j.biochi.2016.08.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 08/07/2016] [Indexed: 01/15/2023]
Abstract
Polyunsaturated fatty acids (PUFA) are oxidized in vivo under oxidative stress through free radical pathway and release cyclic oxygenated metabolites, which are commonly classified as isoprostanes and isofurans. The discovery of isoprostanes goes back twenty-five years compared to fifteen years for isofurans, and great many are discovered. The biosynthesis, the nomenclature, the chemical synthesis of furanoids from α-linolenic acid (ALA, C18:3 n-3), arachidonic acid (AA, C20:4 n-6), adrenic acid (AdA, 22:4 n-6) and docosahexaenoic acid (DHA, 22:6 n-3) as well as their identification and implication in biological systems are highlighted in this review.
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Affiliation(s)
- Claire Cuyamendous
- Institut des Biomolécules Max Mousseron, UMR 5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie de Montpellier, 15 Avenue Charles Flahault, Bâtiment D, 34093, Montpellier Cedex 05, France
| | - Aurélien de la Torre
- Institut des Biomolécules Max Mousseron, UMR 5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie de Montpellier, 15 Avenue Charles Flahault, Bâtiment D, 34093, Montpellier Cedex 05, France
| | - Yiu Yiu Lee
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong Special Administrative Region
| | - Kin Sum Leung
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong Special Administrative Region
| | - Alexandre Guy
- Institut des Biomolécules Max Mousseron, UMR 5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie de Montpellier, 15 Avenue Charles Flahault, Bâtiment D, 34093, Montpellier Cedex 05, France
| | - Valérie Bultel-Poncé
- Institut des Biomolécules Max Mousseron, UMR 5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie de Montpellier, 15 Avenue Charles Flahault, Bâtiment D, 34093, Montpellier Cedex 05, France
| | - Jean-Marie Galano
- Institut des Biomolécules Max Mousseron, UMR 5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie de Montpellier, 15 Avenue Charles Flahault, Bâtiment D, 34093, Montpellier Cedex 05, France
| | - Jetty Chung-Yung Lee
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong Special Administrative Region
| | - Camille Oger
- Institut des Biomolécules Max Mousseron, UMR 5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie de Montpellier, 15 Avenue Charles Flahault, Bâtiment D, 34093, Montpellier Cedex 05, France
| | - Thierry Durand
- Institut des Biomolécules Max Mousseron, UMR 5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie de Montpellier, 15 Avenue Charles Flahault, Bâtiment D, 34093, Montpellier Cedex 05, France.
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Padmanabhan H, Brookes MJ, Iqbal T. Iron and colorectal cancer: evidence from in vitro and animal studies. Nutr Rev 2015; 73:308-17. [DOI: 10.1093/nutrit/nuu015] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Beguin Y, Aapro M, Ludwig H, Mizzen L, Osterborg A. Epidemiological and nonclinical studies investigating effects of iron in carcinogenesis--a critical review. Crit Rev Oncol Hematol 2013; 89:1-15. [PMID: 24275533 DOI: 10.1016/j.critrevonc.2013.10.008] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 10/17/2013] [Accepted: 10/31/2013] [Indexed: 12/11/2022] Open
Abstract
The efficacy and tolerability of intravenous (i.v.) iron in managing cancer-related anemia and iron deficiency has been clinically evaluated and reviewed recently. However, long-term data in cancer patients are not available; yet, long-term i.v. iron treatment in hemodialysis patients is not associated with increased cancer risk. This review summarizes epidemiological and nonclinical data on the role of iron in carcinogenesis. In humans, epidemiological data suggest correlations between certain cancers and increased iron exposure or iron overload. Nonclinical models that investigated whether iron can enhance carcinogenesis provide only limited evidence relevant for cancer patients since they were typically based on high iron doses as well as injection routes and iron formulations which are not used in the clinical setting. Nevertheless, in the absence of long-term outcome data from prospectively defined trials in i.v. iron-treated cancer patients, iron supplementation should be limited to periods of concomitant anti-tumor treatment.
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Affiliation(s)
| | | | - Heinz Ludwig
- Center for Oncology and Haematology, Wilhelminenspital, Vienna, Austria
| | | | - Anders Osterborg
- Karolinska Institutet and Karolinska Hospital, Stockholm, Sweden
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Ford SJ, Obeidy P, Lovejoy DB, Bedford M, Nichols L, Chadwick C, Tucker O, Lui GYL, Kalinowski DS, Jansson PJ, Iqbal TH, Alderson D, Richardson DR, Tselepis C. Deferasirox (ICL670A) effectively inhibits oesophageal cancer growth in vitro and in vivo. Br J Pharmacol 2013; 168:1316-28. [PMID: 23126308 DOI: 10.1111/bph.12045] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Revised: 10/09/2012] [Accepted: 10/15/2012] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND AND PURPOSE Growing evidence implicates iron in the aetiology of gastrointestinal cancer. Furthermore, studies demonstrate that iron chelators possess potent anti-tumour activity, although whether iron chelators show activity against oesophageal cancer is not known. EXPERIMENTAL APPROACH The effect of the iron chelators, deferoxamine (DFO) and deferasirox, on cellular iron metabolism, viability and proliferation was assessed in two oesophageal adenocarcinoma cell lines, OE33 and OE19, and the squamous oesophageal cell line, OE21. A murine xenograft model was employed to assess the effect of deferasirox on oesophageal tumour burden. The ability of chelators to overcome chemoresistance and to enhance the efficacy of standard chemotherapeutic agents (cisplatin, fluorouracil and epirubicin) was also assessed. KEY RESULTS Deferasirox and DFO effectively inhibited cellular iron acquisition and promoted intracellular iron mobilization. The resulting reduction in cellular iron levels was reflected by increased transferrin receptor 1 expression and reduced cellular viability and proliferation. Treating oesophageal tumour cell lines with an iron chelator in addition to a standard chemotherapeutic agent resulted in a reduction in cellular viability and proliferation compared with the chemotherapeutic agent alone. Both DFO and deferasirox were able to overcome cisplatin resistance. Furthermore, in human xenograft models, deferasirox was able to significantly suppress tumour growth, which was associated with decreased tumour iron levels. CONCLUSIONS AND IMPLICATIONS The clinically established iron chelators, DFO and deferasirox, effectively deplete iron from oesophageal tumour cells, resulting in growth suppression. These data provide a platform for assessing the utility of these chelators in the treatment of oesophageal cancer patients.
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Affiliation(s)
- S J Ford
- School of Cancer Sciences, Department of Medical & Dental Sciences, University of Birmingham, Birmingham, UK
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Abstract
Iron is an essential nutrient that facilitates cell proliferation and growth. However, iron also has the capacity to engage in redox cycling and free radical formation. Therefore, iron can contribute to both tumour initiation and tumour growth; recent work has also shown that iron has a role in the tumour microenvironment and in metastasis. Pathways of iron acquisition, efflux, storage and regulation are all perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumour cell survival. Signalling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy.
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Affiliation(s)
- Suzy V Torti
- Departments of Molecular, Microbial and Structural Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
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22
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Abstract
BACKGROUND High iron levels can increase the formation of noxious oxygen radicals, which are thought to promote carcinogenesis. OBJECTIVE The aim of this prospective study was to determine whether iron biomarkers and HFE genotypes, which influence iron regulation, constitute risk factors for colorectal cancer. DESIGN This is a prospective nested case-referent study. SETTINGS The study was performed within the population-based Northern Sweden Health and Disease Study. PATIENTS The study included 226 cases of colorectal cancer and 437 matched referents. MAIN OUTCOME MEASURES Conditional regression analysis was performed. Adjustments for smoking, smoking and BMI, and HFE C282Y and H63D were performed. RESULTS The highest quintile of total iron-binding capacity showed significantly higher risk for colorectal cancer, unadjusted OR 2.35 (95% CI 1.38-4.02). When stratified by sex, the findings were only present in women (OR 3.34 (95% CI 1.59-7.02)). Ferritin was associated with reduced risk throughout quintiles 2 to 5 both in univariate and multivariate models. LIMITATIONS Colorectal cancer may influence iron markers because of occult bleeding. Homozygotes for HFE C282Y were too few to make conclusions for this group. The relatively short follow-up time might be insufficient to detect risk of iron biomarkers. CONCLUSIONS High iron levels do not increase the risk of colorectal cancer. HFE genotypes influencing iron uptake had no effect on colorectal cancer risk.
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23
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Corpet DE. Red meat and colon cancer: Should we become vegetarians, or can we make meat safer? Meat Sci 2011; 89:310-6. [DOI: 10.1016/j.meatsci.2011.04.009] [Citation(s) in RCA: 147] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Revised: 04/07/2011] [Accepted: 04/11/2011] [Indexed: 01/13/2023]
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Effects of selenium on colon carcinogenesis induced by azoxymethane and dextran sodium sulfate in mouse model with high-iron diet. Lab Anim Res 2011; 27:9-18. [PMID: 21826154 PMCID: PMC3145991 DOI: 10.5625/lar.2011.27.1.9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2010] [Revised: 11/01/2010] [Accepted: 11/02/2010] [Indexed: 01/17/2023] Open
Abstract
Selenium (Se) is known to prevent several cancers while the relationship between high iron and the risk of colorectal cancer is controversial. To investigate the effects of Se in colon carcinogenesis, we subjected three different levels of Se and high-iron diet to a mouse model of colon cancer in which animals were treated with three azoxymethane (AOM) injections followed by dextran sodium sulfate (DSS) administration. There were five experimental groups including vehicle group [normal-Fe (NFe, 45 ppm)+medium-Se (MSe, 0.1 ppm)], positive control group (AOM/DSS+NFe+MSe), AOM/DSS+high-Fe (HFe, 450 ppm)+low-Se (LSe, 0.02 ppm), AOM/DSS+HFe+MSe, and AOM/DSS+HFe+high-Se (HSe, 0.5 ppm). The animals were fed on the three different Se diets for 24 weeks. The incidence of colon tumor in the high-Se diet group (AOM/DSS+HFe+HSe) showed 19.4% lower than positive control group, 5.9% lower than AOM/DSS+HFe+MSe diet group, and 11.1% lower than AOM/DSS+HFe+LSe group. The tumor multiplicity was significantly higher in the low-Se diet group (AOM/DSS+HFe+LSe) compare to all other AOM/DSS treated groups. In the high-Se diet group, the activity of hepatic GPx was comparable to that of positive control group, and significantly higher than those of low-Se or medium-Se diet groups. Expression level of hepatic GPx-1 showed similar results. Hepatic malondialdehyde (MDA) level (indicator of oxidative stress) in the low-Se diet group showed the highest compared to the other groups, and it was significantly higher than positive control group. In the high-Se diet group the level of MDA in the liver was significantly lower than all other AOM/DSS treated groups. High-Se diet group showed significantly lower proliferative index than low-Se and medium-Se groups. The apoptotic indices in low-Se group and medium-Se group were significantly lower than positive control group. However, apoptotic index of high-Se diet group was significantly higher than all other AOM/DSS treated groups. These findings suggest that dietary Se supplement may have protective effect against colon cancer by decreasing proliferation, increasing apoptosis of tumor cells, and reducing oxidative stress in mice with high iron diet.
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Eckard J, Dai J, Wu J, Jian J, Yang Q, Chen H, Costa M, Frenkel K, Huang X. Effects of cellular iron deficiency on the formation of vascular endothelial growth factor and angiogenesis. Iron deficiency and angiogenesis. Cancer Cell Int 2010; 10:28. [PMID: 20723262 PMCID: PMC2936284 DOI: 10.1186/1475-2867-10-28] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2010] [Accepted: 08/19/2010] [Indexed: 11/10/2022] Open
Abstract
Background Young women diagnosed with breast cancer are known to have a higher mortality rate from the disease than older patients. Specific risk factors leading to this poorer outcome have not been identified. In the present study, we hypothesized that iron deficiency, a common ailment in young women, contributes to the poor outcome by promoting the hypoxia inducible factor-1α (HIF-1α and vascular endothelial growth factor (VEGF) formation. This hypothesis was tested in an in vitro cell culture model system. Results Human breast cancer MDA-MB-231 cells were transfected with transferrin receptor-1 (TfR1) shRNA to constitutively impair iron uptake. Cellular iron status was determined by a set of iron proteins and angiogenesis was evaluated by levels of VEGF in cells as well as by a mouse xenograft model. Significant decreases in ferritin with concomitant increases in VEGF were observed in TfR1 knockdown MDA-MB-231 cells when compared to the parental cells. TfR1 shRNA transfectants also evoked a stronger angiogenic response after the cells were injected subcutaneously into nude mice. The molecular mechanism appears that cellular iron deficiency elevates VEGF formation by stabilizing HIF-1α. This mechanism is also true in human breast cancer MCF-7 and liver cancer HepG2 cells. Conclusions Cellular iron deficiency increased HIF-1α, VEGF, and angiogenesis, suggesting that systemic iron deficiency might play an important part in the tumor angiogenesis and recurrence in this young age group of breast cancer patients.
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Affiliation(s)
- Jonathan Eckard
- Department of Environmental Medicine and New York University (NYU) Cancer Institute, NYU School of Medicine, New York, NY 10016, USA.
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Ferrand A, Lachal S, Bramante G, Kovac S, Shulkes A, Baldwin GS. Stimulation of proliferation in the colorectal mucosa by gastrin precursors is blocked by desferrioxamine. Am J Physiol Gastrointest Liver Physiol 2010; 299:G220-7. [PMID: 20395538 PMCID: PMC2904120 DOI: 10.1152/ajpgi.00046.2010] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Precursors of the peptide hormone gastrin stimulate proliferation in the colorectal mucosa and promote the development of colorectal carcinoma. Gastrins bind two ferric ions selectively and with high affinity, and the biological activity of glycine-extended gastrin (Ggly) in vitro is dependent on the presence of ferric ions. The aim of the present study was to determine whether or not iron is required for biological activity of progastrin and Ggly in vivo. Rats that had undergone a colostomy were infused with Ggly, and proliferation was measured in the defunctioned rectal mucosa. Proliferation was also measured in the colonic mucosa of hGAS and MTI-Ggly mice, which, by definition, overexpress progastrin and Ggly, respectively. The requirement for iron was assessed by thrice-weekly injection of the chelating agent desferrioxamine (DFO). The proliferation index in the defunctioned rectal mucosa was significantly increased in the Ggly-infused rats, and the increase was significantly reduced after treatment with DFO. Treatment with DFO significantly reduced the crypt height and proliferation index in the colonic mucosa of hGAS and MTI-Ggly mice but had no effect on the same variables in wild-type mice. These observations are consistent with the hypothesis that the biological activity of progastrin and Ggly in vivo is dependent on the presence of ferric ions and further suggest that chelating agents may block the stimulatory effects of gastrin precursors in the development of colorectal carcinoma.
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Affiliation(s)
- Audrey Ferrand
- University of Melbourne Department of Surgery, Austin Health, Melbourne, Victoria, Australia
| | - Shamilah Lachal
- University of Melbourne Department of Surgery, Austin Health, Melbourne, Victoria, Australia
| | - Gianni Bramante
- University of Melbourne Department of Surgery, Austin Health, Melbourne, Victoria, Australia
| | - Suzana Kovac
- University of Melbourne Department of Surgery, Austin Health, Melbourne, Victoria, Australia
| | - Arthur Shulkes
- University of Melbourne Department of Surgery, Austin Health, Melbourne, Victoria, Australia
| | - Graham S. Baldwin
- University of Melbourne Department of Surgery, Austin Health, Melbourne, Victoria, Australia
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Park HJ, Davis SR, Liang HY, Rosenberg DW, Bruno RS. Chlorogenic acid differentially alters hepatic and small intestinal thiol redox status without protecting against azoxymethane-induced colon carcinogenesis in mice. Nutr Cancer 2010; 62:362-70. [PMID: 20358474 DOI: 10.1080/01635580903407239] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States. Epidemiological data have suggested that coffee consumption is inversely related to CRC risk, which may be attributed to chlorogenic acid (CGA), an ester of caffeic acid (CA) and quinic acid. This study was conducted to determine whether chronic dietary CGA supplementation would attenuate tumorigenesis and oxidative stress in a mouse model of azoxymethane (AOM)-induced colon cancer. Mice (4-wk old; n = 15/group) were fed CGA (0%, 0.01%, or 0.1%) for 20 wk and received 6 weekly intraperitoneal AOM injections (10 mg/kg). CGA and CA dose-dependently accumulated in the small intestinal mucosa. AOM induced (P < 0.05) colonic aberrant crypt foci (14.2 +/- 1.9/field) and tumors (14.6 +/- 1.1/colon), which were correlated (r = .677; P < 0.05), and CGA at either dose did not reduce tumorigenesis. Hepatic GSH/GSSG and Cys/CySS ratios were unaffected by AOM, but CGA at 0.1% increased these ratios by decreasing GSSG and CySS. CGA did not affect the ratios of small intestinal GSH/GSSG or Cys/CySS, which were decreased in response to AOM treatment. Collectively, these data indicated that CGA did not protect against AOM-induced tumorigenesis but affected hepatic thiol redox status in this colon cancer model.
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Affiliation(s)
- Hea Jin Park
- University of Connecticut, Storrs, Connecticut 06269-4017, USA
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Chua ACG, Klopcic B, Lawrance IC, Olynyk JK, Trinder D. Iron: An emerging factor in colorectal carcinogenesis. World J Gastroenterol 2010; 16:663-72. [PMID: 20135713 PMCID: PMC2817053 DOI: 10.3748/wjg.v16.i6.663] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The carcinogenic potential of iron in colorectal cancer (CRC) is not fully understood. Iron is able to undergo reduction and oxidation, making it important in many physiological processes. This inherent redox property of iron, however, also renders it toxic when it is present in excess. Iron-mediated generation of reactive oxygen species via the Fenton reaction, if uncontrolled, may lead to cell damage as a result of lipid peroxidation and oxidative DNA and protein damage. This may promote carcinogenesis through increased genomic instability, chromosomal rearrangements as well as mutations of proto-oncogenes and tumour suppressor genes. Carcinogenesis is also affected by inflammation which is exacerbated by iron. Population studies indicate an association between high dietary iron intake and CRC risk. In this editorial, we examine the link between iron-induced oxidative stress and inflammation on the pathogenesis of CRC.
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Ishikawa SI, Asano T, Takenoshita S, Nozawa Y, Arihara K, Itoh M. Egg yolk proteins suppress azoxymethane-induced aberrant crypt foci formation and cell proliferation in the colon of rats. Nutr Res 2009; 29:64-9. [PMID: 19185779 DOI: 10.1016/j.nutres.2008.12.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2008] [Revised: 12/04/2008] [Accepted: 12/11/2008] [Indexed: 10/21/2022]
Abstract
Dietary proteins can influence colonic carcinogenesis; some proteins have a promotional effect, whereas others exhibit a preventive effect. Dietary egg yolk proteins have been reported to suppress the expression of colon tumors in rats. In this study, we investigated the effect of consumption egg yolk proteins on cell proliferation in a rat model of azoxymethane (AOM)-induced colon cancer. We hypothesize, based on the literature of egg yolk protein actions, that they protect against colon tumor development. Therefore, male F344 rats were fed a purified AIN-93G diet containing either 20% casein (control) or 20% egg yolk proteins for 5 weeks. After 1 week on the experimental diet, the rats were administered weekly subcutaneous injections of saline or AOM for 2 weeks to induce aberrant crypt foci. Rats were administered an intraperitoneal injection of 5-bromo-2'-deoxyuridine 1 hour before being euthanized for examination of DNA synthesis in the colonic mucosa. The contents of the cecum were analyzed for the presence of short-chain fatty acids (SCFAs). In the AOM-injected rats, the yolk protein diet suppressed aberrant crypt foci formation and reduced the proliferative 5-bromo-2'-deoxyuridine-labeling index in the proximal colon when compared with the control diet. A significant increase in cecal SCFAs was observed in the rats that were fed egg yolk proteins. These results indicate that dietary egg yolk proteins have a preventive effect on AOM-induced large bowel carcinogenesis in rats; it exerts this effect by altering cell proliferation through SCFA production. This study suggests that the consumption of egg yolk proteins might be protective against colon carcinogenesis.
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Affiliation(s)
- Shin-Ichi Ishikawa
- School of Veterinary Medicine, Kitasato University, Towada, Aomori 034-8628, Japan.
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Abstract
The study of experimental colon carcinogenesis in rodents has a long history, dating back almost 80 years. There are many advantages to studying the pathogenesis of carcinogen-induced colon cancer in mouse models, including rapid and reproducible tumor induction and the recapitulation of the adenoma-carcinoma sequence that occurs in humans. The availability of recombinant inbred mouse panels and the existence of transgenic, knock-out and knock-in genetic models further increase the value of these studies. In this review, we discuss the general mechanisms of tumor initiation elicited by commonly used chemical carcinogens and how genetic background influences the extent of disease. We will also describe the general features of lesions formed in response to carcinogen treatment, including the underlying molecular aberrations and how these changes may relate to the pathogenesis of human colorectal cancer.
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Affiliation(s)
- Daniel W Rosenberg
- Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030-3101, USA.
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Intracellular redox status and oxidative stress: implications for cell proliferation, apoptosis, and carcinogenesis. Arch Toxicol 2008; 82:273-99. [PMID: 18443763 DOI: 10.1007/s00204-008-0304-z] [Citation(s) in RCA: 326] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2008] [Accepted: 04/03/2008] [Indexed: 02/06/2023]
Abstract
Oxidative stress can be defined as the imbalance between cellular oxidant species production and antioxidant capability. Reactive oxygen species (ROS) are involved in a variety of different cellular processes ranging from apoptosis and necrosis to cell proliferation and carcinogenesis. In fact, molecular events, such as induction of cell proliferation, decreased apoptosis, and oxidative DNA damage have been proposed to be critically involved in carcinogenesis. Carcinogenicity and aging are characterized by a set of complex endpoints, which appear as a series of molecular reactions. ROS can modify many intracellular signaling pathways including protein phosphatases, protein kinases, and transcription factors, suggesting that the majority of the effects of ROS are through their actions on signaling pathways rather than via non-specific damage of macromolecules; however, exact mechanisms by which redox status induces cells to proliferate or to die, and how oxidative stress can lead to processes evoking tumor formation are still under investigation.
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Brookes MJ, Boult J, Roberts K, Cooper BT, Hotchin NA, Matthews G, Iqbal T, Tselepis C. A role for iron in Wnt signalling. Oncogene 2007; 27:966-75. [PMID: 17700530 DOI: 10.1038/sj.onc.1210711] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
There is an emerging body of evidence implicating iron in carcinogenesis and in particular colorectal cancer, but whether this involves Wnt signalling, a major oncogenic signalling pathway has not been studied. We aimed to determine the effect of iron loading on Wnt signalling using mutant APC (Caco-2 and SW480) and wild-type APC (HEK-293 and human primary fibroblasts) containing cell lines. Elevating cellular iron levels in Caco-2 and SW480 cells caused increased Wnt signalling as indicated by increased TOPFLASH reporter activity, increased mRNA expression of two known targets, c-myc and Nkd1, and increased cellular proliferation. In contrast wild-type APC and beta-catenin-containing lines, HEK 293 and human primary fibroblasts were not responsive to iron loading. This was verified in SW480 cells that no longer induced iron-mediated Wnt signalling when transfected with wild-type APC. The cell line LS174T, wild type for APC but mutant for beta-catenin, was also responsive suggesting that the role of iron is to regulate beta-catenin. Furthermore, we show that E-cadherin status has no influence on iron-mediated Wnt signalling. We thus speculate that excess iron could exacerbate tumorigenesis in the background of APC loss, a common finding in cancers.
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Affiliation(s)
- M J Brookes
- CRUK Institute for Cancer Studies, University of Birmingham, Birmingham, UK
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Paulsen JE, Knutsen H, Ølstørn HB, Løberg EM, Alexander J. Identification of flat dysplastic aberrant crypt foci in the colon of azoxymethane-treated A/J mice. Int J Cancer 2006; 118:540-6. [PMID: 16094649 DOI: 10.1002/ijc.21416] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The role of aberrant crypt foci (ACF) as preneoplastic lesions in colon carcinogenesis is not clear. In Min/+ mice and their wild-type littermates treated with azoxymethane (AOM), we previously identified a subgroup of flat ACF that seem more immediate precursors of tumors than the classical elevated ACF. In the present study, we identified a similar subgroup of flat ACF in AOM-treated A/J mice and compared them with nascent tumors and classical elevated ACF. At week 1 and 2 after birth, A/J mice were injected subcutaneously with AOM (10 mg/kg bw/injection). At weeks 7-14, we examined the luminal surface of unsectioned colon preparations stained with methylene blue in the inverse light microscope. The lesions were also examined by histopathology and immunohistochemistry. Surface examination revealed flat ACF, classical elevated ACF and nascent tumors. Since flat ACF were not observed as elevated structures, their bright blue appearance and compressed pit pattern of crypt openings seen with transillumination were used as criteria for their identification. Flat ACF and nascent tumors displayed a uniform picture of severe dysplasia, compressed pit pattern, overexpression of cytoplasmic/nuclear beta-catenin and nuclear overexpression of cyclin D1. Apparently, flat ACF and tumors represented the same type of dysplastic lesions at different stages of crypt multiplication. In contrast, classical elevated ACF did not seem to be as clearly related to tumorigenesis. They infrequently (1/20) possessed severe dysplasia, overexpression of cytoplasmic/nuclear beta-catenin, or nuclear overexpression of cyclin D1, and they did not have compressed crypt openings. Furthermore, flat ACF grew significantly faster than classical elevated ACF. In conclusion, our data indicate a development from flat ACF to adenoma characterized by aberrant activation of the Wnt signaling pathway and fast crypt multiplication. Classical elevated ACF do not seem to be as closely related to tumorigenesis.
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Affiliation(s)
- Jan Erik Paulsen
- Department of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway
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Ilsley JNM, Nakanishi M, Flynn C, Belinsky GS, De Guise S, Adib JN, Dobrowsky RT, Bonventre JV, Rosenberg DW. Cytoplasmic Phospholipase A2Deletion Enhances Colon Tumorigenesis. Cancer Res 2005; 65:2636-43. [PMID: 15805260 DOI: 10.1158/0008-5472.can-04-3446] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cellular pools of free arachidonic acid are tightly controlled through enzymatic release of the fatty acid and subsequent utilization by downstream enzymes including the cyclooxygenases. Arachidonic acid cleavage from membrane phospholipids is accomplished by the actions of phospholipase A(2) (PLA(2)). Upon release, free arachidonic acid provides substrate for the synthesis of eicosanoids. However, under certain conditions, arachidonic acid may participate in ceramide-mediated apoptosis. Disruption of arachidonic acid homeostasis can shift the balance of cell turnover in favor of tumorigenesis, via overproduction of tumor-promoting eicosanoids or alternatively by limiting proapoptotic signals. In the following study, we evaluated the influence of genetic deletion of a key intracellular phospholipase, cytoplasmic PLA(2) (cPLA(2)), on azoxymethane-induced colon tumorigenesis. Heterozygous and null mice, upon treatment with the organotropic colon carcinogen, azoxymethane, developed a significant (P < 0.05) increase in colon tumor multiplicity (7.2-fold and 5.5-fold, respectively) relative to their wild-type littermates. This enhanced tumor sensitivity may be explained, in part, by the attenuated levels of apoptosis observed by terminal deoxynucleotidyl transferase-mediated nick end labeling staining within the colonic epithelium of heterozygous and null mice ( approximately 50% of wild type). The lower frequency of apoptotic cells corresponded with reduced ceramide levels (69% and 46% of wild-type littermates, respectively). Remarkably, increased tumorigenesis resulting from cPLA(2) deletion occurred despite a significant reduction in prostaglandin E(2) production, even in cyclooxygenase-2-overexpressing tumors. These data contribute new information that supports a fundamental role of cPLA(2) in the control of arachidonic acid homeostasis and cell turnover. Our findings indicate that the proapoptotic role of cPLA(2) in the colon may supercede its contribution to eicosanoid production in tumor development.
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Affiliation(s)
- Jillian N M Ilsley
- Program in Colorectal Cancer, Center for Molecular Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
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