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1
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Sahakian L, Robinson AM, Sahakian L, Stavely R, Kelley MR, Nurgali K. APE1/Ref-1 as a Therapeutic Target for Inflammatory Bowel Disease. Biomolecules 2023; 13:1569. [PMID: 38002251 PMCID: PMC10669584 DOI: 10.3390/biom13111569] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/18/2023] [Accepted: 10/22/2023] [Indexed: 11/26/2023] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the gastrointestinal tract. The prevalence of IBD is increasing with approximately 4.9 million cases reported worldwide. Current therapies are limited due to the severity of side effects and long-term toxicity, therefore, the development of novel IBD treatments is necessitated. Recent findings support apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1) as a target in many pathological conditions, including inflammatory diseases, where APE1/Ref-1 regulation of crucial transcription factors impacts significant pathways. Thus, a potential target for a novel IBD therapy is the redox activity of the multifunctional protein APE1/Ref-1. This review elaborates on the status of conventional IBD treatments, the role of an APE1/Ref-1 in intestinal inflammation, and the potential of a small molecule inhibitor of APE1/Ref-1 redox activity to modulate inflammation, oxidative stress response, and enteric neuronal damage in IBD.
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Affiliation(s)
- Lauren Sahakian
- Institute for Health & Sport, Victoria University, Melbourne, VIC 3021, Australia; (L.S.); (A.M.R.)
| | - Ainsley M. Robinson
- Institute for Health & Sport, Victoria University, Melbourne, VIC 3021, Australia; (L.S.); (A.M.R.)
| | - Linda Sahakian
- Department of Medicine Western Health, The University of Melbourne, Melbourne, VIC 3010, Australia; (L.S.); (R.S.)
| | - Rhian Stavely
- Department of Medicine Western Health, The University of Melbourne, Melbourne, VIC 3010, Australia; (L.S.); (R.S.)
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Mark R. Kelley
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Kulmira Nurgali
- Institute for Health & Sport, Victoria University, Melbourne, VIC 3021, Australia; (L.S.); (A.M.R.)
- Department of Medicine Western Health, The University of Melbourne, Melbourne, VIC 3010, Australia; (L.S.); (R.S.)
- Regenerative Medicine and Stem Cells Program, Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
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2
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Bacteria as Nanoparticle Carriers for Immunotherapy in Oncology. Pharmaceutics 2022; 14:pharmaceutics14040784. [PMID: 35456618 PMCID: PMC9027800 DOI: 10.3390/pharmaceutics14040784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/28/2022] [Accepted: 03/31/2022] [Indexed: 02/05/2023] Open
Abstract
The use of nanocarriers to deliver antitumor agents to solid tumors must overcome biological barriers in order to provide effective clinical responses. Once within the tumor, a nanocarrier should navigate into a dense extracellular matrix, overcoming intratumoral pressure to push it out of the diseased tissue. In recent years, a paradigm change has been proposed, shifting the target of nanomedicine from the tumoral cells to the immune system, in order to exploit the natural ability of this system to capture and interact with nanometric moieties. Thus, nanocarriers have been engineered to interact with immune cells, with the aim of triggering specific antitumor responses. The use of bacteria as nanoparticle carriers has been proposed as a valuable strategy to improve both the accumulation of nanomedicines in solid tumors and their penetration into the malignancy. These microorganisms are capable of propelling themselves into biological environments and navigating through the tumor, guided by the presence of specific molecules secreted by the diseased tissue. These capacities, in addition to the natural immunogenic nature of bacteria, can be exploited to design more effective immunotherapies that yield potent synergistic effects to induce efficient and selective immune responses that lead to the complete eradication of the tumor.
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3
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Han T, Hu X, Li K, Zhang D, Zhang Y, Li J. Bifidobacterium infantis Maintains Genome Stability in Ulcerative Colitis via Regulating Anaphase-Promoting Complex Subunit 7. Front Microbiol 2021; 12:761113. [PMID: 34795654 PMCID: PMC8593188 DOI: 10.3389/fmicb.2021.761113] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022] Open
Abstract
Probiotics represents a promising intestinal microbiota-targeted therapeutic method for the treatment of ulcerative colitis (UC). Several lines of evidence implicate that Bifidobacterium infantis serves as a probiotic strain with proven efficacy in maintaining the remission of UC. However, the exact mechanisms underlying the beneficial effects of B. infantis on UC progression have yet to be elucidated. Herein, we provide evidence that B. infantis acts as a key predisposing factor for the maintenance of host genome stability. First, we showed that the fecal microbiota transplantation (FMT) of UC-derived feces contributes to more severely DNA damage in dextran sodium sulfate (DSS)-induced mice likely due to mucosa-associated microbiota alterations, as reflected by the rapid appearance of DNA double strand breaks (DSBs), a typical marker of genome instability. Genomic DNA damage analysis of colon tissues derived from healthy controls, patients with UC or dysplasia, and colitis associated cancer (CAC) patients, revealed an enhanced level of DSBs with aggravation in the degree of the intestinal mucosal lesions. To evaluate whether B. infantis modulates the host genome stability, we employed the DSS-induced colitis model and a TNFα-induced intestinal epithelial cell model. Following the administration of C57BL/6 mice with B. infantis via oral gavage, we found that the development of DSS-induced colitis in mice was significantly alleviated, in contrast to the colitis model group. Notably, B. infantis administration decreased DSB levels in both DSS-induced colitis and TNF-treated colonial cell model. Accordingly, our bioinformatic and functional studies demonstrated that B. infantis altered signal pathways involved in ubiquitin-mediated proteolysis, transcriptional misregulation in cancer, and the bacterial invasion of epithelial cells. Mechanistically, B. infantis upregulated anaphase-promoting complex subunit 7 (APC7), which was significantly suppressed in colitis condition, to activate the DNA repair pathway and alter the genome stability, while downregulation of APC7 abolished the efficiency of B. infantis treatment to induce a decrease in the level of DSBs in TNFα-induced colonial cells. Collectively, our results support that B. infantis orchestrates a molecular network involving in APC7 and genome stability, to control UC development at the clinical, biological, and mechanistic levels. Supplying B. infantis and targeting its associated pathway will yield valuable insight into the clinical management of UC patients.
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Affiliation(s)
- Taotao Han
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaomin Hu
- Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Sciences, Beijing, China.,State Key Laboratory of Complex Severe and Rare Diseases, Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kemin Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Di Zhang
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Yan Zhang
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
| | - Jingnan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Sciences, Beijing, China
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4
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D'Amico AM, Vasquez KM. The multifaceted roles of DNA repair and replication proteins in aging and obesity. DNA Repair (Amst) 2021; 99:103049. [PMID: 33529944 DOI: 10.1016/j.dnarep.2021.103049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 12/14/2022]
Abstract
Efficient mechanisms for genomic maintenance (i.e., DNA repair and DNA replication) are crucial for cell survival. Aging and obesity can lead to the dysregulation of genomic maintenance proteins/pathways and are significant risk factors for the development of cancer, metabolic disorders, and other genetic diseases. Mutations in genes that code for proteins involved in DNA repair and DNA replication can also exacerbate aging- and obesity-related disorders and lead to the development of progeroid diseases. In this review, we will discuss the roles of various DNA repair and replication proteins in aging and obesity as well as investigate the possible mechanisms by which aging and obesity can lead to the dysregulation of these proteins and pathways.
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Affiliation(s)
- Alexandra M D'Amico
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard, Austin, TX, 78723, USA
| | - Karen M Vasquez
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard, Austin, TX, 78723, USA.
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5
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Structures and stability of simple DNA repeats from bacteria. Biochem J 2020; 477:325-339. [PMID: 31967649 PMCID: PMC7015867 DOI: 10.1042/bcj20190703] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 12/20/2019] [Accepted: 01/03/2020] [Indexed: 01/12/2023]
Abstract
DNA is a fundamentally important molecule for all cellular organisms due to its biological role as the store of hereditary, genetic information. On the one hand, genomic DNA is very stable, both in chemical and biological contexts, and this assists its genetic functions. On the other hand, it is also a dynamic molecule, and constant changes in its structure and sequence drive many biological processes, including adaptation and evolution of organisms. DNA genomes contain significant amounts of repetitive sequences, which have divergent functions in the complex processes that involve DNA, including replication, recombination, repair, and transcription. Through their involvement in these processes, repetitive DNA sequences influence the genetic instability and evolution of DNA molecules and they are located non-randomly in all genomes. Mechanisms that influence such genetic instability have been studied in many organisms, including within human genomes where they are linked to various human diseases. Here, we review our understanding of short, simple DNA repeats across a diverse range of bacteria, comparing the prevalence of repetitive DNA sequences in different genomes. We describe the range of DNA structures that have been observed in such repeats, focusing on their propensity to form local, non-B-DNA structures. Finally, we discuss the biological significance of such unusual DNA structures and relate this to studies where the impacts of DNA metabolism on genetic stability are linked to human diseases. Overall, we show that simple DNA repeats in bacteria serve as excellent and tractable experimental models for biochemical studies of their cellular functions and influences.
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6
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Baeza A. Tumor Targeted Nanocarriers for Immunotherapy. Molecules 2020; 25:molecules25071508. [PMID: 32225049 PMCID: PMC7180856 DOI: 10.3390/molecules25071508] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 03/23/2020] [Accepted: 03/24/2020] [Indexed: 12/13/2022] Open
Abstract
The paramount discovery of passive accumulation of nanoparticles in tumoral tissues triggered the development of a wide number of different nanoparticles capable of transporting therapeutic agents to tumoral tissues in a controlled and selective way. These nanocarriers have been endowed with important capacities such as stimuli-responsive properties, targeting abilities, or the capacity to be monitored by imaging techniques. However, after decades of intense research efforts, only a few nanomedicines have reached the market. The reasons for this disappointing outcome are varied, from the high tumor-type dependence of enhanced permeation and retention (EPR) effect to the poor penetration capacity of nanocarriers within the cancerous tissue, among others. The rapid nanoparticle clearance by immune cells, considered another important barrier, which compromises the efficacy of nanomedicines, would become an important ally in the fight against cancer. In the last years, the fine-tuned ability of immune cells to recognize and engulf nanoparticles have been exploited to deliver immunoregulating agents to specific immune cell populations selectively. In this work, the recent advances carried out in the development of nanocarriers capable of operating with immune and tumoral cells in order to orchestrate an efficient antitumoral response will be presented. The combination of nanoparticles and immunotherapy would deliver powerful weapons to the clinicians that offer safer and more efficient antitumoral treatments for the patients.
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Affiliation(s)
- Alejandro Baeza
- Dpto. Materiales y Producción Aeroespacial, ETSI Aeronáutica y del Espacio, Universidad Politécnica de Madrid, 28040 Madrid, Spain
- Dpto. Materiales y Producción Aeroespacial, ETSI Aeronáutica y del Espacio, Universidad Politécnica de Madrid, 28040 Madrid, Spain
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7
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Granofszky N, Lang M, Khare V, Schmid G, Scharl T, Ferk F, Jimenez K, Knasmüller S, Campregher C, Gasche C. Identification of PMN-released mutagenic factors in a co-culture model for colitis-associated cancer. Carcinogenesis 2018; 39:146-157. [PMID: 29106440 PMCID: PMC5826597 DOI: 10.1093/carcin/bgx118] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 10/30/2017] [Indexed: 02/07/2023] Open
Abstract
Microsatellite instability (MSI) is present in ulcerative colitis (UC) and colitis-associated colorectal cancers (CAC). Certain factors released by polymorphonuclear cells (PMNs) may drive mucosal frameshift mutations resulting in MSI and cancer. Here, we applied a co-culture system with PMNs and colon epithelial cells to identify such culprit factors. Subjecting HCT116 + chr3 and human colonic epithelial cells (HCEC)-1CT MSI-reporter cell lines harboring mono-, di- or tetranucleotide DNA repeats linked to enhanced green fluorescent protein (EGFP) to activated PMNs induced frameshift mutations within all repeats, as quantified by flow cytometry. Activated PMNs released superoxide and hydrogen peroxide (H2O2), as measured by lucigenin-amplified chemiluminescence and fluorometry, respectively. Catalase, which scavenges H2O2, reduced such PMN-induced MSI. The NADPH-oxidase inhibitor apocynin, which blocks the oxidative burst in PMNs, similarly inhibited PMN-induced MSI. A bead-based multiplex assay revealed that PMNs release a wide range of cytokines such as interleukin (IL)-8, IL-6 and tumor necrosis factor-α (TNF-α). In vitro, these cytokines increased MSI in colon epithelial cells, and the Janus kinase (JAK) inhibitor tofacitinib abolished IL-6-induced or PMN-induced MSI. Intracellular reactive oxygen species (ROS) formation, as measured by 2’,7’–dichlorofluorescein diacetate (DCFDA) assay, was induced upon cytokine treatment. DNA oxidation upon IL-6 was present, as detected by formamidopyrimidine glycosylase (FPG)-modified comet assay. In conclusion, activated PMNs induce frameshift mutations in colon epithelial cells resulting in MSI. Both oxidative burst with release of ROS and PMN-secreted cytokines, such as IL-8, IL-6 or TNF-α, contribute to MSI. ROS scavengers and/or specific inhibitors of cytokine signaling may delay or prevent cancer development in the setting of colitis.
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Affiliation(s)
- Nicolas Granofszky
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Michaela Lang
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Vineeta Khare
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Gerald Schmid
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Theresa Scharl
- ACIB GmbH, c/o Institute of Applied Statistics and Computing, University of Natural Resources and Life Sciences, Vienna, Austria
| | - Franziska Ferk
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Kristine Jimenez
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Siegfried Knasmüller
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Christoph Campregher
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Christoph Gasche
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
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8
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Noonan SA, Morrissey ME, Martin P, Biniecka M, Ó'Meachair S, Maguire A, Tosetto M, Nolan B, Hyland J, Sheahan K, O'Donoghue D, Mulcahy H, Fennelly D, O'Sullivan J. Tumour vasculature immaturity, oxidative damage and systemic inflammation stratify survival of colorectal cancer patients on bevacizumab treatment. Oncotarget 2018. [PMID: 29535825 PMCID: PMC5828217 DOI: 10.18632/oncotarget.24276] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Despite treatment of patients with metastatic colorectal cancer (mCRC) with bevacizumab plus chemotherapy, response rates are modest and there are no biomarkers available that will predict response. The aim of this study was to assess if markers associated with three interconnected cancer-associated biological processes, specifically angiogenesis, inflammation and oxidative damage, could stratify the survival outcome of this cohort. Levels of angiogenesis, inflammation and oxidative damage markers were assessed in pre-bevacizumab resected tumour and serum samples of mCRC patients by dual immunofluorescence, immunohistochemistry and ELISA. This study identified that specific markers of angiogenesis, inflammation and oxidative damage stratify survival of patients on this anti-angiogenic treatment. Biomarkers of immature tumour vasculature (% IMM, p=0.026, n=80), high levels of oxidative damage in the tumour epithelium (intensity of 8-oxo-dG in nuclear and cytoplasmic compartments, p=0.042 and 0.038 respectively, n=75) and lower systemic pro-inflammatory cytokines (IL6 and IL8, p=0.053 and 0.049 respectively, n=61) significantly stratify with median overall survival (OS). In summary, screening for a panel of biomarkers for high levels of immature tumour vasculature, high levels of oxidative DNA damage and low levels of systemic pro-inflammatory cytokines may be beneficial in predicting enhanced survival outcome following bevacizumab treatment for mCRC.
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Affiliation(s)
- Sinead A Noonan
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Maria E Morrissey
- Trinity Translational Medicine Institute (TTMI), Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Petra Martin
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Monika Biniecka
- Education and Research Centre, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Shane Ó'Meachair
- Centre for Health Decision Science (CHeDS), School of Computer Science and Statistics, Trinity College Dublin, Dublin, Ireland
| | - Aoife Maguire
- Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Miriam Tosetto
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Blathnaid Nolan
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - John Hyland
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Kieran Sheahan
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Diarmuid O'Donoghue
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Hugh Mulcahy
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - David Fennelly
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Jacintha O'Sullivan
- Trinity Translational Medicine Institute (TTMI), Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin, Ireland
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9
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Marwa Abu-Serie MAS, Maha El Demellawy MED, Mohamed El-Sayed MES, Fatma El-Rashidy FER. In vitro animal cancer model for assessment of sulfated polysaccharides extract of Ulva lactuca as colon cancer therapeutic and chemopreventive agents. INTERNATIONAL JOURNAL OF CANCER THERAPY AND ONCOLOGY 2015. [DOI: 10.14319/ijcto.32.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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10
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Shpak M, Goldberg MM, Cowperthwaite MC. Rapid and convergent evolution in the glioblastoma multiforme genome. Genomics 2015; 105:159-67. [PMID: 25576655 DOI: 10.1016/j.ygeno.2014.12.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 12/08/2014] [Accepted: 12/31/2014] [Indexed: 12/11/2022]
Abstract
Determining which mutations drive tumor progression is a defining question in cancer genomics. We analyzed sequence evolution in Glioblastoma multiforme (GBM) by computing the number of parallel mutations and by estimating ω=dN/dS, a measure of the strength and direction of selection. The ω values of almost all 7617 mutated genes in GBM are much higher than in germline genes. We identified only 21 genes under significant positive selection in GBM, as well as 29 genes under significant purifying selection, including several zinc finger proteins. Therefore, most of the high ω values in the GBM genome are due to weaker purifying selection rather than positive selection. We also found multiple recurrent mutations in GBM, several of which are associated with patient survival time. Our results suggest that convergence and neutral evolution play a significant role in GBM, and that sites with recurrent mutations can serve as molecular diagnostics of the clinical course of GBM tumors.
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Affiliation(s)
- Max Shpak
- NeuroTexas Institute, St. David's Healthcare, Austin, TX 78705, United States; Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, TX 78712, United States; Fresh Pond Research Institute, Cambridge, MA 02140, United States.
| | - Marcus M Goldberg
- Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, TX 78712, United States
| | - Matthew C Cowperthwaite
- NeuroTexas Institute, St. David's Healthcare, Austin, TX 78705, United States; Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, TX 78712, United States; Texas Advanced Computing Center, University of Texas at Austin, Austin, TX 78758, United States
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11
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Abstract
Past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype. Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment. In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike.
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Affiliation(s)
- Victoria R Zellmer
- Department of Biological Science, Harper Cancer Research Institute, University of Notre Dame, A130 Harper Hall, Notre Dame, IN 46556 USA
| | - Siyuan Zhang
- Department of Biological Science, Harper Cancer Research Institute, University of Notre Dame, A130 Harper Hall, Notre Dame, IN 46556 USA
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12
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Scarpa M, Castagliuolo I, Castoro C, Pozza A, Scarpa M, Kotsafti A, Angriman I. Inflammatory colonic carcinogenesis: A review on pathogenesis and immunosurveillance mechanisms in ulcerative colitis. World J Gastroenterol 2014; 20:6774-6785. [PMID: 24944468 PMCID: PMC4051917 DOI: 10.3748/wjg.v20.i22.6774] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is characterized by repeated flare-ups of inflammation that can lead to oncogenic insults to the colonic epithelial. UC-associated carcinogenesis presents a different sequence of tumorigenic events compared to those that contribute to the development of sporadic colorectal cancer. In fact, in UC, the early events are represented by oxidative DNA damage and DNA methylation that can produce an inhibition of oncosuppressor genes, mutation of p53, aneuploidy, and microsatellite instability. Hypermethylation of tumor suppressor and DNA mismatch repair gene promoter regions is an epigenetic mechanism of gene silencing that contribute to tumorigenesis and may represent the first step in inflammatory carcinogenesis. Moreover, p53 is frequently mutated in the early stages of UC-associated cancer. Aneuploidy is an independent risk factor for forthcoming carcinogenesis in UC. Epithelial cell-T-cell cross-talk mediated by CD80 is a key factor in controlling the progression from low to high grade dysplasia in UC-associated carcinogenesis.
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MESH Headings
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/immunology
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Colitis, Ulcerative/complications
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/pathology
- Colonic Neoplasms/etiology
- Colonic Neoplasms/genetics
- Colonic Neoplasms/immunology
- Colonic Neoplasms/metabolism
- Colonic Neoplasms/pathology
- DNA Damage
- DNA Methylation
- Disease Progression
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Humans
- Inflammation Mediators/metabolism
- Neoplasm Grading
- Oncogenes
- Oxidative Stress
- Risk Factors
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
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13
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Monteagudo Á, Santos J. Studying the capability of different cancer hallmarks to initiate tumor growth using a cellular automaton simulation. Application in a cancer stem cell context. Biosystems 2013; 115:46-58. [PMID: 24262634 DOI: 10.1016/j.biosystems.2013.11.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Revised: 10/29/2013] [Accepted: 11/03/2013] [Indexed: 02/06/2023]
Abstract
We used a cellular automaton model for cancer growth simulation at cellular level, based on the presence of different cancer hallmarks acquired by the cells. The presence of the hallmarks in each of the cells determines cell mitotic and apoptotic behaviors. Depending on the presence of the different hallmarks and some associated parameters of the hallmarks, the system can evolve to different dynamics. We used the cellular automaton model to inspect the capability of different hallmarks to generate tumor growth in different conditions, using this study in a cancer stem cell context to analyze the capability of the hallmarks to tumor regrowth in different circumstances.
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Affiliation(s)
- Ángel Monteagudo
- University of A Coruña, Department of Computer Science, Campus de Elviña s/n, 15071 A Coruña, Spain
| | - José Santos
- University of A Coruña, Department of Computer Science, Campus de Elviña s/n, 15071 A Coruña, Spain.
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Harpaz N, Ward SC, Mescoli C, Itzkowitz SH, Polydorides AD. Precancerous lesions in inflammatory bowel disease. Best Pract Res Clin Gastroenterol 2013; 27:257-67. [PMID: 23809244 DOI: 10.1016/j.bpg.2013.03.014] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Accepted: 03/08/2013] [Indexed: 01/31/2023]
Abstract
Reduction of mortality from colorectal cancer is a prime goal in the clinical management of patients with extensive, longstanding ulcerative colitis and colonic Crohn's disease. The cornerstone of current cancer prevention efforts is endoscopic surveillance for colorectal dysplasia, or intraepithelial neoplasia, the direct histological precursor of cancer. A diagnosis of dysplasia provides a reliable indicator of heightened cancer risk and an end-point for colonoscopic surveillance allowing most patients to undergo prophylactic colectomy before the development of incurable cancer. This article reviews the classification, pathological criteria and clinical implications of colorectal dysplasia, current recommendations for the performance of surveillance colonoscopy, recent technical advances in colonoscopic imaging to enhance the detection of dysplasia, and a summary of the molecular genetic events implicated in its development.
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Affiliation(s)
- Noam Harpaz
- Department of Pathology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA.
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15
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Fu L, Wang G, Shevchuk MM, Nanus DM, Gudas LJ. Activation of HIF2α in kidney proximal tubule cells causes abnormal glycogen deposition but not tumorigenesis. Cancer Res 2013; 73:2916-25. [PMID: 23447580 DOI: 10.1158/0008-5472.can-12-3983] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Renal cell carcinoma (RCC) is the most common primary cancer arising from the kidney in adults, with clear cell renal cell carcinoma (ccRCC) representing approximately 75% of all RCCs. Increased expression of the hypoxia-induced factors-1α (HIF1α) and HIF2α has been suggested as a pivotal step in ccRCC carcinogenesis, but this has not been thoroughly tested. Here, we report that expression of a constitutively activated form of HIF2α (P405A, P530A, and N851A, named as HIF2αM3) in the proximal tubules of mice is not sufficient to promote ccRCC by itself, nor does it enhance HIF1αM3 oncogenesis when coexpressed with constitutively active HIF1αM3. Neoplastic transformation in kidneys was not detected at up to 33 months of age, nor was increased expression of Ki67 (MKI67), γH2AX (H2AFX), or CD70 observed. Furthermore, the genome-wide transcriptome of the transgenic kidneys does not resemble human ccRCC. We conclude that a constitutively active HIF2α is not sufficient to cause neoplastic transformation of proximal tubules, arguing against the idea that HIF2α activation is critical for ccRCC tumorigenesis.
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Affiliation(s)
- Leiping Fu
- Department of Pharmacology and Pathology, Weill Cornell Medical College, Cornell University, New York, New York 10065, USA
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da Costa NM, Hautefeuille A, Cros MP, Melendez ME, Waters T, Swann P, Hainaut P, Pinto LFR. Transcriptional regulation of thymine DNA glycosylase (TDG) by the tumor suppressor protein p53. Cell Cycle 2012; 11:4570-8. [PMID: 23165212 DOI: 10.4161/cc.22843] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Thymine DNA glycosylase (TDG) belongs to the superfamily of uracil DNA glycosylases (UDG) and is the first enzyme in the base-excision repair pathway (BER) that removes thymine from G:T mismatches at CpG sites. This glycosylase activity has also been found to be critical for active demethylation of genes involved in embryonic development. Here we show that wild-type p53 transcriptionally regulates TDG expression. Chromatin immunoprecipitation (ChIP) and luciferase assays indicate that wild-type p53 binds to a domain of TDG promoter containing two p53 consensus response elements (p53RE) and activates its transcription. Next, we have used a panel of cell lines with different p53 status to demonstrate that TDG mRNA and protein expression levels are induced in a p53-dependent manner under different conditions. This panel includes isogenic breast and colorectal cancer cell lines with wild-type or inactive p53, esophageal squamous cell carcinoma cell lines lacking p53 or expressing a temperature-sensitive p53 mutant and normal human bronchial epithelial cells. Induction of TDG mRNA expression is accompanied by accumulation of TDG protein in both nucleus and cytoplasm, with nuclear re-localization occurring upon DNA damage in p53-competent, but not -incompetent, cells. These observations suggest a role for p53 activity in TDG nuclear translocation. Overall, our results show that TDG expression is directly regulated by p53, suggesting that loss of p53 function may affect processes mediated by TDG, thus negatively impacting on genetic and epigenetic stability.
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Lai LA, Risques RA, Bronner MP, Rabinovitch PS, Crispin D, Chen R, Brentnall TA. Pan-colonic field defects are detected by CGH in the colons of UC patients with dysplasia/cancer. Cancer Lett 2012; 320:180-8. [PMID: 22387989 PMCID: PMC3406733 DOI: 10.1016/j.canlet.2012.02.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Revised: 02/21/2012] [Accepted: 02/23/2012] [Indexed: 02/08/2023]
Abstract
BAC arrays were used to evaluate genomic instability along the colon of patients with ulcerative colitis (UC). Genomic instability increases with disease progression and biopsies more proximal to dysplasia showed increased instability. Pan-colonic field copy number gain or loss involving small (<1Mb) regions were detected in most patients and were particularly apparent in the UC progressor patients who had dysplasia or cancer. Chromosomal copy gains or losses affecting large regions were mainly restricted to dysplastic biopsies. Areas of significant chromosomal losses were detected in the UC progressors on chromosomes 2q36, 3q25, 3p21, 4q34, 4p16.2, 15q22, and 16p13 (p-value⩽0.04). These results extend our understanding of the dynamic nature of pan-colonic genomic instability in this disease.
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Affiliation(s)
- Lisa A Lai
- Department of Medicine, University of Washington, Seattle, WA, United States
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18
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Abstract
The inflammatory bowel diseases (IBD); Crohn's and Ulcerative colitis, result from an altered host response to intestinal flora. Recurrent inflammation with ulceration and tissue restitution confers an increased risk of cancer in both UC and Crohns, and genome wide searches have identified a number of disease susceptibility alleles. The carcinogenesis pathway in colitis-associated colorectal cancer (CACRC) is less clearly understood than it's sporadic counterpart. Clonal ordering experiments have indicated the order and timing of chromosomal instability and common genetic mutations. Epigenetic changes such as DNA methylation and histone modification are thought to play an increasingly important role in inflammation induced carcinogenesis. Clonal expansion of procarcinogenic mutations can lead to large fields of mutant tissue from which colitis associated cancers can arise (field cancerisation). Endoscopic screening is the mainstay of surveillance in high-risk patients although the development of appropriate, clinically applicable biomarkers remains a research priority. Despite the expanding field of biological therapy in inflammatory bowel disease the ASA compounds remain the best-studied and most efficacious chemopreventive agents. Colitis associated CRC appears to have a different aetiology, carcinogenesis pathway and clinical course to its sporadic counterpart. Further research including long-term follow up of patient cohorts taking biological therapies will improve the detection and treatment of these important, inflammation-induced malignancies.
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Fu L, Wang G, Shevchuk MM, Nanus DM, Gudas LJ. Generation of a mouse model of Von Hippel-Lindau kidney disease leading to renal cancers by expression of a constitutively active mutant of HIF1α. Cancer Res 2011; 71:6848-56. [PMID: 21908555 DOI: 10.1158/0008-5472.can-11-1745] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Renal cancers are highly aggressive and clinically challenging, but a transgenic mouse model to promote pathologic studies and therapeutic advances has yet to be established. Here, we report the generation of a transgenic mouse model of von Hippel-Lindau (VHL) renal cancer termed the TRACK model (transgenic model of cancer of the kidney). TRACK mice specifically express a mutated, constitutively active HIF1α in kidney proximal tubule (PT) cells. Kidney histologies displayed by TRACK mice are highly similar to histologies seen in patients with VHL disease, including areas of distorted tubular structure, cells with clear cytoplasm and increased glycogen and lipid deposition, multiple renal cysts, and early onset of clear cell renal cell carcinoma (ccRCC). Distorted tubules in TRACK mice exhibit higher levels of CA-IX, Glut1, and VEGF than tubules in nontransgenic control mice. Furthermore, these tubules exhibit increased numbers of endothelial cells, increased cell proliferation, and increased expression of the human ccRCC marker CD70(TNFSF7). Moreover, PT cells in kidney tubules from TRACK mice exhibit increased genomic instability, as monitored by elevated levels of γH2AX. Our findings establish that activated HIF1α in murine kidney PT cells is sufficient to promote cell proliferation, angiogenesis, genomic instability, and other phenotypic alterations characteristic of human VHL kidney disease, establishing the TRACK mouse as a valid preclinical model of human renal cell carcinoma.
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Affiliation(s)
- Leiping Fu
- Department of Pharmacology, Weill Cornell Cancer Center, Weill Cornell Medical College (WCMC) of Cornell University, New York, New York, USA
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Payne CM, Crowley-Skillicorn C, Bernstein C, Holubec H, Bernstein H. Molecular and cellular pathways associated with chromosome 1p deletions during colon carcinogenesis. Clin Exp Gastroenterol 2011; 4:75-119. [PMID: 21753893 PMCID: PMC3132853 DOI: 10.2147/ceg.s17114] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Indexed: 11/23/2022] Open
Abstract
Chromosomal instability is a major pathway of sporadic colon carcinogenesis. Chromosome arm 1p appears to be one of the "hot spots" in the non-neoplastic mucosa that, when deleted, is associated with the initiation of carcinogenesis. Chromosome arm 1p contains genes associated with DNA repair, spindle checkpoint function, apoptosis, multiple microRNAs, the Wnt signaling pathway, tumor suppression, antioxidant activities, and defense against environmental toxins. Loss of 1p is dangerous since it would likely contribute to genomic instability leading to tumorigenesis. The 1p deletion-associated colon carcinogenesis pathways are reviewed at the molecular and cellular levels. Sporadic colon cancer is strongly linked to a high-fat/low-vegetable/low-micronutrient, Western-style diet. We also consider how selected dietary-related compounds (eg, excess hydrophobic bile acids, and low levels of folic acid, niacin, plant-derived antioxidants, and other modulatory compounds) might affect processes leading to chromosomal deletions, and to the molecular and cellular pathways specifically altered by chromosome 1p loss.
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Affiliation(s)
- Claire M Payne
- Department of Cell Biology and Anatomy, College of Medicine, University of Arizona Tucson, AZ, USA
| | | | - Carol Bernstein
- Department of Cell Biology and Anatomy, College of Medicine, University of Arizona Tucson, AZ, USA
| | - Hana Holubec
- Department of Cell Biology and Anatomy, College of Medicine, University of Arizona Tucson, AZ, USA
| | - Harris Bernstein
- Department of Cell Biology and Anatomy, College of Medicine, University of Arizona Tucson, AZ, USA
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Altered mRNA expression of telomere binding proteins (TPP1, POT1, RAP1, TRF1 and TRF2) in ulcerative colitis and Crohn's disease. Dig Liver Dis 2010; 42:544-8. [PMID: 20061197 DOI: 10.1016/j.dld.2009.12.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2009] [Revised: 12/04/2009] [Accepted: 12/13/2009] [Indexed: 12/11/2022]
Abstract
AIMS To determine mRNA expression of telomeric binding proteins in inflammatory bowel disease (IBD), and to note any effects of pharmacotherapy on telomere binding protein expression. METHODS Peripheral blood mononuclear cells (PBMC) obtained from 31 IBD patients and 13 controls were activated with phytohaemagglutinin and purified to yield activated (CD25+) T lymphocytes. TPP1, POT1, RAP1, TRF1 and TRF2 mRNA expression in PBMC and activated T lymphocytes was measured with RT-PCR. RESULTS In activated (CD25+) T lymphocytes, mean TRF2 mRNA levels were lower in both UC (6.6 vs 10, p=0.004) and CD subjects (6.9 vs 10; p=0.004). Similarly. in activated (CD25+) T lymphocytes mean RAP1 mRNA expression was significantly lower in UC subjects (4.5 vs 9.8, p=0.029) but not in CD subjects. In resting PBMC, mean TRF1 mRNA levels were lower in both UC (2.6 vs 3.5; p=0.008) and CD subjects (1.0 vs 3.5; p=0.04). No difference in PBMC and activated (CD25+) T lymphocytes mRNA levels of TPP1 and POT1 were noted in either UC or CD subjects. An association with 5-aminosalicylate therapy (R(2)=0.4) was only detected with RAP1 mRNA expression. TRF2 mRNA expression was inversely associated with disease duration only in UC subjects (p=0.05; R(2)=-0.6). CONCLUSIONS The downregulation of TRF2 and RAP1 mRNA expression in CD25+ T-lymphocytes in IBD suggests that these telomere binding proteins play a role in telomere regulation and may contribute to the telomeric fusions and chromosomal abnormalities observed in UC. These findings may also indicate a systemic process of telomere uncapping which could represent a biomarker for IBD associated cancer risk.
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Harpaz N, Polydorides AD. Colorectal dysplasia in chronic inflammatory bowel disease: pathology, clinical implications, and pathogenesis. Arch Pathol Lab Med 2010; 134:876-95. [PMID: 20524866 DOI: 10.5858/134.6.876] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
CONTEXT Colorectal cancer, the most lethal long-term complication of chronic inflammatory bowel disease (IBD), is the culmination of a complex sequence of molecular and histologic derangements of the intestinal epithelium that are initiated and at least partially sustained by chronic inflammation. Dysplasia, the earliest histologic manifestation of this process, plays an important role in cancer prevention by providing the first clinical alert that this sequence is underway and serving as an endpoint in colonoscopic surveillance of patients at high risk for colorectal cancer. OBJECTIVE To review the histology, nomenclature, clinical implications, and molecular pathogenesis of dysplasia in IBD. DATA SOURCE Literature review and illustrations from case material. CONCLUSIONS The diagnosis and grading of dysplasia in endoscopic surveillance biopsies play a decisive role in the management of patients with IBD. Although interpathologist variation, endoscopic sampling problems, and incomplete information regarding the natural history of dysplastic lesions are important limiting factors, indirect evidence that surveillance may be an effective means of reducing cancer-related mortality in the population with IBD has helped validate the histologic criteria, nomenclature, and clinical recommendations that are the basis of current practice among pathologists and clinicians. Emerging technologic advances in endoscopy may permit more effective surveillance, but ultimately the greatest promise for cancer prevention in IBD lies in expanding our thus far limited understanding of the molecular pathogenetic relationships between neoplasia and chronic inflammation.
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Affiliation(s)
- Noam Harpaz
- Department of Pathology, The Mount Sinai School of Medicine, New York, New York 10092, USA.
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23
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Yang JY, Ha SA, Yang YS, Kim JW. p-Glycoprotein ABCB5 and YB-1 expression plays a role in increased heterogeneity of breast cancer cells: correlations with cell fusion and doxorubicin resistance. BMC Cancer 2010; 10:388. [PMID: 20649952 PMCID: PMC2913965 DOI: 10.1186/1471-2407-10-388] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Accepted: 07/22/2010] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Cancer cells recurrently develop into acquired resistance to the administered drugs. The iatrogenic mechanisms of induced chemotherapy-resistance remain elusive and the degree of drug resistance did not exclusively correlate with reductions of drug accumulation, suggesting that drug resistance may involve additional mechanisms. Our aim is to define the potential targets, that makes drug-sensitive MCF-7 breast cancer cells turn to drug-resistant, for the anti-cancer drug development against drug resistant breast cancer cells. METHODS Doxorubicin resistant human breast MCF-7 clones were generated. The doxorubicin-induced cell fusion events were examined. Heterokaryons were identified and sorted by FACS. In the development of doxorubicin resistance, cell-fusion associated genes, from the previous results of microarray, were verified using dot blot array and quantitative RT-PCR. The doxorubicin-induced expression patterns of pro-survival and pro-apoptotic genes were validated. RESULTS YB-1 and ABCB5 were up regulated in the doxorubicin treated MCF-7 cells that resulted in certain degree of genomic instability that accompanied by the drug resistance phenotype. Cell fusion increased diversity within the cell population and doxorubicin resistant MCF-7 cells emerged probably through clonal selection. Most of the drug resistant hybrid cells were anchorage independent. But some of the anchorage dependent MCF-7 cells exhibited several unique morphological appearances suggesting minor population of the fused cells maybe de-differentiated and have progenitor cell like characteristics. CONCLUSION Our work provides valuable insight into the drug induced cell fusion event and outcome, and suggests YB-1, GST, ABCB5 and ERK3 could be potential targets for the anti-cancer drug development against drug resistant breast cancer cells. Especially, the ERK-3 serine/threonine kinase is specifically up-regulated in the resistant cells and known to be susceptible to synthetic antagonists.
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Affiliation(s)
- Ji Yeon Yang
- Molecular Genetic Laboratory, College of Medicine, The Catholic University of Korea, Seoul 137-040, Republic of Korea
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24
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Abstract
Invasive tumors (cancers or malignant lesions) typically develop in the setting in which there is the presence of putative non-invasive lesions and the development of these non-invasive lesions frequently precedes the development of cancers. For some organs, such as the oral cavity, cervix and skin, the respective putative pre-invasive lesions can be observed over time and documented to progress to invasive lesions. However, for less readily observable lesions, such as those of the prostate, the progression of the pre-invasive lesions, e.g., prostatic intraepithelial neoplasia (PIN) and prostatic proliferative inflammatory atrophy (PIA) to prostatic cancer are more difficult to document. Thus, for most organ systems, specific pre-invasive neoplastic lesions have been proposed based upon the apparent observations of one or more of the following: 1) microinvasive disease developing from a pre-invasive neoplastic lesion, 2) the general association of the pre-invasive lesion with invasive lesions, 3) the subsequent development of invasive lesions following diagnosis of the pre-invasive lesion, 4) correlations of the molecular features of the putative pre-invasive lesion with the matching invasive lesions, and 5) reductions in the rate of cancer following removal of the pre-invasive lesion. When there are mixtures of pre-invasive lesions with actual cancers in the same case, some of the above specific associations are more difficult to make. Several terms have been used to describe pre-invasive lesions, many of which are now less useful as our knowledge of these lesions increases. It is now commonly accepted that these lesions are a features of the spectrum of neoplastic development and most are accepted as ``neoplastic lesions'' with associated molecular features, even though they may be reversible even if they have mutations in suppressor genes (e.g., p53) or are associated with viral etiologies (e.g., cervical intraepithelial neoplasia). The overall term, "pre-invasive neoplasia", seems to best describe these putative pre-invasive lesions. Thus, terms such as incipient neoplasia should be abandoned. The term "intra-epithelial neoplasia" with an associated grade, which has been developed for pre-invasive neoplastic lesions of the cervix, i.e. cervical intraepithelial neoplasia (CIN), seems to be a terminology that adds consistency across epithelial organs. Thus, adoption of these terms for the additional organ sites of pancreas (PanIN) and prostate (PIN) seems accepted. Less descriptive terms such as the degrees of dysplasia of the oral cavity and bronchopulmonary system and actinic keratosis and Bowen's disease of the skin might be better designated as oral intraepithelial neoplasia (OIN), pulmonary intraepithelial neoplasia (PulIN) and dermal intraepithelial neoplasia (DIN). The etiology of pre-invasive neoplasia is the etiology of the matching cancers. Some obvious initiating factors include exposure to the whole range of ionizing and non-ionizing radiation, tobacco abuse and a broad range of other carcinogens (e.g., benzene). A frequent initiation factor is the setting of long standing continuing damage, inflammation and repair (LOCDIR) which leads to early molecular features associated with neoplasia after about one year. An excellent example of this is ulcerative colitis (UC) in which dysregulation of microsatellite repair enzymes have been documented one year following diagnosis of UC. While the nomenclature, description, diagnosis and etiology of pre-invasive neoplasia has advanced, approaches to therapy of such lesions have not progressed adequately even though it has been identified that, for example, removal of polyps periodically from the colorectum, DCIS from the breast, and high grade CIN from the cervix, results in a reduction in the development of cancers of the colorectum, breast, and cervix, respectively. With the development of more molecularly targeted therapy with fewer side effects, preventive therapies may be more successfully targeted to pre-invasive neoplastic lesions.
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Affiliation(s)
- William E Grizzle
- Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Payne CM, Bernstein C, Dvorak K, Bernstein H. Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis. Clin Exp Gastroenterol 2008; 1:19-47. [PMID: 21677822 PMCID: PMC3108627 DOI: 10.2147/ceg.s4343] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage) are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer.
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Affiliation(s)
- Claire M Payne
- Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, Arizona, USA
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26
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Abstract
Oxidative stress is defined as an imbalance between generation of reactive oxygen species (ROS) and decreased antioxidant defense systems. Oxidative stress develops particularly in inflammatory reactions because the inflammatory cells, neutrophils, and macrophages produce large amounts of ROS. It has been known for a long time that oxidative stress in inflamed tissue can pave the way for malignant tumors, and that it is a major pathogenetic factor for the well-established correlation between inflammatory diseases and cancer. Oxidative stress has long been associated with the pathogenesis of chronic inflammatory bowel disease (IBD)-related colorectal cancer. This article provides an overview of the pathology of ROS and presents recent advances concerning the role of ROS in IBD-related colorectal carcinogenesis (Fig. 1).
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Løvig T, Andersen SN, Clausen OP, Rognum TO. Microsatellite instability in long-standing ulcerative colitis. Scand J Gastroenterol 2007; 42:586-91. [PMID: 17454879 DOI: 10.1080/00365520601013747] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Ulcerative colitis (UC) is a chronic inflammatory disease of the colon associated with a high risk of developing colorectal cancer. Several genetic alterations have been documented in dysplasia and cancer developing in UC. Concerning microsatellite instability (MSI), many contradictory results have been published. We therefore analysed a large, well-characterized UC material for MSI to elucidate its significance in long-standing UC. MATERIAL AND METHODS From 33 patients, a total of 159 microdissected lesions and 165 mucosa samples obtained adjacent to the tissue blocks were analysed for MSI using the five standard markers recommended by the National Cancer Institute; D2S123, D5S346, D17S250, BAT-25 and BAT-26. In addition, 12 of the patients were investigated by a mini-satellite marker at the D1S7 locus. RESULTS High-level MSI (MSI-H) was detected in one villous adenoma with high-grade dysplasia and right-sided location. This represents 3.6% (1/28) of dysplastic mucosa investigated. No other lesions showed MSI in the five standard markers or at the D1S7 locus. CONCLUSIONS This study suggests that MSI is rare in UC-related neoplasia as well as non-neoplastic lesions, and does not contribute to the development of dysplasia.
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Affiliation(s)
- Tone Løvig
- Institute of Forensic Medicine, Department of Pathology, Akershus University Hospital HF, Lørenskog, Norway.
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Risques RA, Rabinovitch PS, Brentnall TA. Cancer surveillance in inflammatory bowel disease: new molecular approaches. Curr Opin Gastroenterol 2006; 22:382-90. [PMID: 16760754 DOI: 10.1097/01.mog.0000231812.95525.a7] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW Patients with chronic inflammatory bowel disease, such as ulcerative colitis and Crohn's disease, have an increased risk of colorectal cancer. Life-long colonoscopy surveillance is performed to detect the presence of dysplasia, but this approach is expensive and time-consuming. Thus, there is intensive research to identify molecular factors with prognostic value. This review summarizes recent research, with a special emphasis on the mechanisms underlying these molecular alterations. RECENT FINDINGS The role of chromosomal instability in the progression to inflammatory bowel disease-associated colorectal cancer is clear and likely relates to chronic cycles of injury, inflammation, repair and telomere shortening. The role of microsatellite instability has been a subject of discussion, and data suggest that microsatellite instability in inflammatory bowel disease might be different from microsatellite instability in sporadic colorectal cancer. Methylation, as a mechanism of gene silencing, also plays a role in ulcerative colitis tumorigenesis. Chronic inflammation has been linked to p53 activation and oxidative stress, contributing to the extensive genomic DNA damage observed in ulcerative colitis. SUMMARY Improved understanding of the molecular biology of cancer progression in inflammatory bowel disease will hopefully lead to the identification of useful prognostic biomarkers. Efforts are needed to prove the clinical utility of the most promising markers now identified.
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Abstract
Intensive research efforts during the last several decades have increased our understanding of carcinogenesis, and have identified a genetic basis for the multi-step process of cancer development. Tumors grow through a process of clonal expansion driven by mutation. Several forms of molecular alteration have been described in human cancers, and these can be generally classified as chromosomal abnormalities and nucleotide sequence abnormalities. Most cancer cells display a phenotype characterized by genomic hypermutability, suggesting that genomic instability may precede the acquisition of transforming mutations in critical target genes. Reduced to its essence, cancer is a disease of abnormal gene expression, and these genetic abnormalities contribute to cancer pathogenesis through inactivation of negative mediators of cell proliferation (including tumor suppressor genes) and activation of positive mediators of cell proliferation (including proto-oncogenes). In several human tumor systems, specific genetic alterations have been shown to correlate with well-defined histopathological stages of tumor development and progression. Although the significance of mutations to the etiological mechanisms of tumor development has been debated, a causal role for such genetic lesions is now commonly accepted for most human cancers. Thus, genetic lesions represent an integral part of the processes of neoplastic transformation, tumorigenesis, and tumor progression, and as such represent potentially valuable markers for cancer detection and staging.
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Affiliation(s)
- William B Coleman
- Department of Pathology and Laboratory Medicine, Curriculum in Toxicology, UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill NC, 27599, USA.
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Chang IY, Kim SH, Cho HJ, Lee DY, Kim MH, Chung MH, You HJ. Human AP endonuclease suppresses DNA mismatch repair activity leading to microsatellite instability. Nucleic Acids Res 2005; 33:5073-81. [PMID: 16147991 PMCID: PMC1201336 DOI: 10.1093/nar/gki829] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The multifunctional mammalian apurinic/apyrimidinic (AP) endonuclease (APE) participates in the repair of AP sites in the cellular DNA as well as participating in the redox regulation of the transcription factor function. The function of APE is considered as the rate-limiting step in DNA base excision repair. Paradoxically, an unbalanced increase in APE protein leads to genetic instability. Therefore, we investigated the mechanisms of genetic instability that are induced by APE. Here, we report that the overexpression of APE protein disrupts the repair of DNA mismatches, which results in microsatellite instability (MSI). We found that expression of APE protein led to the suppression of the repair of DNA mismatches in the normal human fibroblast cells. Western blot analysis revealed that hMSH6 protein was markedly reduced in the APE-expressing cells. Moreover, the addition of purified Mutalpha (MSH2 and MSH6 complex) to the extracts from the APE-expressing cells led to the restoration of mismatch repair (MMR) activity. By performing MMR activity assay and MSI analysis, we found that the co-expression of hMSH6 and APE exhibited the microsatellite stability, whereas the expression of APE alone generated the MSI-high phenotype. The APE-mediated decrease in MMR activity described here demonstrates the presence of a new and highly effective APE-mediated mechanism for MSI.
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Affiliation(s)
- In-Youb Chang
- Research Center for Proteinous Materials, Chosun University375 Seusuk-dong, Gwangju 501-759, Korea
- Department of Anatomy, School of Medicine, Chosun University375 Seusuk-dong, Gwangju 501-759, Korea
| | - Soo-Hyun Kim
- Research Center for Proteinous Materials, Chosun University375 Seusuk-dong, Gwangju 501-759, Korea
- Department of Pharmacology, School of Medicine, Chosun University375 Seusuk-dong, Gwangju 501-759, Korea
| | - Hyun-Ju Cho
- Research Center for Proteinous Materials, Chosun University375 Seusuk-dong, Gwangju 501-759, Korea
- Department of Pharmacology, School of Medicine, Chosun University375 Seusuk-dong, Gwangju 501-759, Korea
| | - Do Young Lee
- Research Center for Proteinous Materials, Chosun University375 Seusuk-dong, Gwangju 501-759, Korea
- Department of Pharmacology, School of Medicine, Chosun University375 Seusuk-dong, Gwangju 501-759, Korea
| | - Mi-Hwa Kim
- Research Center for Proteinous Materials, Chosun University375 Seusuk-dong, Gwangju 501-759, Korea
- Department of Pharmacology, School of Medicine, Chosun University375 Seusuk-dong, Gwangju 501-759, Korea
| | - Myung-Hee Chung
- Department of Pharmacology, College of medicine, Seoul National University28, Yongon-dong, Seoul 110-799, Korea
| | - Ho Jin You
- Research Center for Proteinous Materials, Chosun University375 Seusuk-dong, Gwangju 501-759, Korea
- Department of Pharmacology, School of Medicine, Chosun University375 Seusuk-dong, Gwangju 501-759, Korea
- To whom correspondence should be addressed. Tel: +82 62 230 6337; Fax: +82 62 233 3720;
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Getliffe KM, Al Dulaimi D, Martin-Ruiz C, Holder RL, von Zglinicki T, Morris A, Nwokolo CU. Lymphocyte telomere dynamics and telomerase activity in inflammatory bowel disease: effect of drugs and smoking. Aliment Pharmacol Ther 2005; 21:121-31. [PMID: 15679761 DOI: 10.1111/j.1365-2036.2005.02311.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The chromosome instability observed in peripheral blood lymphocytes in ulcerative colitis could be a biomarker of cancer susceptibility. AIM To determine whether accelerated telomere shortening could explain chromosome instability and assess the effect of drugs and smoking on telomere dynamics in these cells. METHODS Peripheral blood lymphocytes were isolated from ulcerative colitis, Crohn's disease and non-inflammatory bowel disease control patients. Telomere lengths were measured by quantitative real-time polymerase chain reaction. After activation and cell separation, telomerase activity and human telomerase reverse transcriptase messenger ribonucleic acid were measured by telomerase repeat amplification protocol enzyme-linked immunosorbent serological assay and quantitative real-time polymerase chain reaction, respectively. RESULTS Age-related telomere loss in peripheral blood lymphocytes was similar in ulcerative colitis, Crohn's disease and control patients. Telomerase activity decreased with age in all groups and correlated positively with telomere length (r = 0.489, P = 0.006). Among Crohn's disease patients, azathioprine was associated with decreased telomerase activity (0.66 vs. 1.54, P = 0.026, P < 0.05) and smoking was associated with decreased human telomerase reverse transcriptase mRNA expression (10.5 vs. 33.3, P = 0.036, P < 0.05). CONCLUSIONS Telomere shortening is not accelerated and therefore cannot be the cause of the chromosome instability observed in ulcerative colitis peripheral blood lymphocytes. Azathioprine and cigarette smoking modify telomerase expression in these cells.
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Affiliation(s)
- K M Getliffe
- Department of Biological Sciences, University of Warwick, Coventry, UK
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Hofseth LJ, Khan MA, Ambrose M, Nikolayeva O, Xu-Welliver M, Kartalou M, Hussain SP, Roth RB, Zhou X, Mechanic LE, Zurer I, Rotter V, Samson LD, Harris CC. The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation. J Clin Invest 2004; 112:1887-94. [PMID: 14679184 PMCID: PMC296999 DOI: 10.1172/jci19757] [Citation(s) in RCA: 144] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Chronic infection and associated inflammation are key contributors to human carcinogenesis. Ulcerative colitis (UC) is an oxyradical overload disease and is characterized by free radical stress and colon cancer proneness. Here we examined tissues from noncancerous colons of ulcerative colitis patients to determine (a) the activity of two base excision-repair enzymes, AAG, the major 3-methyladenine DNA glycosylase, and APE1, the major apurinic site endonuclease; and (b) the prevalence of microsatellite instability (MSI). AAG and APE1 were significantly increased in UC colon epithelium undergoing elevated inflammation and MSI was positively correlated with their imbalanced enzymatic activities. These latter results were supported by mechanistic studies using yeast and human cell models in which overexpression of AAG and/or APE1 was associated with frameshift mutations and MSI. Our results are consistent with the hypothesis that the adaptive and imbalanced increase in AAG and APE1 is a novel mechanism contributing to MSI in patients with UC and may extend to chronic inflammatory or other diseases with MSI of unknown etiology.
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Affiliation(s)
- Lorne J Hofseth
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA
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Guo HH, Loeb LA. Tumbling down a different pathway to genetic instability. J Clin Invest 2004; 112:1793-5. [PMID: 14679175 PMCID: PMC297004 DOI: 10.1172/jci20502] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Ulcerative colitis (UC), a chronic inflammatory condition associated with a predisposition to colon cancer, is frequently characterized by DNA damage in the form of microsatellite instability (MSI). A new report links inflammation in UC with increases in the DNA repair enzymes 3-methyladenine DNA glycosylase and apurinic/apyrimidinic endonuclease, and, paradoxically, with increased MSI. These findings may represent a novel mechanism contributing to MSI in chronic inflammation.
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Affiliation(s)
- Haiwei H Guo
- Jospeh Gottstein Research Laboratory, Department of Pathology, University of Washington, Seattle 98195-7705, USA
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35
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Hofseth LJ, Khan MA, Ambrose M, Nikolayeva O, Xu-Welliver M, Kartalou M, Hussain SP, Roth RB, Zhou X, Mechanic LE, Zurer I, Rotter V, Samson LD, Harris CC. The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation. J Clin Invest 2004. [PMID: 14679184 DOI: 10.1172/jci200319757] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Chronic infection and associated inflammation are key contributors to human carcinogenesis. Ulcerative colitis (UC) is an oxyradical overload disease and is characterized by free radical stress and colon cancer proneness. Here we examined tissues from noncancerous colons of ulcerative colitis patients to determine (a) the activity of two base excision-repair enzymes, AAG, the major 3-methyladenine DNA glycosylase, and APE1, the major apurinic site endonuclease; and (b) the prevalence of microsatellite instability (MSI). AAG and APE1 were significantly increased in UC colon epithelium undergoing elevated inflammation and MSI was positively correlated with their imbalanced enzymatic activities. These latter results were supported by mechanistic studies using yeast and human cell models in which overexpression of AAG and/or APE1 was associated with frameshift mutations and MSI. Our results are consistent with the hypothesis that the adaptive and imbalanced increase in AAG and APE1 is a novel mechanism contributing to MSI in patients with UC and may extend to chronic inflammatory or other diseases with MSI of unknown etiology.
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Affiliation(s)
- Lorne J Hofseth
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA
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Goodman JE, Hofseth LJ, Hussain SP, Harris CC. Nitric oxide and p53 in cancer-prone chronic inflammation and oxyradical overload disease. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2004; 44:3-9. [PMID: 15199542 DOI: 10.1002/em.20024] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Nitric oxide (NO(.)), which is generated under chronic inflammatory conditions that predispose individuals to cancer, has paradoxical effects. NO(.) can activate p53, which can result in anti-carcinogenic effects, or it can be mutagenic and increase cancer risk. We explored the mechanisms by which NO(.) induced p53 activation in vitro and found that NO(.) induced p53 accumulation and phosphorylation, particularly at ser-15, via ATM and ATR kinases, which then led to cell cycle arrest at G(2)/M. We next examined proteins in these pathways in both inflamed and normal human colon tissue. Inducible nitric oxide synthase (iNOS) levels and p53-P-ser15 levels were positively correlated with the degree of inflammation and with each other. Additionally, the p53 targets, HDM-2 and p21 (WAF1), were present in ulcerative colitis (UC) colon, but undetectable in normal colon, consistent with activated p53. We also found higher p53 mutant frequencies of both G:C --> A:T transitions at the CpG site of codon 248 and C:G --> T:A transitions at codon 247 in lesional colon tissue from UC cases versus nonlesional tissue from these cases or colon tissue from normal adult controls. Consistent with nitrosative stress and the deamination of 5-methylcytosine, p53 mutations were also detected in sporadic colon cancer tissue and were associated with iNOS activity in these tissues. These studies identified a potential mechanistic link between NO(.) and p53 in UC and sporadic colon cancer.
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Affiliation(s)
- Julie E Goodman
- Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
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Habermann JK, Upender MB, Roblick UJ, Krüger S, Freitag S, Blegen H, Bruch HP, Schimmelpenning H, Auer G, Ried T. Pronounced chromosomal instability and multiple gene amplifications characterize ulcerative colitis–associated colorectal carcinomas. ACTA ACUST UNITED AC 2003; 147:9-17. [PMID: 14580765 DOI: 10.1016/s0165-4608(03)00219-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Patients with ulcerative colitis have a significantly increased lifetime risk for the development of colorectal carcinomas. While genetic and genomic changes during carcinogenesis have been thoroughly studied in sporadic colorectal cancers, less is known about ulcerative colitis-associated colorectal carcinomas. The aim of this study was to extend the identification of specific genomic imbalances to ulcerative colitis-associated colorectal carcinomas and to establish a comprehensive map of DNA gains and losses by investigating 23 tumor specimens from 23 patients. The molecular cytogenetic characterization was performed using comparative genomic hybridization; immunohistochemistry was used to measure proliferative activity and laminin-5 expression as a marker for invasiveness. The results indicate that these tumors are invariably aneuploid, with a high proliferative activity and increased invasive potential. The average number of copy alterations correlates with increased cyclin A levels (P=0.044), which is an independent predictor of risk of carcinoma development in ulcerative colitis. Despite severe genetic instability, the general pattern of specific chromosomal aberrations that defines sporadic colorectal carcinomas is maintained in ulcerative colitis-associated malignancies. High-level copy number increases (amplifications) are dispersed throughout the genome. Strikingly, these amplifications are much more frequent than in sporadic carcinomas and map to chromosomal regions that have not been described before.
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Affiliation(s)
- Jens K Habermann
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 50, Room 1408, 50 South Drive, Bethesda, MD 20892-8010, USA
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Skopelitou AS, Katsanos KH, Michail M, Mitselou A, Tsianos EV. Immunohistochemical expression of FHIT gene product in inflammatory bowel disease: significance and correlation with clinicopathological data. Eur J Gastroenterol Hepatol 2003; 15:665-73. [PMID: 12840679 DOI: 10.1097/00042737-200306000-00014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE To investigate the expression of Fhit protein in 53 patients with ulcerative colitis and Crohn's disease, as well as in 13 ulcerative-colitis-associated adenocarcinomas, and its eventual relationship with clinicopathological data and response to therapy. MATERIALS AND METHODS We performed immunohistochemistry in archival material of formalin-fixed, paraffin-embedded tissues using the anti-Fhit antibody and the streptavidin-biotin peroxidase method. RESULTS In 35/38 cases of ulcerative colitis, Fhit protein (pFhit) was absent or reduced. In the remaining three cases, it was expressed normally. In 12/15 cases of Crohn's disease, pFhit was absent or reduced, as it was in 4/13 cases of ulcerative-colitis-associated adenocarcinoma. Statistically significant differences of pFhit expression were observed between the active phase and the chronic healed phase of ulcerative colitis, and between the active phase and the normal colon mucosa. Also, statistically significant differences of pFhit expression were observed between (1) the resolving phase of ulcerative colitis and normal colon mucosa, (2) the chronic healed phase and normal colon mucosa, and (3) Crohn's disease and normal colon mucosa. Interestingly, a statistically very significant difference in pFhit expression was noticed between ulcerative colitis and ulcerative-colitis-associated adenocarcinoma. CONCLUSIONS Our results show that immunohistochemical expression of pFhit is completely absent or very reduced in idiopathic bowel disease (IBD) as well as in several ulcerative-colitis-associated adenocarcinomas in north-western Greece. These findings suggest that the FHIT gene might be involved in IBD and in a subgroup of ulcerative-colitis-associated carcinogenesis, although larger series should be tested.
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Hofseth LJ, Saito S, Hussain SP, Espey MG, Miranda KM, Araki Y, Jhappan C, Higashimoto Y, He P, Linke SP, Quezado MM, Zurer I, Rotter V, Wink DA, Appella E, Harris CC. Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. Proc Natl Acad Sci U S A 2003; 100:143-8. [PMID: 12518062 PMCID: PMC140909 DOI: 10.1073/pnas.0237083100] [Citation(s) in RCA: 260] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Free radical-induced cellular stress contributes to cancer during chronic inflammation. Here, we investigated mechanisms of p53 activation by the free radical, NO. NO from donor drugs induced both ataxia-telangiectasia mutated (ATM)- and ataxia-telangiectasia mutated and Rad3-related-dependent p53 posttranslational modifications, leading to an increase in p53 transcriptional targets and a G(2)M cell cycle checkpoint. Such modifications were also identified in cells cocultured with NO-releasing macrophages. In noncancerous colon tissues from patients with ulcerative colitis (a cancer-prone chronic inflammatory disease), inducible NO synthase protein levels were positively correlated with p53 serine 15 phosphorylation levels. Immunostaining of HDM-2 and p21(WAF1) was consistent with transcriptionally active p53. Our study highlights a pivotal role of NO in the induction of cellular stress and the activation of a p53 response pathway during chronic inflammation.
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Affiliation(s)
- Lorne J Hofseth
- Laboratories of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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41
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O'Sullivan JN, Bronner MP, Brentnall TA, Finley JC, Shen WT, Emerson S, Emond MJ, Gollahon KA, Moskovitz AH, Crispin DA, Potter JD, Rabinovitch PS. Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet 2002; 32:280-4. [PMID: 12355086 DOI: 10.1038/ng989] [Citation(s) in RCA: 256] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2002] [Accepted: 08/05/2002] [Indexed: 12/16/2022]
Abstract
Ulcerative colitis, a chronic inflammatory disease of the colon, is associated with a high risk of colorectal carcinoma that is thought to develop through genomic instability. We considered that the rapid cell turnover and oxidative injury observed in ulcerative colitis might accelerate telomere shortening, thereby increasing the potential of chromosomal ends to fuse, resulting in cycles of chromatin bridge breakage and fusion and chromosomal instability associated with tumor cell progression. Here we have used quantitative fluorescence in situ hybridization to compare chromosomal aberrations and telomere shortening in non-dysplastic mucosa taken from individuals affected by ulcerative colitis, either with (UC progressors) or without (UC non-progressors) dysplasia or cancer. Losses, but not gains, of chromosomal arms and centromeres are highly correlated with telomere shortening. Chromosomal losses are greater and telomeres are shorter in biopsy samples from UC progressors than in those from UC non-progressors or control individuals without ulcerative colitis. A mechanistic link between telomere shortening and chromosomal instability is supported by a higher frequency of anaphase bridges--an intermediate in the breakage and fusion of chromatin bridges--in UC progressors than in UC non-progressors or control individuals. Our study shows that telomere length is correlated with chromosomal instability in a precursor of human cancer.
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Affiliation(s)
- Jacintha N O'Sullivan
- Department of Pathology, University of Washington, Seattle, Washington 98195-7705, USA
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Lung JC, Chu JS, Yu JC, Yue CT, Lo YL, Shen CY, Wu CW. Aberrant expression of cell-cycle regulator cyclin D1 in breast cancer is related to chromosomal genomic instability. Genes Chromosomes Cancer 2002; 34:276-84. [PMID: 12007188 DOI: 10.1002/gcc.10072] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
To account for the accumulation of genomic alterations required for tumor progression, it has been suggested that the genomes of cancer cells are unstable and that this instability results from defective mutators (the "mutator phenotype" theory). To examine the hypothesis that abnormal cell-cycle regulators act as the mutators contributing to genomic instability, the present study, based on primary tumor tissues from 71 patients with breast cancer, was performed to determine whether there was an association between aberrant expression of cell-cycle regulators (cyclin A, cyclin D1, cyclin E, RB1, p21, and p27) and chromosomal instability. Comparative genomic hybridization was used to measure chromosomal changes, reflecting genomic instability in individual tumors, whereas immunohistochemistry was used to detect aberrant expression of cell-cycle regulators. Overexpression of cyclin D1 was found to be significantly correlated with increased chromosomal instability (defined as harboring more than 7 chromosomal changes), with 63% of tumors overexpressing and 27% of tumors not overexpressing, with cyclin D1 showing chromosomal instability (P < 0.05). Interestingly, this relationship was independent of cell outgrowth (as detected by the proliferation marker Ki-67) and was particularly significant in tumors not expressing p27 or in tumors with detectable RB1. These results suggest that cyclin D1 plays an alternative role in the regulation of genomic stability.
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Affiliation(s)
- Jia-Chyi Lung
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
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Abstract
OBJECTIVE Pancreatic cancer has an extremely poor prognosis and the cellular mechanisms contributing to pancreatic cancer are relatively unknown. The goals of this review are to present the epidemiological and experimental data that supports inflammation as a key mediator of pancreatic cancer development, to explain how inflammatory pathways may create an environment that supports tumor formation, and to discuss how the use of novel agents directed at these pathways may be used for the treatment of pancreatic malignancy. SUMMARY BACKGROUND DATA Inflammation has been identified as a significant factor in the development of other solid tumor malignancies. Both hereditary and sporadic forms of chronic pancreatitis are associated with an increased risk of developing pancreatic cancer. The combined increase in genomic damage and cellular proliferation, both of which are seen with inflammation, strongly favors malignant transformation of pancreatic cells. Cytokines, reactive oxygen species, and mediators of the inflammatory pathway (e.g., NF-kappaB and COX-2) have been shown to increase cell cycling, cause loss of tumor suppressor function, and stimulate oncogene expression; all of which may lead to pancreatic malignancy. Anti-cytokine vaccines, inhibitors of pro-inflammatory NF-kappaB and COX-2 pathways, thiazolidinediones, and anti-oxidants are potentially useful for the prevention or treatment of pancreatic cancer. Redirection of experimental interests toward pancreatic inflammation and mechanisms of carcinogenesis may identify other novel anti-inflammatory agents or other ways to screen for or prevent pancreatic cancer. CONCLUSION Pancreatic inflammation, mediated by cytokines, reactive oxygen species, and upregulated pro-inflammatory pathways, may play a key role in the early development of pancreatic malignancy.
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Affiliation(s)
- Buckminster Farrow
- Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston 77555, USA
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44
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Blagosklonny MV. How carcinogens (or telomere dysfunction) induce genetic instability: associated-selection model. FEBS Lett 2001; 506:169-72. [PMID: 11602239 DOI: 10.1016/s0014-5793(01)02894-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Carcinogens induce carcinogen-specific genetic instability (defects in DNA repair). According to the 'direct-selection' model, defects in DNA repair per se provide an immediate growth advantage. According to the 'associated-selection' model, carcinogens merely select for cells with adaptive mutations. Like any mutations, adaptive mutations occur predominantly in genetically unstable cells. The 'associated-selection' model predicts that carcinogen-driven selection minimizes cytotoxic but maximizes mutagenic effects of carcinogens. A purely mutagenic (neither cytotoxic, nor cytostatic) environment will favor effective DNA repair, whereas any growth-limiting conditions (telomerase deficiency, anticancer drugs) will select for genetically unstable cells. Genetic instability is a postmark of selective pressure rather than a hallmark of cancer per se. Once selected, genetic instability facilitates the development of resistance to any other growth-limiting conditions. As an example, a putative link between prior exposure to carcinogens and the ability to develop a telomerase-independent growth is discussed.
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Affiliation(s)
- M V Blagosklonny
- Medicine Branch, National Cancer Institute, NIH, Bldg. 10, R 12 N 226, Bethesda, MD 20892, USA.
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Tuder RM, Yeager ME, Geraci M, Golpon HA, Voelkel NF. Severe pulmonary hypertension after the discovery of the familial primary pulmonary hypertension gene. Eur Respir J 2001; 17:1065-9. [PMID: 11491145 DOI: 10.1183/09031936.01.00202701] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The recent discoveries of the familial primary pulmonary hypertension gene and somatic mutations in key cell growth and cell death regulatory genes in primary pulmonary hypertension have added a new dimension to severe pulmonary hypertension research. These findings have already impacted on how the disease is viewed, and ultimately, how severe pulmonary hypertension is diagnosed and treated. However, this new information raises several fundamental questions related to the role of bone morphogenetic protein receptor signalling in the control of lung vascular cell function. Furthermore, additional genes and gene products may also be involved in the pathogenesis of the disease. The way severe pulmonary hypertension is viewed and studied is on the verge of shifting from a vasoconstrictive to a cell growth paradigm.
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Affiliation(s)
- R M Tuder
- Dept of Pathology, University of Colorado Health Sciences Center, USA
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Sturlan S, Oberhuber G, Beinhauer BG, Tichy B, Kappel S, Wang J, Rogy MA. Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development. Carcinogenesis 2001; 22:665-71. [PMID: 11285204 DOI: 10.1093/carcin/22.4.665] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Interleukin-10-deficient mice develop colitis and colorectal cancer similar to the inflammatory bowel disease associated cancer in humans. The aim of this study was to identify possible mutations of oncogenes and tumour suppressor genes involved in tumorigenesis in Interleukin-10 (IL-10)-deficient mice. Twenty colon carcinomas from IL-10-deficient mice were screened for mutations in the K-ras and p53 genes by 'cold' single-strand-conformation polymorphism. Immunohistochemical staining was performed to detect mutations in the proteins P53, APC and MSH2, and the transforming growth factor beta type II receptor. Microsatellite instability was analysed at eight chromosomal loci and plasma levels of transforming growth factor beta1 (TGF-beta1) were also measured. At 9 weeks, 14% of the animals developed colorectal cancer, and at 10-31 weeks the incidence of carcinoma was 65%. No mutations were detected in the analysed oncogene and tumour suppressor genes. Plasma TGF-beta1 levels in IL-10-deficient mice 10-31 weeks old were higher than in wild-type littermates e.g. 45.7 +/- 4.6 ng/ml versus 19.8 +/- 4.5 ng/ml (P<0.01). No alterations in K-ras, p53, APC: and Msh2 genes suggests that other genes are involved in the development of these tumours. Elevated TGF-beta1 plasma levels correspond to the high incidence of dysplasia and cancer. Normal expression of the TGF-beta II receptors hints at genetic alterations in other members of the TGF-beta receptor signal transduction pathway.
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Affiliation(s)
- S Sturlan
- Department of General Surgery, University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
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47
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Yeager ME, Halley GR, Golpon HA, Voelkel NF, Tuder RM. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res 2001; 88:E2-E11. [PMID: 11139485 DOI: 10.1161/01.res.88.1.e2] [Citation(s) in RCA: 166] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Primary pulmonary hypertension (PPH) is a frequently fatal disease whose pathobiology is poorly understood. Monoclonal endothelial cell growth is present within plexiform lesions of patients with PPH but not secondary PH because of congenital heart malformations. We hypothesized that endothelial cells within PPH plexiform lesions harbor mutations permissive for clonal cell growth. We found that endothelial cells in PPH plexiform lesions demonstrated microsatellite instability within the human MutS Homolog 2 gene (10 of 20 lesions) and displayed microsatellite site mutations and reduced protein expression of transforming growth factor-beta receptor type II (6 of 19 lesions) and Bax (4 of 19 lesions). These results suggest that, in PPH, proliferated endothelial cells have genetic alterations associated with microsatellite instability and concomitant perturbation of growth and apoptosis gene expression akin to neoplasia. The full text of this article is available at http://www.circresaha.org.
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Affiliation(s)
- M E Yeager
- Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado, USA
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Au WW, Oh HY, Grady J, Salama SA, Heo MY. Usefulness of genetic susceptibility and biomarkers for evaluation of environmental health risk. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2001; 37:215-225. [PMID: 11317339 DOI: 10.1002/em.1030] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Recent attention is focused on understanding the genetic basis for individual susceptibility to the development of chronic disease. An emphasis is concentrated on establishing an association between inheritance of polymorphic chemical metabolizing genes and development of environmental cancer (e.g., lung cancer among cigarette smokers). The early reports of such associations have been very encouraging. However, some reported positive associations were not substantiated in subsequent studies using larger sample sizes and different ethnic populations. In this review, some confounding factors that contribute to the discrepancies are presented (e.g., ethnic-dependent distribution of variant gene alleles, differential expression of metabolizing genes, and inadequate study design). It is possible that the precision of the association can be improved if the mentioned investigations are complemented with concurrent studies of biological activities/effects. The usefulness of integrating metabolic susceptibility with biomarker measurement for understanding the development of lung cancers is presented. The importance of using adequate sample size and experimental design is emphasized. Development of a reliable approach for prediction of environmental disease not only will provide fundamental information regarding the genetic basis of human disease but will be useful for reducing disease burden in the population and for advancing patient care. Environ. Mol. Mutagen. 37:215-225, 2001. © 2001 Wiley-Liss, Inc.
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Affiliation(s)
- W W Au
- Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, Texas 77555-1110, USA.
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Duesberg P, Stindl R, Hehlmann R. Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalyzed by aneuploidy. Proc Natl Acad Sci U S A 2000; 97:14295-300. [PMID: 11121035 PMCID: PMC18912 DOI: 10.1073/pnas.97.26.14295] [Citation(s) in RCA: 122] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2000] [Indexed: 11/18/2022] Open
Abstract
The mutation rates of cancer cells to drug and multidrug resistance are paradoxically high, i.e., 10(-3) to 10(-6), compared with those altering phenotypes of recessive genes in normal diploid cells of about 10(-12). Here the hypothesis was investigated that these mutations are due to chromosome reassortments that are catalyzed by aneuploidy. Aneuploidy, an abnormal number of chromosomes, is the most common genetic abnormality of cancer cells and is known to change phenotypes (e.g., Down's syndrome). Moreover, we have shown recently that aneuploidy autocatalyzes reassortments of up to 2% per chromosome per mitosis because it unbalances spindle proteins, even centrosome numbers, via gene dosage. The hypothesis predicts that a selected phenotype is associated with multiple unselected ones, because chromosome reassortments unbalance simultaneously thousands of regulatory and structural genes. It also predicts variants of a selected phenotype based on variant reassortments. To test our hypothesis we have investigated in parallel the mutation rates of highly aneuploid and of normal diploid Chinese hamster cells to resistance against puromycin, cytosine arabinoside, colcemid, and methotrexate. The mutation rates of aneuploid cells ranged from 10(-4) to 10(-6), but no drug-resistant mutants were obtained from diploid cells in our conditions. Further selection increased drug resistance at similar mutation rates. Mutants selected from cloned cells for resistance against one drug displayed different unselected phenotypes, e.g., polygonal or fusiform cellular morphology, flat or three-dimensional colonies, and resistances against other unrelated drugs. Thus our hypothesis offers a unifying explanation for the high mutation rates of aneuploid cancer cells and for the association of selected with unselected phenotypes, e.g., multidrug resistance. It also predicts drug-specific chromosome combinations that could become a basis for selecting alternative chemotherapy against drug-resistant cancer.
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Affiliation(s)
- P Duesberg
- Department of Molecular and Cell Biology, Stanley Hall, University of California, Berkeley, CA 94720, USA.
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Abstract
Cancers increase during aging in mammals, and an accumulating body of evidence suggests that mutational events too do likewise. Mutational events are intimately involved in the malignant process. One current view is that mutator phenotypes are required in malignant cells for a sufficient number of critical target genes to be affected. These mutator phenotypes are believed to result from underlying deficiencies in genes necessary to maintain genomic stability. This review will provide a framework for a discussion of cancer and aging by detailing with a pair of wise approach studies that address the relations between aging, cancer, and mutations. Results from these studies will be used to suggest that a mutator phenotype develops in the cells of older individuals in the absence of an underlying genetic deficiency. Instead, it is proposed that a mixture of chromosomal aberrations, DNA damage, and chronic exposure to genotoxic forces, including oxidative stress, provide the basis for this age-accelerated mutator phenotype.
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Affiliation(s)
- M S Turker
- Center for Research on Occupational and Environmental Toxicology, L606, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201, USA.
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