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Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 2023; 14:46-70. [PMID: 37304923 PMCID: PMC10251250 DOI: 10.4291/wjgp.v14.i3.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/01/2023] Open
Abstract
In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.
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Affiliation(s)
- Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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2
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Rodgers CB, Mustard CJ, McLean RT, Hutchison S, Pritchard AL. A B-cell or a key player? The different roles of B-cells and antibodies in melanoma. Pigment Cell Melanoma Res 2022; 35:303-319. [PMID: 35218154 PMCID: PMC9314792 DOI: 10.1111/pcmr.13031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 02/01/2022] [Accepted: 02/21/2022] [Indexed: 12/17/2022]
Abstract
The B‐cell system plays an important role in the melanoma immune response; however, consensus has yet to be reached in many facets. Here, we comprehensively review human studies only, due to fundamental differences in the humoral response with animal models. Tumour‐infiltrating B‐cells are associated with contradictory prognostic values, reflecting a lack of agreement between studies on cell subset classification and differences in the markers used, particularly the common use of a single marker not differentiating multiple subsets. Tertiary lymphoid structures (TLS) organise T‐cells and B‐cells within tumours to generate a local anti‐tumour response and TLS presence associates with improved survival in response to immune checkpoint blockade, in late‐stage disease. Autoantibody production is increased in melanoma patients and has been proposed as biomarkers for diagnosis, prognosis and treatment/toxicity response; however, no consistent targets are yet identified. The function of antibodies in an anti‐tumour response is determined by its isotype and subclass; IgG4 is immune‐suppressive and robustly correlate with poor patient survival in melanoma. We conclude that the current B‐cell literature needs careful interpretation based on the methods used and that we need a consensus of markers to define B‐cells and associated lymphoid organs. Furthermore, future studies need to not only examine antibody targets, but also isotypes when considering functional roles.
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Affiliation(s)
- Chloe B Rodgers
- Genetics and Immunology Department, Division of Biomedical Research, Institute of Health Research and Innovation, University of the Highlands and Islands, Inverness, UK
| | - Colette J Mustard
- Genetics and Immunology Department, Division of Biomedical Research, Institute of Health Research and Innovation, University of the Highlands and Islands, Inverness, UK
| | - Ryan T McLean
- Genetics and Immunology Department, Division of Biomedical Research, Institute of Health Research and Innovation, University of the Highlands and Islands, Inverness, UK
| | - Sharon Hutchison
- Genetics and Immunology Department, Division of Biomedical Research, Institute of Health Research and Innovation, University of the Highlands and Islands, Inverness, UK
| | - Antonia L Pritchard
- Genetics and Immunology Department, Division of Biomedical Research, Institute of Health Research and Innovation, University of the Highlands and Islands, Inverness, UK
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Belousov PV. The Autoantibodies against Tumor-Associated Antigens as Potential Blood-Based Biomarkers in Thyroid Neoplasia: Rationales, Opportunities and Challenges. Biomedicines 2022; 10:biomedicines10020468. [PMID: 35203677 PMCID: PMC8962333 DOI: 10.3390/biomedicines10020468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/06/2022] [Accepted: 02/07/2022] [Indexed: 11/24/2022] Open
Abstract
The Autoantibodies targeting Tumor-Associated Antigens (TAA-AAbs) emerge as a result of a variety of tumor-related immunogenic stimuli and may be regarded as the eyewitnesses to the anti-tumor immune response. TAA-AAbs may be readily detected in peripheral blood to unveil the presence of a particular TAA-expressing tumor, and a fair number of TAAs eliciting the tumor-associated autoantibody response have been identified. The potential of TAA-AAbs as tumor biomarkers has been extensively studied in many human malignancies with a major influence on public health; however, tumors of the endocrine system, and, in particular, the well-differentiated follicular cell-derived thyroid neoplasms, remain understudied in this context. This review provides a detailed perspective on and legitimate rationales for the potential use of TAA-AAbs in thyroid neoplasia, with particular reference to the already established diagnostic implications of the TAA-AAbs in human cancer, to the windows for improvement and diagnostic niches in the current workup strategies in nodular thyroid disease and differentiated thyroid cancer that TAA-AAbs may successfully occupy, as well as to the proof-of-concept studies demonstrating the usefulness of TAA-AAbs in thyroid oncology, particularly for the pre-surgical discrimination between tumors of different malignant potential in the context of the indeterminate results of the fine-needle aspiration cytology.
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Affiliation(s)
- Pavel V. Belousov
- National Center for Personalized Medicine of Endocrine Diseases, National Medical Research Center for Endocrinology, Ministry of Health of the Russian Federation, 117036 Moscow, Russia; or
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
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Acebes-Fernández V, Landeira-Viñuela A, Juanes-Velasco P, Hernández AP, Otazo-Perez A, Manzano-Román R, Gongora R, Fuentes M. Nanomedicine and Onco-Immunotherapy: From the Bench to Bedside to Biomarkers. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E1274. [PMID: 32610601 PMCID: PMC7407304 DOI: 10.3390/nano10071274] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 06/16/2020] [Accepted: 06/23/2020] [Indexed: 12/12/2022]
Abstract
The broad relationship between the immune system and cancer is opening a new hallmark to explore for nanomedicine. Here, all the common and synergy points between both areas are reviewed and described, and the recent approaches which show the progress from the bench to the beside to biomarkers developed in nanomedicine and onco-immunotherapy.
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Affiliation(s)
- Vanessa Acebes-Fernández
- Department of Medicine and Cytometry General Service-Nucleus, CIBERONC CB16/12/00400, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain; (V.A.-F.); (A.L.-V.); (P.J.-V.); (A.-P.H.); (A.O.-P.); (R.G.)
| | - Alicia Landeira-Viñuela
- Department of Medicine and Cytometry General Service-Nucleus, CIBERONC CB16/12/00400, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain; (V.A.-F.); (A.L.-V.); (P.J.-V.); (A.-P.H.); (A.O.-P.); (R.G.)
| | - Pablo Juanes-Velasco
- Department of Medicine and Cytometry General Service-Nucleus, CIBERONC CB16/12/00400, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain; (V.A.-F.); (A.L.-V.); (P.J.-V.); (A.-P.H.); (A.O.-P.); (R.G.)
| | - Angela-Patricia Hernández
- Department of Medicine and Cytometry General Service-Nucleus, CIBERONC CB16/12/00400, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain; (V.A.-F.); (A.L.-V.); (P.J.-V.); (A.-P.H.); (A.O.-P.); (R.G.)
| | - Andrea Otazo-Perez
- Department of Medicine and Cytometry General Service-Nucleus, CIBERONC CB16/12/00400, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain; (V.A.-F.); (A.L.-V.); (P.J.-V.); (A.-P.H.); (A.O.-P.); (R.G.)
| | - Raúl Manzano-Román
- Proteomics Unit, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain;
| | - Rafael Gongora
- Department of Medicine and Cytometry General Service-Nucleus, CIBERONC CB16/12/00400, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain; (V.A.-F.); (A.L.-V.); (P.J.-V.); (A.-P.H.); (A.O.-P.); (R.G.)
| | - Manuel Fuentes
- Department of Medicine and Cytometry General Service-Nucleus, CIBERONC CB16/12/00400, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain; (V.A.-F.); (A.L.-V.); (P.J.-V.); (A.-P.H.); (A.O.-P.); (R.G.)
- Proteomics Unit, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain;
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The lymphocyte cytokinesis block micronucleus test in human populations occupationally exposed to vinyl chloride: A systematic review and meta-analysis. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2017; 774:1-11. [DOI: 10.1016/j.mrrev.2017.07.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 07/27/2017] [Accepted: 07/28/2017] [Indexed: 01/19/2023]
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Abstract
Liver cancer remains one of the most common human cancers with a high mortality rate. Therapies for hepatocellular carcinoma (HCC) remain ineffective, due to the heterogeneity of HCC with regard to both the etiology and mutation spectrum, as well as its chemotherapy resistant nature; thus surgical resection and liver transplantation remain the gold standard of patient care. The most common etiologies of HCC are extrinsic factors. Humans have multiple defense mechanisms against extrinsic factor-induced carcinogenesis, of which tumor suppressors play crucial roles in preventing normal cells from becoming cancerous. The tumor suppressor p53 is one of the most frequently mutated genes in liver cancer. p53 regulates expression of genes involved in cell cycle progression, cell death, and cellular metabolism to avert tumor development due to carcinogens. This review article mainly summarizes extrinsic factors that induce liver cancer and potentially have etiological association with p53, including aflatoxin B1, vinyl chloride, non-alcoholic fatty liver disease, iron overload, and infection of hepatitis viruses.
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Affiliation(s)
- Tim Link
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Tomoo Iwakuma
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Ledda C, Loreto C, Zammit C, Marconi A, Fago L, Matera S, Costanzo V, Sanzà GF, Palmucci S, Ferrante M, Costa C, Fenga C, Biondi A, Pomara C, Rapisarda V. Non‑infective occupational risk factors for hepatocellular carcinoma: A review (Review). Mol Med Rep 2017; 15:511-533. [PMID: 28000892 PMCID: PMC5364850 DOI: 10.3892/mmr.2016.6046] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 07/01/2016] [Indexed: 02/07/2023] Open
Abstract
Liver cancer is the second leading worldwide cause of cancer‑associated mortalities. Hepatocellular carcinoma, which accounts for the majority of liver tumors, ranks fifth among types of human cancer. Well‑established risk factors for liver cancer include the hepatitis B and C viruses, aflatoxins, alcohol consumption, and oral contraceptives. Tobacco smoking, androgenic steroids, and diabetes mellitus are suspected risk factors. Current knowledge regarding non‑infective occupational risk factors for liver cancer is inconclusive. The relevance of liver disorders to occupational medicine lies in the fact that the majority of chemicals are metabolized in the liver, and toxic metabolites generated via metabolism are the predominant cause of liver damage. However, their non‑specific clinical manifestations that are similar in a number of liver diseases make diagnosis difficult. Furthermore, concomitant conditions, such as viral hepatitis and alcohol or drug abuse, may mask liver disorders that result from occupational hepatotoxic agents and block the demonstration of an occupational cause. The identification of environmental agents that result in human cancer is a long and often difficult process. The purpose of the present review is to summarize current knowledge regarding the association of non‑infective occupational risk exposure and HCC, to encourage further research and draw attention to this global occupational public health problem.
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Affiliation(s)
- Caterina Ledda
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
- Hygiene and Public Health, Department of Medical Sciences, Surgical and Advanced Technologies ‘GF Ingrassia’, University of Catania, I-95123 Catania, Italy
| | - Carla Loreto
- Human Anatomy and Histology, Department of Biomedical and Biotechnology Sciences, University of Catania, I-95123 Catania, Italy
| | - Christian Zammit
- Anatomy Department, Faculty of Medicine and Surgery, University of Malta, MSD-2080 Msida, Malta
| | - Andrea Marconi
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Lucrezia Fago
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Serena Matera
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Valentina Costanzo
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Giovanni Fuccio Sanzà
- Division of Radiology, ‘Policlinico-Vittorio Emanuele’ University Hospital, University of Catania, I-95123 Catania, Italy
| | - Stefano Palmucci
- Division of Radiology, ‘Policlinico-Vittorio Emanuele’ University Hospital, University of Catania, I-95123 Catania, Italy
| | - Margherita Ferrante
- Hygiene and Public Health, Department of Medical Sciences, Surgical and Advanced Technologies ‘GF Ingrassia’, University of Catania, I-95123 Catania, Italy
| | - Chiara Costa
- Occupational Medicine, Department of the Environment, Safety, Territory, Food and Health Sciences, University of Messina, I-98125 Messina, Italy
| | - Concettina Fenga
- Occupational Medicine, Department of the Environment, Safety, Territory, Food and Health Sciences, University of Messina, I-98125 Messina, Italy
| | - Antonio Biondi
- General Surgery, Department of General Surgery and Medical-Surgical Specialties, University of Catania, I-95123 Catania, Italy
| | - Cristoforo Pomara
- Anatomy Department, Faculty of Medicine and Surgery, University of Malta, MSD-2080 Msida, Malta
- Forensic Pathology, Department of Clinical and Experimental Medicine, University of Foggia, I-71122 Foggia, Italy
| | - Venerando Rapisarda
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
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8
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Perz E, Kuhn JG. Review : p53 in the pathogenesis, diagnosis, and treatment of cancer. J Oncol Pharm Pract 2016. [DOI: 10.1177/107815529800400201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Objective. The cellular functions of p53, the conse quences of the loss of p53 function, and the potential impact of p53 in oncology are reviewed within the framework of an overview of the molecular basis of cancer and cell cycle control. Data Sources. A MEDLINE search of articles from 1976 to the present was conducted using the terms p53 protein and p53 gene. The search was restricted to the English language. Oncology and molecular biology textbooks were used as additional references. Data Extraction. We reviewed the literature to discuss the cellular function of p53, the mechanisms of p53 inactivation, the cellular consequences of the loss of p53 function, the role of p53 loss in tumori genesis, and the potential applications of this knowl edge. Data Synthesis. p53 mutations are found in ~ 50% of human cancers. Knowledge of p53 functions and defects provides the basis for potential applica tions in the areas of cancer epidemiology, cancer diagnosis, and determination of prognosis. An under standing of the functions and defects of p53 also presents a host of opportunities for the design of novel cancer therapies. Therapeutic approaches be ing studied include the restoration of p53 by gene therapy, the alteration of mutant p53 expression by antisense therapy, and the use of p53 mutations as a target for directing therapy to cancer cells; some of these approaches are already under phase I investiga tion. As knowledge of p53 unfolds, additional thera peutic approaches will certainly be developed. The story of p53 illustrates that the manipulation of mo lecular interactions is a new frontier in therapeutics and offers an additional role for oncology pharmacy specialists.
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Affiliation(s)
- Elizabeth Perz
- Department of Pharmacology, The University of Texas Health Science Center at San Antonio, College of Pharmacy, The University of Texas at Austin, Austin, Texas
| | - John G. Kuhn
- Department of Pharmacology, The University of Texas Health Science Center at San Antonio, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, College of Pharmacy, The University of Texas at Austin, Austin, Texas
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Yang ZC, Ling L, Xu ZW, Sui XD, Feng S, Zhang J. Are p53 Antibodies a Diagnostic Indicator for Patients with Oral Squamous Cell Carcinoma? Systematic Review and Meta-Analysis. Asian Pac J Cancer Prev 2016; 17:109-15. [PMID: 26838194 DOI: 10.7314/apjcp.2016.17.1.109] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND P53 has been reported to be involved with tumorigenesis and has also been implicated as a significant biomarker in oral squamous cell carcinoma(OSCC). However, the diagnostic value of p53 antibodies remains controversial; hence, we comprehensively and quantitatively assessed the potential in the present systematic review. MATERIALS AND METHODS A comprehensive search was performed using PubMed and Embase, up to October 31, 2014, without language restriction. Studies were assessed for quality using QUADAS (quality assessment of studies of diagnostic accuracy). The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were pooled separately and compared with overall accuracy measures using diagnostic odds ratios (DORs) and symmetric summary receiver operating characteristic (SROC) curves. RESULTS Of 150 studies initially identified, 7 eligible regarding serum p53 antibodies met the inclusion criteria. Some 85.7% (6/7) were of relatively high quality (QUADAS score≥7). The summary estimates for quantitative analysis of serum p53 antibody in the diagnosis of squamous cell carcinoma were: PLR 2.06 [95% confidence interval (CI) : 1.35-3.15], NLR 0.85 (95%CI: 0.80- 0.90) and DOR 2.47 (95%CI: 1.49- 4.12). CONCLUSIONS This meta-analysis suggests that the use of s-p53-antibodies has potential diagnostic value with relatively high sensitivity and specificity for OSCC particularly with serum specimens for discrimination of OSCCs from healthy controls. However, its discrimination power is not perfect because of low sensitivity.
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Affiliation(s)
- Zhi-Cheng Yang
- Department of Oral Maxillary Facial Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China E-mail :
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Ceccaroli C, Pulliero A, Geretto M, Izzotti A. Molecular fingerprints of environmental carcinogens in human cancer. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS 2015; 33:188-228. [PMID: 26023758 DOI: 10.1080/10590501.2015.1030491] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Identification of specific molecular changes (fingerprints) is important to identify cancer etiology. Exploitable biomarkers are related to DNA, epigenetics, and proteins. DNA adducts are the turning point between environmental exposures and biological damage. DNA mutational fingerprints are induced by carcinogens in tumor suppressor and oncogenes. In an epigenetic domain, methylation changes occurs in specific genes for arsenic, benzene, chromium, and cigarette smoke. Alteration of specific microRNA has been reported for environmental carcinogens. Benzo(a)pyrene, cadmium, coal, and wood dust hits specific heat-shock proteins and metalloproteases. The multiple analysis of these biomarkers provides information on the carcinogenic mechanisms activated by exposure to environmental carcinogens.
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Affiliation(s)
- C Ceccaroli
- a Department of Health Sciences, University of Genoa , Italy
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Woodrick J, Gupta S, Khatkar P, Sarangi S, Narasimhan G, Trehan A, Adhikari S, Roy R. Slow repair of lipid peroxidation-induced DNA damage at p53 mutation hotspots in human cells caused by low turnover of a DNA glycosylase. Nucleic Acids Res 2014; 42:9033-46. [PMID: 25081213 PMCID: PMC4132702 DOI: 10.1093/nar/gku520] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 05/21/2014] [Accepted: 05/24/2014] [Indexed: 12/16/2022] Open
Abstract
Repair of oxidative stress- and inflammation-induced DNA lesions by the base excision repair (BER) pathway prevents mutation, a form of genomic instability which is often observed in cancer as 'mutation hotspots'. This suggests that some sequences have inherent mutability, possibly due to sequence-related differences in repair. This study has explored intrinsic mutability as a consequence of sequence-specific repair of lipid peroxidation-induced DNA adduct, 1, N(6)-ethenoadenine (εA). For the first time, we observed significant delay in repair of ϵA at mutation hotspots in the tumor suppressor gene p53 compared to non-hotspots in live human hepatocytes and endothelial cells using an in-cell real time PCR-based method. In-cell and in vitro mechanism studies revealed that this delay in repair was due to inefficient turnover of N-methylpurine-DNA glycosylase (MPG), which initiates BER of εA. We determined that the product dissociation rate of MPG at the hotspot codons was ≈5-12-fold lower than the non-hotspots, suggesting a previously unknown mechanism for slower repair at mutation hotspots and implicating sequence-related variability of DNA repair efficiency to be responsible for mutation hotspot signatures.
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Affiliation(s)
- Jordan Woodrick
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, DC 20057, USA
| | - Suhani Gupta
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, DC 20057, USA
| | - Pooja Khatkar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, DC 20057, USA
| | - Sanchita Sarangi
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, DC 20057, USA
| | - Ganga Narasimhan
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, DC 20057, USA
| | - Akriti Trehan
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, DC 20057, USA
| | - Sanjay Adhikari
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, DC 20057, USA
| | - Rabindra Roy
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, DC 20057, USA
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Talhaoui I, Couve S, Gros L, Ishchenko AA, Matkarimov B, Saparbaev MK. Aberrant repair initiated by mismatch-specific thymine-DNA glycosylases provides a mechanism for the mutational bias observed in CpG islands. Nucleic Acids Res 2014; 42:6300-13. [PMID: 24692658 PMCID: PMC4041421 DOI: 10.1093/nar/gku246] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Revised: 03/09/2014] [Accepted: 03/13/2014] [Indexed: 12/13/2022] Open
Abstract
The human thymine-DNA glycosylase (TDG) initiates the base excision repair (BER) pathway to remove spontaneous and induced DNA base damage. It was first biochemically characterized for its ability to remove T mispaired with G in CpG context. TDG is involved in the epigenetic regulation of gene expressions by protecting CpG-rich promoters from de novo DNA methylation. Here we demonstrate that TDG initiates aberrant repair by excising T when it is paired with a damaged adenine residue in DNA duplex. TDG targets the non-damaged DNA strand and efficiently excises T opposite of hypoxanthine (Hx), 1,N(6)-ethenoadenine, 7,8-dihydro-8-oxoadenine and abasic site in TpG/CpX context, where X is a modified residue. In vitro reconstitution of BER with duplex DNA containing Hx•T pair and TDG results in incorporation of cytosine across Hx. Furthermore, analysis of the mutation spectra inferred from single nucleotide polymorphisms in human population revealed a highly biased mutation pattern within CpG islands (CGIs), with enhanced mutation rate at CpA and TpG sites. These findings demonstrate that under experimental conditions used TDG catalyzes sequence context-dependent aberrant removal of thymine, which results in TpG, CpA→CpG mutations, thus providing a plausible mechanism for the putative evolutionary origin of the CGIs in mammalian genomes.
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Affiliation(s)
- Ibtissam Talhaoui
- Groupe Réparation de l’ADN, Université Paris Sud, Laboratoire Stabilité Génétique et Oncogenèse CNRS, UMR 8200, Gustave Roussy, F-94805 Villejuif Cedex, France
| | - Sophie Couve
- Laboratoire de Génétique Oncologique EPHE, INSERM U753, Gustave Roussy, F-94805 Villejuif, France
| | - Laurent Gros
- Groupe Réparation de l’ADN, Université Paris Sud, Laboratoire Stabilité Génétique et Oncogenèse CNRS, UMR 8200, Gustave Roussy, F-94805 Villejuif Cedex, France
- AB Science SA, 75008 Paris, France
| | - Alexander A. Ishchenko
- Groupe Réparation de l’ADN, Université Paris Sud, Laboratoire Stabilité Génétique et Oncogenèse CNRS, UMR 8200, Gustave Roussy, F-94805 Villejuif Cedex, France
| | - Bakhyt Matkarimov
- Nazarbayev University Research and Innovation System, Astana 010000, Kazakhstan
| | - Murat K. Saparbaev
- Groupe Réparation de l’ADN, Université Paris Sud, Laboratoire Stabilité Génétique et Oncogenèse CNRS, UMR 8200, Gustave Roussy, F-94805 Villejuif Cedex, France
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Cho H, Kim S, Shin HY, Chung EJ, Kitano H, Hyon Park J, Park L, Chung JY, Hewitt SM, Kim JH. Expression of stress-induced phosphoprotein1 (STIP1) is associated with tumor progression and poor prognosis in epithelial ovarian cancer. Genes Chromosomes Cancer 2014; 53:277-88. [PMID: 24488757 DOI: 10.1002/gcc.22136] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 11/25/2013] [Accepted: 11/25/2013] [Indexed: 11/11/2022] Open
Abstract
Stress-induced phosphoprotein1 (STIP1) is a candidate biomarker in epithelial ovarian cancer (EOC). In this study, we investigated in detail the expression of STIP1, as well as its functions, in EOC. STIP1 expression was assessed by immunohistochemistry (IHC) and the results were compared with clinicopathologic factors, including survival data. The effects of STIP1 gene silencing via small interfering RNA (siRNA) were examined in EOC cells and a xenograft model. The expression of STIP1 protein in EOC was significantly higher than in the other study groups (P < 0.001), and this increase of expression was significantly associated with tumor stage (P = 0.005), tumor grade (P = 0.029), and lymph node metastasis (P = 0.020). In multivariate analysis, overall survival in EOC was significantly shorter in cases with high STIP1 expression (HR = 2.78 [1.01-7.63], P = 0.047). STIP1 silencing in EOC cells resulted in inhibition of cell proliferation and invasion. In addition, in vivo experiments using STIP1 siRNA clearly showed a strong inhibition of tumor growth and a modulation of expression of prosurvival and apoptotic genes, further suggesting that STIP1 silencing can prevent cell proliferation and invasion. In conclusion, increased STIP1 expression is associated with poor survival outcome in EOC, and STIP1 may represent a useful therapeutic target in EOC patients.
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Affiliation(s)
- Hanbyoul Cho
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
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14
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Curigliano G, Spitaleri G, Dettori M, Locatelli M, Scarano E, Goldhirsch A. Vaccine immunotherapy in breast cancer treatment: promising, but still early. Expert Rev Anticancer Ther 2014; 7:1225-41. [PMID: 17892423 DOI: 10.1586/14737140.7.9.1225] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cancer vaccine-based immunotherapy should potentiate immunosurveillance function, preventing and protecting against growing tumors. Tumor cells usually activate the immune system, including T lymphocytes and natural killer cells, which are able to eliminate the transformed cells. Immunosubversion mechanisms related to tumor cells antigenic immunoediting induces mechanisms of tolerance and immunoescape. This condition impairs not only host-generated immunosurveillance, but also attempts to harness the immune response for therapeutic purposes. Most trials evaluating breast cancer vaccines have been carried out in patients in the metastatic and adjuvant setting. The aim of this review is to analyze the activity of vaccination strategies in current clinical trials. We summarize the differential approaches, protein-based and cell-based vaccines, focusing on vaccines targeting HER2/neu protein. Another focus of the review is to provide the reader with future challenges in the field, taking into account both the immunological and clinical aspects to better target the goal.
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Affiliation(s)
- Giuseppe Curigliano
- European Institute of Oncology, Department of Medicine, Division of Medical Oncology, Via Ripamonti 435, 20141 Milan, Italy.
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15
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Järås K, Anderson K. Autoantibodies in cancer: prognostic biomarkers and immune activation. Expert Rev Proteomics 2014; 8:577-89. [DOI: 10.1586/epr.11.48] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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16
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Zhang J, Xu Z, Yu L, Chen M, Li K. Assessment of the potential diagnostic value of serum p53 antibody for cancer: a meta-analysis. PLoS One 2014; 9:e99255. [PMID: 24911057 PMCID: PMC4049633 DOI: 10.1371/journal.pone.0099255] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 05/13/2014] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Mutant p53 protein over-expression has been reported to induce serum antibodies against p53. We assessed the diagnostic precision of serum p53 (s-p53) antibodies for diagnosis of cancer patients and compared the positive rates of the s-p53 antibody in different types of cancers. METHODS We systematically searched PubMed and Embase, through May 31, 2012. Studies were assessed for quality using QUADAS (quality assessment of studies of diagnostic accuracy). The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were pooled separately and compared with overall accuracy measures using diagnostic odds ratios (DORs) and Area under the curve(AUC). Meta regression and subgroup analyses were done, and heterogeneity and publication bias were assessed. RESULTS Of 1089 studies initially identified, 100 eligible studies with 23 different types of tumor met the inclusion criteria for the meta-analysis (cases = 15953, controls = 8694). However, we could conduct independent meta analysis on only 13 of 36 types of tumors. Approximately 56% (56/100) of the included studies were of high quality (QUADAS score≥8). The summary estimates for quantitative analysis of serum p53 antibody in the diagnosis of cancers were: PLR 5.75 (95% CI: 4.60-7.19), NLR 0.81 (95%CI: 0.79-0.83) and DOR 7.56 (95% CI: 6.02-9.50). However, for the 13 types of cancers on which meta-analysis was conducted, the ranges for PLR (2.33-11.05), NLR (0.74-0.97), DOR (2.86-13.80), AUC(0.29-0.81), and positive rate (4.47%-28.36%) indicated significant heterogeneity. We found that breast, colorectal, esophageal, gastric, hepatic, lymphoma, lung and ovarian cancer had relatively reasonable diagnostic accuracy. The remaining results of the five types of cancers suggested that s-p53 antibody had limited value. CONCLUSIONS The current evidence suggests that s-p53 antibody has potential diagnostic value for cancer, especially for breast, colorectal, esophageal, gastric, hepatic, lymphoma, lung and ovarian cancer. The results showed that s-p53 antibody had high correlation with cancers.
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Affiliation(s)
- Jun Zhang
- Department of Preventive Medicine, Shantou University Medical College, Shantou, Guangdong, China
| | - Zhiwei Xu
- Department of Medical Quality Control, 302 PLA hospital, Beijing, China
| | - Lingxiang Yu
- Department of Hepatobiliary Surgery, 302 PLA hospital, Beijing, China
| | - Meilan Chen
- Department of Preventive Medicine, Shantou University Medical College, Shantou, Guangdong, China
| | - Ke Li
- Department of Preventive Medicine, Shantou University Medical College, Shantou, Guangdong, China
- * E-mail:
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17
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Pedersen JW, Gentry-Maharaj A, Fourkala EO, Dawnay A, Burnell M, Zaikin A, Pedersen AE, Jacobs I, Menon U, Wandall HH. Early detection of cancer in the general population: a blinded case-control study of p53 autoantibodies in colorectal cancer. Br J Cancer 2012; 108:107-14. [PMID: 23169294 PMCID: PMC3553520 DOI: 10.1038/bjc.2012.517] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background: Recent reports from cancer screening trials in high-risk populations suggest that autoantibodies can be detected before clinical diagnosis. However, there is minimal data on the role of autoantibody signatures in cancer screening in the general population. Methods: Informative p53 peptides were identified in sera from patients with colorectal cancer using an autoantibody microarray with 15-mer overlapping peptides covering the complete p53 sequence. The selected peptides were evaluated in a blinded case–control study using stored serum from the multimodal arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening where women gave annual blood samples. Cases were postmenopausal women who developed colorectal cancer following recruitment, with 2 or more serum samples preceding diagnosis. Controls were age-matched women with no history of cancer. Results: The 50 640 women randomised to the multimodal group were followed up for a median of 6.8 (inter-quartile range 5.9–8.4) years. Colorectal cancer notification was received in 101 women with serial samples of whom 97 (297 samples) had given consent for secondary studies. They were matched 1 : 1 with 97 controls (296 serial samples). The four most informative peptides identified 25.8% of colorectal cancer patients with a specificity of 95%. The median lead time was 1.4 (range 0.12–3.8) years before clinical diagnosis. Conclusion: Our findings suggest that in the general population, autoantibody signatures are detectable during preclinical disease and may be of value in cancer screening. In colorectal cancer screening in particular, where the current need is to improve compliance, it suggests that p53 autoantibodies may contribute towards risk stratification.
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Affiliation(s)
- J W Pedersen
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen N, DK-2200, Denmark
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18
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Brandt-Rauf PW, Li Y, Long C, Monaco R, Kovvali G, Marion MJ. Plastics and carcinogenesis: The example of vinyl chloride. J Carcinog 2012; 11:5. [PMID: 22529741 PMCID: PMC3327051 DOI: 10.4103/1477-3163.93700] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Accepted: 01/10/2012] [Indexed: 12/30/2022] Open
Abstract
The manufacture, use and disposal of various plastics can pose numerous health risks, including the risk of cancer. A model example of carcinogenic risk from plastics is provided by polyvinyl chloride, since it is composed of the known human carcinogen vinyl chloride (VC). In recent years, much has been learned about the molecular biological pathways of VC carcinogenesis. This has led to molecular epidemiologic studies of VC carcinogenesis in exposed human populations which have identified useful biomarkers of exposure, effect and susceptibility for VC. These studies have in turn provided the basis for new molecular approaches for the prevention and treatment of VC cancers. This model could have much wider applicability for many other carcinogenic exposures and many other human cancers.
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Affiliation(s)
- Paul Wesley Brandt-Rauf
- Division of Environmental and Occupational Health Sciences, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | - Yongliang Li
- Division of Environmental and Occupational Health Sciences, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | - Changmin Long
- Division of Environmental and Occupational Health Sciences, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | - Regina Monaco
- Division of Environmental and Occupational Health Sciences, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | - Gopala Kovvali
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - Marie-Jeanne Marion
- Unite 871, Institut National del la Sante et de la Recherche Medicale, Lyon, France
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19
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Zhang J, Xv Z, Wu X, Li K. Potential diagnostic value of serum p53 antibody for detecting esophageal cancer: a meta-analysis. PLoS One 2012; 7:e52896. [PMID: 23285221 PMCID: PMC3532438 DOI: 10.1371/journal.pone.0052896] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Accepted: 11/22/2012] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Mutant p53 protein overexpression has been reported to induce serum antibodies against p53. Various studies assessing the diagnostic value of serum p53 antibody in patients with esophageal cancer remain controversial. This study aims to comprehensively and quantitatively summarize the potential diagnostic value of serum p53 antibody in esophageal cancer. METHODS We systematically searched PubMed and Embase until 31st May 2012, without language restriction. Studies were assessed for quality using QUADAS (quality assessment of studies of diagnostic accuracy). Positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were pooled separately and compared with overall accuracy measures diagnostic odds ratio (DOR) and symmetric summary receiver operating characteristic (sROC). The PLR and NLR and their 95% confidence interval (CI) were calculated using a fixed effects model according to the Mantel-Haensed method and random effects model based on the work of Der Simonian and laird, respectively. RESULTS Fifteen studies (cases = 1079, controls = 2260) met the inclusion criteria for the meta-analysis. Approximately 53.33% (8/15) of the included studies were of high quality (QUADAS score≥8), which were retrospective case-control studies. The summary estimates for quantitative analysis of serum p53 antibody in the diagnosis of esophageal cancer were PLR 6.95 (95% CI: 4.77-9.51), NLR 0.75 (95%CI: 0.72-0.78) and DOR 9.65 (95%CI: 7.04-13.22). However, we found significant heterogeneity between NLRs. CONCLUSIONS The current evidence suggests serum p53 antibody has a potential diagnostic value for esophageal cancer. However, its discrimination power is not perfect because of low sensitivity. IMPACT These results suggest that s-p53-antibody may be useful for monitoring residual tumor cells and for aiding in the selection of candidates for less invasive treatment procedures because of the high specificity of s-p53-antibody. Further studies may need to identify patterns of multiple biomarkers to further increase the power of EC detection.
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Affiliation(s)
- Jun Zhang
- Department of Preventive Medicine, Shantou University Medical College, Shantou, Guangdong, China
- * E-mail: (KL); (JZ)
| | - Zhiwei Xv
- Department of Preventive Medicine, Shantou University Medical College, Shantou, Guangdong, China
| | - Xuefeng Wu
- Department of Preventive Medicine, Shantou University Medical College, Shantou, Guangdong, China
| | - Ke Li
- Department of Preventive Medicine, Shantou University Medical College, Shantou, Guangdong, China
- * E-mail: (KL); (JZ)
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20
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Auto-anticorps dirigés contre les antigènes associés aux tumeurs : nouveaux outils pour la détection précoce du cancer du poumon. Bull Cancer 2011; 98:1419-30. [DOI: 10.1684/bdc.2011.1499] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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21
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BALOGH GABRIELAA, MAILO DANIEL, NARDI HECTOR, CORTE MARIAMARTA, VINCENT ESTEBAN, BARUTTA ELENA, LIZARRAGA GUILLERMO, LIZARRAGA PABLO, MONTERO HECTOR, GENTILI ROBERTO. Serological levels of mutated p53 protein are highly detected at early stages in breast cancer patients. Exp Ther Med 2010; 1:357-361. [PMID: 22993549 PMCID: PMC3445953 DOI: 10.3892/etm_00000056] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2009] [Accepted: 11/09/2009] [Indexed: 02/01/2023] Open
Abstract
The aim of this study was to compare the sensitivity of the serological level of anti-p53 antibodies in breast cancer patients and to correlate its expression level with patient age, histological stage and grade of tumor differentiation. Total p53 protein expression (mutant and wild-type) was also determined in the breast cancer tissues using immunohistochemistry (IHC). The serological levels of mutant p53 expression were found to be age-dependent, reaching the highest level at 50 years of age. Faint or low detection was observed in patients ≤30 years of age. Anti-p53-antibodies were detected in patients ≤40 and ≥61 years of age. The serological levels of mutant p53 protein were highly detected in all stages of breast cancer, including the early stages. However, anti-p53 antibodies reached a high level of detection only in stage III breast carcinomas. No expression was found in patients with benign breast disease. The detection of p53 mutations was dependent on the grade of tumor differentiation, achieving the highest level in the poorly differentiated breast carcinomas. Results from IHC were highly correlated with serological p53 mutational analysis. Our findings indicate that mutant p53 in serum is a promising novel parameter for the evaluation of cellular biology and the prognosis of breast cancer from its early stages using blood samples. Anti-p53 antibodies were demonstrated to be less sensitive in this study. It is also possible to use the expression of mutant p53 protein as a molecular marker to differentiate benign breast disease from breast carcinoma prior to surgery.
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Affiliation(s)
- GABRIELA A. BALOGH
- CERZOS-CONICET, Centro Científico Tecnológico Bahía Blanca, Bahia Blanca-8000,
Argentina
| | - DANIEL MAILO
- CERZOS-CONICET, Centro Científico Tecnológico Bahía Blanca, Bahia Blanca-8000,
Argentina
| | - HECTOR NARDI
- CERZOS-CONICET, Centro Científico Tecnológico Bahía Blanca, Bahia Blanca-8000,
Argentina
| | - MARIA MARTA CORTE
- CERZOS-CONICET, Centro Científico Tecnológico Bahía Blanca, Bahia Blanca-8000,
Argentina
| | - ESTEBAN VINCENT
- CERZOS-CONICET, Centro Científico Tecnológico Bahía Blanca, Bahia Blanca-8000,
Argentina
| | - ELENA BARUTTA
- CERZOS-CONICET, Centro Científico Tecnológico Bahía Blanca, Bahia Blanca-8000,
Argentina
| | - GUILLERMO LIZARRAGA
- CERZOS-CONICET, Centro Científico Tecnológico Bahía Blanca, Bahia Blanca-8000,
Argentina
| | - PABLO LIZARRAGA
- CERZOS-CONICET, Centro Científico Tecnológico Bahía Blanca, Bahia Blanca-8000,
Argentina
| | - HECTOR MONTERO
- CERZOS-CONICET, Centro Científico Tecnológico Bahía Blanca, Bahia Blanca-8000,
Argentina
| | - ROBERTO GENTILI
- CERZOS-CONICET, Centro Científico Tecnológico Bahía Blanca, Bahia Blanca-8000,
Argentina
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22
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Kumar S, Mohan A, Guleria R. Prognostic implications of circulating anti-p53 antibodies in lung cancer--a review. Eur J Cancer Care (Engl) 2010; 18:248-54. [PMID: 19432918 DOI: 10.1111/j.1365-2354.2008.01019.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Many independent prognostic markers have been identified for predicting survival and helping in the management of lung cancer cases. p53 protein overexpression and mutation have been the topic of numerous such publications. However, little is known about the role of anti-p53 antibodies as a prognostic marker in lung cancer. We searched the MEDLINE database and the bibliographies of the retrieved manuscripts and reviews. The retrieved studies are grouped according to the cohort studied. Out of 179 citations retrieved, 17 met our criteria. Seven studies used only non-small-cell lung cancer; four studies used only small-cell lung cancer; and six studies used the mixed cohort of both types of lung cancer. The studies varied in the concept design, cohort studied and the methodology. The prognostic role of anti-p53 antibodies in lung cancer remains contradictory and as some studies show an association with poor prognosis, others show a favourable association and still others showing no association what so ever. The frequency of detection of anti-p53 antibody is very low, highly specific with result being independent of the cohort studied. Adequate clinical trials, with optimized cohort, antigen and assay validation, are needed to address patients and physician's concerns regarding these associations.
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Affiliation(s)
- S Kumar
- Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
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23
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Abstract
Vinyl chloride monomer is a known cause of angiosarcoma of the liver. It also has other toxic effects on the liver, and it has recently been suggested that exposure to vinyl chloride also causes hepatocellular carcinoma. However, the data on which this conclusion is based is incomplete. There is inadequate ascertainment of unequivocal diagnoses. In the largest studies lack of data meant that confounding diseases such as viral hepatitis or alcoholic liver disease could not be assessed. At best, the increase in risk is minimal, based on more than 22,000 exposed workers and more than 640,000 person years of observation. However, based on the available data the hypothesis that vinyl chloride causes or contributes to the development of hepatocellular carcinoma remains unproven.
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24
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Shaarawy M, Sheiba M. Diagnostic and prognostic significance of circulating tumor suppressor gene p53 autoantibodies in patients with gestational trophoblastic tumors. Acta Oncol 2009; 43:43-8. [PMID: 15068319 DOI: 10.1080/02841860310018062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Seventy-two patients with gestational trophoblastic tumors (GTTs) and 20 first-trimester healthy pregnant women (controls) participated in this study. According to the WHO scoring system, GTTs were subgrouped into 24 hydatiform mole spontaneous regression (HMSR), 18 postmolar high-risk (PMHR) and 16 low- and 14 high-risk cases of choriocarcinoma. Patients with choriocarcinoma were treated with hysterectomy and methotrexate chemotherapy, whereas molar pregnancy was managed by either oxytocin infusion followed by suction evacuation or by hysterectomy. Serum p53 autoantibodies were determined by enzyme-linked immunosorbant assay and serum hCGbeta was determined by radioimmunoassay before and throughout the 12 months after treatment. p53 autoantibodies were not detected in normal pregnancy and cases of HMSR but were detected in all cases of PMHR and choriocarcinoma. Concentrations of p53 autoantibodies were higher in choriocarcinoma than in PMHR cases. Serial measurements of p53 autoantibodies dropped to an undetectable level within 1 and 6 months after treatment in cases of PMHR and low-risk choriocarcinoma, respectively. Decreasing values of p53 autoantibodies in high-risk choriocarcinoma remained higher than the cut-off level of controls. There was a significant positive correlation between p53 autoantibodies and serum hCGbeta concentration in GTTs. In conclusion, detection of p53 autoantibodies has a high potential for the differential diagnosis of GTTs and their serial measurements are clinically useful to monitor disease progression and to assess response to therapy in GTTs.
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Affiliation(s)
- Mohamed Shaarawy
- Department of Obstetrics and Gynecology, Faculty of Medicine, Cairo University, Cairo, Egypt.
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25
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Reuschenbach M, von Knebel Doeberitz M, Wentzensen N. A systematic review of humoral immune responses against tumor antigens. Cancer Immunol Immunother 2009; 58:1535-44. [PMID: 19562338 DOI: 10.1007/s00262-009-0733-4] [Citation(s) in RCA: 218] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2009] [Accepted: 06/16/2009] [Indexed: 12/13/2022]
Abstract
This review summarizes studies on humoral immune responses against tumor-associated antigens (TAAs) with a focus on antibody frequencies and the potential diagnostic, prognostic, and etiologic relevance of antibodies against TAAs. We performed a systematic literature search in Medline and identified 3,619 articles on humoral immune responses and TAAs. In 145 studies, meeting the inclusion criteria, humoral immune responses in cancer patients have been analyzed against over 100 different TAAs. The most frequently analyzed antigens were p53, MUC1, NY-ESO-1, c-myc, survivin, p62, cyclin B1, and Her2/neu. Antibodies against these TAAs were detected in 0-69% (median 14%) of analyzed tumor patients. Antibody frequencies were generally very low in healthy individuals, with the exception of few TAAs, especially MUC1. For several TAAs, including p53, Her2/neu, and NY-ESO-1, higher antibody frequencies were reported when tumors expressed the respective TAA. Antibodies against MUC1 were associated with a favorable prognosis while antibodies against p53 were associated with poor disease outcome. These data suggest different functional roles of endogenous antibodies against TAAs. Although data on prediagnostic antibody levels are scarce and antibody frequencies for most TAAs are at levels precluding use in diagnostic assays for cancer early detection, there is some promising data on achieving higher sensitivity for cancer detection using panels of TAAs.
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Affiliation(s)
- Miriam Reuschenbach
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120, Heidelberg, Germany.
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26
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Belousov PV, Kuprash DV, Sazykin AY, Khlgatian SV, Penkov DN, Shebzukhov YV, Nedospasov SA. Cancer-associated antigens and antigen arrays in serological diagnostics of malignant tumors. BIOCHEMISTRY (MOSCOW) 2008; 73:562-72. [PMID: 18605981 DOI: 10.1134/s000629790805009x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The appearance of antibodies to cancer-associated antigens in biological fluids (particularly, in blood sera) of cancer patients is now a well-established fact, and their detection by immunochemical methods is a promising approach to diagnostics of malignant neoplasms. In this review, we consider some immunobiological aspects of the most extensively studied cancer-associated B-cell antigens, various applications of autoantibodies as cancer biomarkers, and prospects for the use of antigen arrays for improving diagnostic sensitivity.
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Affiliation(s)
- P V Belousov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
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27
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Li Y, Zhou M, Marion MJ, Lee S, Brandt-Rauf PW. Polymorphisms in glutathioneS-transferases in French vinyl chloride workers. Biomarkers 2008; 10:72-9. [PMID: 16097394 DOI: 10.1080/13547500500070364] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The authors have recently demonstrated a significant gene-environment interaction between vinyl chloride exposure and polymorphisms in the DNA repair protein XRCC1 on the occurrence of mutant p53 biomarkers of vinyl chloride-induced genetic damage. The aim of this study was to examine the polymorphisms in the glutathione S-transferases (GSTs) as potential modifiers of this relationship, since these enzymes may be involved in the phase II metabolism of the reactive intermediates of vinyl chloride. A cohort of 211 French vinyl chloride workers was genotyped for common polymorphisms in GSTM1, GSTT1 and GSTP1. Although no independent, statistically significant effect of these polymorphisms on the occurrence of the mutant p53 biomarker was found, the null GSTM1 and null GSTT1 polymorphisms were found to interact with the XRCC 1 polymorphism to increase the occurrence of the biomarker such that, for example, workers with at least one variant XRCC1 allele who were null for both GSTM1 and GSTT1 had a significant odds ratio for the biomarker (OR =8.4, 95% CI = 1.3 54.0) compared with workers who were wild-type for all alleles, controlling for potential confounders including cumulative vinyl chloride exposure.
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Affiliation(s)
- Y Li
- Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, 60 Haven Avenue, B-1, New York, NY 10032, USA
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28
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Yongliang Li, Paul W. Brandt-Rauf,. Circulating anti-p53 antibodies in lung cancer and relationship to histology and smoking. Biomarkers 2008; 4:381-90. [DOI: 10.1080/135475099230769] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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29
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Abstract
Although autoantibodies have been recognized as participants in pathogenesis of tissue injury, the collateral role of autoantibodies as reporters from the immune system identifying cellular participants in tumorigenesis has not been fully appreciated. The immune system appears to be capable of sensing aberrant structure, distribution, and function of certain cellular components involved in tumorigenesis and making autoantibody responses to the tumor-associated antigens (TAAs). Autoantibodies to TAAs can report malignant transformation before standard clinical studies and may be useful as early detection biomarkers. The autoantibody response also provides insights into factors related to how cellular components may be rendered immunogenic. As diagnostic biomarkers, specific TAA miniarrays for identifying autoantibody profiles could have sufficient sensitivity in differentiating between types of tumors. Such anti-TAA profiles could also be used to monitor response to therapy. The immune system of cancer patients reveals the immune interactive sites or the autoepitopes of participants in tumorigenesis, and this information should be used in the design of immunotherapy.
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Affiliation(s)
- Eng M Tan
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
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30
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Tjalsma H, Schaeps RMJ, Swinkels DW. Immunoproteomics: From biomarker discovery to diagnostic applications. Proteomics Clin Appl 2008; 2:167-80. [DOI: 10.1002/prca.200780012] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2007] [Indexed: 11/08/2022]
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Helmig S, Schneider J. Oncogene and tumor-suppressor gene products as serum biomarkers in occupational-derived lung cancer. Expert Rev Mol Diagn 2007; 7:555-68. [PMID: 17892364 DOI: 10.1586/14737159.7.5.555] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Since lung cancer is the most frequent occupational cancer and one of the leading causes of cancer mortality in the world, it is one of the biggest challenges for research. In the literature, there are inconsistent results regarding the utility of the serum biomarkers p53, anti-p53 antibodies, EGF receptor or Ras. Based on the published results, routine use of these biomarkers for detection of occupationally derived lung carcinomas is not currently recommended. In this review, we summarize the literature and discuss the relevance of these oncogene and tumor-suppressor gene products as serum biomarkers in occupational-derived lung cancer.
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Affiliation(s)
- Simone Helmig
- Institut und Poliklinik für Arbeits- und Sozialmedizin, Aulweg 129, D-35392 Giessen, Germany.
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Wang ZS, Wang WX, Xiong CL, Zhan N, Li H. Spontaneous ruptured primary hepatic angiosarcoma coincident with Schistosoma Japonica liver fibrosis. Hepatol Res 2007; 37:572-6. [PMID: 17540001 DOI: 10.1111/j.1872-034x.2007.00067.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM We report herein a case of spontaneous ruptured primary hepatic angiosarcoma coincident with Schistosoma Japonica liver fibrosis and review the correlative literature. METHODS The resected specimen was examined by histopathological and immunohistochemical evaluation. RESULTS The final diagnosis was spontaneous ruptured primary hepatic angiosarcoma coincident with Schistosoma Japonica liver fibrosis Conclusion: Considering the nature of primary hepatic angiosarcoma, in particular the ruptured hepatic angiosarcoma, it is obviously desirable to avoid any unnecessary delay or definitive surgical treatment. It is presumed that angiosarcoma in the liver has a possible association with S. japonicum and the deposition of ovae in liver.
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Affiliation(s)
- Ze-Sheng Wang
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China
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Yoshizawa S, Matsuoka K, Inoue N, Takaishi H, Ogata H, Iwao Y, Mukai M, Fujita T, Kawakami Y, Hibi T. Clinical significance of serum p53 antibodies in patients with ulcerative colitis and its carcinogenesis. Inflamm Bowel Dis 2007; 13:865-73. [PMID: 17285596 DOI: 10.1002/ibd.20112] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND For early detection of ulcerative colitis (UC)-associated colorectal cancer (CRC), surveillance colonoscopy is recommended in UC patients at high risk. However, poor acceptability deteriorates its effectiveness and a suitable marker for selecting patients at high risk is needed. Here we evaluated clinical usefulness of the measurement of anti-p53 antibodies (Abs) by enzyme-linked immunosorbent assay (ELISA) using sera samples from UC patients. METHODS Sera from 286 patients with UC, 82 patients with sporadic CRC, and 63 healthy controls (HC) were obtained. Serum anti-p53 antibodies were detected with ELISA. Immunohistochemical detection was also performed in patients who developed dysplasia or CRC. RESULTS Serum p53 Ab was positive in 15.0% of UC, while it was positive only in 1.6% of HCs. In sporadic CRCs, 52.4% of 82 patients were positive. In UC patients with disease duration equal to or longer than 8 years, positivity of serum p53 Ab was significantly higher than those in patients with shorter duration. Eight of 13 (61.5%) UC patients with CRC or dysplasia were positive for serum p53 Abs, which was significantly higher than that in patients without neoplasia. All UC patients with CRC were positive for p53 staining, while 2 were negative for serum p53 Ab. Finally, levels of serum p53 Ab had fallen in 4 patients with CRC we could monitor after surgery. CONCLUSIONS This study revealed that p53 Ab developed in the progression of UC-associated CRC but not in all patients with neoplasia, suggesting that serological detection of p53 Abs by ELISA is not suitable in primarily selecting patients at high risk; however, it is helpful in salvaging patients who drop from a surveillance program.
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Affiliation(s)
- Shigeo Yoshizawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Mechtersheimer G, Penzel R, Hofmann WJ, Schirmacher P. Primäre Sarkome und Sarkommetastasen in der Leber. DER PATHOLOGE 2006; 27:251-62. [PMID: 16773310 DOI: 10.1007/s00292-006-0841-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The considerable progress made in radiology, in surgical management with curative intent, and in the identification of molecularly targeted small molecules, such as the tyrosine kinase inhibitor imatinib mesylate, in the treatment of gastrointestinal stromal tumors has greatly influenced the treatment of sarcoma manifestations within the liver. This requires not only the unequivocal pathomorphological differentiation of sarcomas from other tumor entities, e. g. spindle cell dedifferentiated/pleomorphic carcinomas, aggressive non-Hodgkin lymphomas or amelanotic malignant melanomas, but also an accurate subtyping of this complex group of tumors. Additionally to macroscopic and histological findings, the recognition of characteristic immunophenotypic constellations and, at least in some types of sarcoma, the identification of molecular signatures, have greatly expanded the diagnostic tools in pathology.
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Affiliation(s)
- G Mechtersheimer
- Pathologisches Institut, Universitätsklinikum, Im Neuenheimer Feld 220/221, 69120, Heidelberg.
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Moszczyński P, Moszczyński P, Źabiński Z, Rutowski J. Liver Angiosarcoma Caused by 22‐Year Exposure to Vinyl Chloride Monomer. J Occup Health 2006. [DOI: 10.1539/joh.40.158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Paulin Moszczyński
- Regional HospitalProvince Immunology Laboratory in Brzesko
- Regional Integrated Hospital in TamowImmunology Laboratory
| | - Paulin Moszczyński
- Regional HospitalProvince Immunology Laboratory in Brzesko
- Regional Integrated Hospital in TamowImmunology Laboratory
| | - Zbigniew Źabiński
- Regional HospitalProvince Immunology Laboratory in Brzesko
- Regional Integrated Hospital in TamowImmunology Laboratory
| | - Jan Rutowski
- Regional HospitalProvince Immunology Laboratory in Brzesko
- Regional Integrated Hospital in TamowImmunology Laboratory
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Shimizu K, Ueda Y, Yamagishi H. Titration of serum p53 antibodies in patients with gastric cancer: a single-institute study of 40 patients. Gastric Cancer 2006; 8:214-9. [PMID: 16328595 DOI: 10.1007/s10120-005-0337-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2005] [Accepted: 05/19/2005] [Indexed: 02/07/2023]
Abstract
BACKGROUND Alterations of the p53 tumor suppressor gene are the most commonly observed genetic abnormalities in many different types of human malignancies. The accumulation of mutant p53 often leads to the production of p53 antibody (p53-Ab) in the sera of patients with various cancers. To evaluate the clinical implications of serum p53-Abs in patients with gastric cancer, we compared p53-Abs with conventional tumor markers such as carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9. METHODS Serum samples were obtained preoperatively from 40 patients with histologically confirmed gastric adenocarcinoma, including 28 (70%) patients in stage Ia. The serum p53-Abs were assessed by enzyme-linked immunosorbent assay, using a new version of a highly specific, quantitative p53-Abs Kit (MESACUP Kit II). RESULTS p53-Abs were detected in 6 (15%) of 40 patients with gastric cancer, including 3 patients with early gastric cancer. Seven (17.5%) of the 40 patients were positive for CEA in serum. However, none of 7 patients with high CEA levels were positive for p53-Abs. No significant correlation of p53-Abs with patient age, sex, pathological parameters, tumor markers such as CEA and CA19-9, or poor survival (P = 0.116) was observed. CONCLUSION Although we employed the latest version of the p53-Abs Kit, the sensitivity of serum p53-Ab in gastric cancer patients was relatively low. No correlation was found between the presence of p53-Ab and the staging of cancer or survival. However, serum p53-Ab was detectable in patients with gastric cancer even in the early stages of disease. In addition, it may be independent of CEA and CA19-9.
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Affiliation(s)
- Keiji Shimizu
- Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-dori Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Robinson WH. Antigen arrays for antibody profiling. Curr Opin Chem Biol 2006; 10:67-72. [PMID: 16406767 DOI: 10.1016/j.cbpa.2005.12.028] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2005] [Accepted: 12/20/2005] [Indexed: 11/24/2022]
Abstract
Antigen array technologies enable large-scale profiling of the specificity of antibody responses against autoantigens, tumor antigens and microbial antigens. Antibody profiling will provide insights into pathogenesis, and will enable development of novel tests for diagnosis and guiding therapy in the clinic. Recent advances in the field include development of antigen array-based approaches to examine immune responses against antigens encoded in genetic libraries, post-translationally modified proteins, and other biomolecules such as lipids. A promising application is the use of antibody profiling to guide development and selection of antigen-specific therapies to treat autoimmune disease. This review discusses these advances and the challenges ahead for development and refinement of antibody profiling technologies for use in the research laboratory and the clinic.
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Affiliation(s)
- William H Robinson
- Geriatric Research, Education and Clinical Center (GRECC), Palo Alto VA Health Care System, Palo Alto, CA 94304, and USA Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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Mocci F, Nettuno M. Plasma Mutant-p53 Protein and Anti-p53 Antibody as a Marker: An Experience in Vinyl Chloride Workers in Italy. J Occup Environ Med 2006; 48:158-64. [PMID: 16474264 DOI: 10.1097/01.jom.0000183097.72738.a7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The objective of this study was to examine the presence of mutant-p53 protein (p53Ag) and antibodies to p53 protein (p53Ab) in a population of workers exposed to vinyl chloride (VC). METHOD We have investigated the presence of two cancer markers in the plasma of 151 subjects exposed to varying concentrations of VC (4-2823 ppm). The investigation took place in two sessions: in 1999, the analysis was limited to p53Ab, and in 2000, the analysis was repeated and extended to include also the mutant-p53Ag. The available information on the subjects in this study includes age, total years of employment in the VC polymerization industry, exposure concentration, results of abdominal ultrasonogram, hepatitis status, smoking and alcohol drinking status, and clinical records. Logistic regression analyses were performed to calculate the association between prevalence of positivity for p53Ab or mutant-p53Ag and cumulative VC exposure concentration after adjustment for confounding factors. t test and chi analyses were performed to test significant differences among groups. RESULTS Three (1.9%) of the 151 workers exposed to VC resulted seropositive for the mutant-p53Ag and five (3.3%) for the p53Ab. All seropositive subjects are distributed in the highest exposure classes (>1000 ppm). No seropositivity was found among controls. The stratified relationship between seropositivity and exposure appeared statistically significant (chi = 23.65 for mutant-p53Ag and 30.35 for p53Ab). CONCLUSIONS revealing its presence in subjects having a history of VC exposure greater than 1000 ppm. On the basis of this study, and the clinical experience of the authors, the presence of a minimum threshold for the carcinogenic effects of VC is hypothesized.
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Affiliation(s)
- Francesco Mocci
- Occupational Medicine Institute, University of Sassari, Via Matteotti 58, 07100 Sassari, Italy.
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Anderson KS, LaBaer J. The sentinel within: exploiting the immune system for cancer biomarkers. J Proteome Res 2005; 4:1123-33. [PMID: 16083262 PMCID: PMC2522321 DOI: 10.1021/pr0500814] [Citation(s) in RCA: 246] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The release of proteins from tumors triggers an immune response in cancer patients. These tumor antigens arise from several mechanisms including tumor-specific alterations in protein expression, mutation, folding, degradation, or intracellular localization. Responses to most tumor antigens are rarely observed in healthy individuals, making the response itself a biomarker that betrays the presence of underlying cancer. Antibody immune responses show promise as clinical biomarkers because antibodies have long half-lives in serum, are easy to measure, and are stable in blood samples. However, our understanding of the specificity and the impact of the immune response in early stages of cancer is limited. The immune response to cancer, whether endogenous or driven by vaccines, involves highly specific T lymphocytes (which target tumor-derived peptides bound to self-MHC proteins) and B lymphocytes (which generate antibodies to tumor-derived proteins). T cell target antigens have been identified either by expression cloning from tumor cDNA libraries, or by prediction based on patterns of antigen expression ("reverse immunology"). B cell targets have been similarly identified using the antibodies in patient sera to screen cDNA libraries derived from tumor cell lines. This review focuses on the application of recent advances in proteomics for the identification of tumor antigens. These advances are opening the door for targeted vaccine development, and for using immune response signatures as biomarkers for cancer diagnosis and monitoring.
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Affiliation(s)
- Karen S Anderson
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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40
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Li Y, Karjalainen A, Koskinen H, Hemminki K, Vainio H, Shnaidman M, Ying Z, Pukkala E, Brandt-Rauf PW. p53 autoantibodies predict subsequent development of cancer. Int J Cancer 2005; 114:157-60. [PMID: 15523685 DOI: 10.1002/ijc.20715] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Because TP53 mutations can induce an immune response and can occur early in the carcinogenic process for some tumors, p53 autoantibodies may be useful biomarkers for risk of development of cancer. Using banked serum samples from an asbestosis cohort at high risk for cancer, we demonstrate for the first time a statistically significant relationship between p53 autoantibodies and the subsequent development of malignancy (hazard ratio [HR] = 5.5, 95% confidence interval [CI] = 2.8-10.9) with a positive predictive value of 0.76 and an average lead time to diagnosis of 3.5 years. p53 autoantibodies were also significantly associated with p53 alterations in the resultant tumors (kappa = 0.78, p = 0.01).
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Affiliation(s)
- Yongliang Li
- Department of Environmental Health Sciences, Columbia University, New York, NY 10032, USA
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41
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Bøe AS, Bredholt G, Knappskog PM, Storstein A, Vedeler CA, Husebye ES. Pyridoxal phosphatase is a novel cancer autoantigen in the central nervous system. Br J Cancer 2004; 91:1508-14. [PMID: 15452547 PMCID: PMC2409937 DOI: 10.1038/sj.bjc.6602142] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Autoantibodies against many proteins are common in sera from patients with various types of cancer. These antibodies are sometimes involved in the development of conditions associated with cancer, such as paraneoplastic neurologic disorders. We used a human brain cDNA expression library and serum from a paraneoplastic neurologic disorder patient to search for new autoantigens in the nervous system. Pyridoxal phosphatase was identified as a novel autoantigen. Expression studies showed that pyridoxal phosphatase was strongly expressed in various parts of the central nervous system. Sera contained antibodies against pyridoxal phosphatase in 22 of 243 (9.1%) patients with lung cancer and eight of 113 (7.1%) with other forms of cancer vs two of 88 (2.3%) healthy control subjects. In addition, 2-4% of patients with different autoimmune diseases had autoantibodies against pyridoxal phosphatase. None of the antipyridoxal phosphatase-positive patients were known to have a paraneoplastic neurologic disorder. Hence, autoantibodies against pyridoxal phosphatase correlate with cancer but not necessarily with the subset of patients with paraneoplastic neurological disorders although serum from such a patient was used to screen the cDNA library. This study showed that yet another enzyme involved in pyridoxal 5'-phosphate metabolism is an autoantigen. Thus, pyridoxal 5'-phosphate seems to be a common denominator for autoantigens involved in autoimmune diseases.
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Affiliation(s)
- A S Bøe
- Division of Endocrinology, Institute of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway.
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42
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Li Y, Marion MJ, Rundle A, Brandt-Rauf PW. A common polymorphism in XRCC1 as a biomarker of susceptibility for chemically induced genetic damage. Biomarkers 2004; 8:408-14. [PMID: 14602524 DOI: 10.1080/13547500310001619301] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We have recently demonstrated a significant dose-response relationship between vinyl chloride exposure and mutant p53 biomarkers in humans. The aim of this study was to examine a common polymorphism in the DNA repair gene XRCC1 as a potential biomarker of susceptibility modifying this relationship, consistent with the known mechanism of production of p53 mutations via vinyl chloride-induced etheno-DNA adducts, which are repaired by XRCC1. A cohort of 211 French vinyl chloride workers were genotyped for the XRCC1 codon 399 polymorphism (CGG>CAG; Arg>Gln). Among the homozygous Arg-Arg individuals, 34% were biomarker positive compared with 47% in the heterozygous Arg-Gln individuals (adjusted odds ratio 1.73, 95% CI0.93-3.22) and 66% in the homozygous Gln-Gln individuals (adjusted odds ratio 3.95, 95% CI 1.68-9.28), with a significant trend for increasing Gln allele dosage (p=0.002). These preliminary results suggest that a common polymorphism in a DNA repair gene can be an important biomarker of susceptibility for chemically induced genetic damage.
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Affiliation(s)
- Yongliang Li
- Mailman School of Public Health, Columbia University, New York, NY 10032, USA
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John Luo JC, Cheng TJ, Du CL, Wang JD. Molecular epidemiology of plasma oncoproteins in vinyl chloride monomer workers in Taiwan. CANCER DETECTION AND PREVENTION 2004; 27:94-101. [PMID: 12670519 DOI: 10.1016/s0361-090x(03)00021-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
AIMS To determine the presence of Asp13-p21-ki-ras oncoprotein and p53 oncoprotein in the plasma of vinyl chloride monomer (VCM)-workers in Taiwan. METHODS We used enhanced chemiluminescence (ECL) western blotting to detect Asp13-p21-ki-ras and ELISA to detect mutant p53 protein (p53-Ag) and anti-p53 antibodies (p53-Ab) in the plasma of VCM-exposed workers. RESULTS Twenty-five out of 251 (10%) VCM-workers were positive for Asp13-p21-ki-ras in plasma, but 0 out of 36 controls were positive. There were 15 out of 95 (15.8%) plasma-positives among the more highly exposed (> 480 ppm-month) workers and 10 out of 156 (6.4%) plasma-positives among the lesser exposed (< or = 480 ppm-month). Compared to the unexposed controls, age and drinking adjusted odds ratios (95% CI) were 1.2 (0.1, 9.8) in the lower exposed workers, and 4.8 (0.8, 28) in the higher exposed workers, and there was a significant linear trend between exposure and plasma positivity (P=0.001). Thirty-three out of 251 (13.2%) VCM-workers were positive for the p53 over-expression (10% with positive p53-Ag and 2.8% with positive p53-Ab). There was a significant association between cumulative VCM exposure concentration and positive p53 expression (P=0.032) among VCM-workers after adjusting for age, hepatitis, drinking and smoking status. CONCLUSIONS Asp13-p21-ki-ras oncoprotein and p53 over-expression (p53-Ag or p53-Ab) can be found in the plasma of VCM-workers in Taiwan, and a significant dose-response relationship exists between plasma oncoproteins expression and VCM exposure.
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Affiliation(s)
- Jiin-Chyuan John Luo
- Department of Public Health, Chang Gung Medical College, 259 Wen-Hua 1st Road, Kwei-Shan, Tao-Yuan, Taiwan ROC
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Tan EM, Shi FD. Relative paradigms between autoantibodies in lupus and autoantibodies in cancer. Clin Exp Immunol 2003; 134:169-77. [PMID: 14616773 PMCID: PMC1808856 DOI: 10.1046/j.1365-2249.2003.02259.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- E M Tan
- W M Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
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45
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Abstract
In some cases, evidence exists that exogenous carcinogenic exposures contribute to the mutation spectrum of the TP53 gene (p53) in human cancers. Although the clearest examples come from dietary and environmental sources, only a restricted number of papers have concentrated specifically on TP53 mutations in tumors from workers exposed to occupational carcinogens. In populations exposed to dietary aflatoxin B1 with liver cancer (AFB1) and ultraviolet (UV)-radiation with skin cancer, a single specific-looking TP53 mutation has been described in some of the tumors. Whether these fingerprints in the TP53 gene can be used to reveal an occupational etiology remains to be shown. In other cases, although differences in the TP53 mutation spectrum exist, they are more diffuse and difficult to interpret at this point. For instance, cigarette smoking seems to induce long-lasting molecular footprints in TP53. However, their use to rule out other occupational exposures as etiological factors in occupational cancers is still very questionable, especially due to the putative synergistic effects of cigarette smoke with other carcinogens. Although interesting implications of possible typical mutation spectra among cancers with other occupational etiologies exist, the data are scanty and await further development of TP53 mutation databases.
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Affiliation(s)
- Kirsi Vähäkangas
- Department of Pharmacology and Toxicology, University of Kuopio, Kuopio, Finland
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46
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Shimada H, Ochiai T, Nomura F. Titration of serum p53 antibodies in 1,085 patients with various types of malignant tumors: a multiinstitutional analysis by the Japan p53 Antibody Research Group. Cancer 2003; 97:682-9. [PMID: 12548611 DOI: 10.1002/cncr.11092] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND There have been very few large-scale, multiinstitutional studies of surveillance of serum p53 antibodies (S-p53 Abs) in patients with various malignant tumors. METHODS A highly specific, quantitative enzyme-linked immunosorbent assay (ELISA) kit was developed and used to evaluate the efficiency of detecting p53 Abs. A cut-off value was established by analyzing sera from 205 healthy volunteers as reference individuals. Sera from 1085 patients with various types of primary malignant tumors were studied for the presence of S-p53 Abs before treatment. Sera from 34 patients were selected randomly for a competition assay to ensure that antibodies were specific to p53 protein. Carcinoembryonic antigen (CEA) was assessed to compare its positive rate with the positive rate of S-p53 Abs. RESULTS The median value of S-p53 Abs in healthy control individuals was 0.33 U/mL (range, 0.0-4.39 U/mL). Based on reference values that were calculated using parametric determination of the lower 0.95 fraction of the reference distribution in healthy control individuals, the cut-off value was determined as 1.3 U/mL. Two hundred twenty-one of 1085 patients (20.4%) were positive for S-p53 Abs. The highest relevance of S-53 Abs was associated with head and neck carcinoma (32%), followed by esophageal carcinoma (30%), colorectal carcinoma (24%), and carcinoma of the uterus (23%). The positive rate for S-p53 Abs was higher compared with the positive rate for CEA in patients with squamous cell carcinoma. CONCLUSIONS Surveillance of S-p53 Abs is useful in detecting various types of malignant tumors, particular in patients with squamous cell carcinoma.
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Affiliation(s)
- Hideaki Shimada
- Department of Academic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
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47
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Portefaix JM, Fanutti C, Granier C, Crapez E, Perham R, Grenier J, Pau B, Del Rio M. Detection of anti-p53 antibodies by ELISA using p53 synthetic or phage-displayed peptides. J Immunol Methods 2002; 259:65-75. [PMID: 11730842 DOI: 10.1016/s0022-1759(01)00494-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Anti-p53 antibodies have been detected in the sera of patients with various types of cancers. In this report, we describe the development of a new ELISA aimed at detecting anti-p53 antibodies using two peptides belonging to immunodominant epitopes of the p53 N-terminal region. We first tested the reactivity of the sera by an indirect ELISA using the peptides as a capture system. Then, the specificity of the reaction was confirmed by an inhibition assay. Two systems of peptide presentation, phage display and the streptavidin/biotin system, were evaluated. Using a panel of sera from cancer patients, both systems were found to be equally reliable, demonstrating that both peptide-based ELISAs can be used for the specific detection of anti-p53 antibodies. The presence of anti-p53 antibodies was associated with p53 alteration whether it be mutation or accumulation.
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Affiliation(s)
- Jean Michel Portefaix
- CNRS-UMR 5094, Centre de Recherche en Cancérologie, CRLC Val d'Aurelle, Montpellier, France
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48
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Abstract
The systematic development and application of biomarkers in environmental health risk assessment is a relatively new field. At first, the major interest was in biomarkers of exposure, borrowing concepts from pharmacology, then it moved from the external estimates of exposure to internal measures of dose, and ultimately, to markers of target dose. While these markers provide evidence of exposures, they do not provide evidence of that toxicological damage has occurred. For this reason, measurements of DNA adducts and protein adducts are of interest, since they may provide bridges between exposures and disease end-points. In parallel, more quantitative and more sensitive end-points for diseases have been sought. Again, with advancing techniques in cytogenetics, extensive studies were conducted on such markers as chromosomal aberrations, micronuclei and other changes deemed to represent genomic damage. However, these types of end-points are quite unspecific for application to new hazards of uncertain human toxic (carcinogenic) potential. Recent work focusing on more specific early-effect markers such as certain oncogenes and tumour-suppressor genes have substantial promise as shown by work with aflatoxins and vinyl chloride. Such studies have also enhanced mechanistic insight. The advances in molecular genetics have led to an upsurge in interest in most susceptibility factors, and identification of polymorphisms of various enzymes has become possible. Ongoing search for "ultra-high risk" individuals may be fruitful, but probably only relevant to a small segment of potentially exposed populations. Factors associated with a small differential risk, however theoretically or mechanistically important, offer only little practical use.
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Affiliation(s)
- H Vainio
- WHO, International Agency for Research on Cancer, Unit of Chemoprevention, 150 Cours Albert Thomas, F-69372 Lyon, France.
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Abu-Shakra M, Buskila D, Ehrenfeld M, Conrad K, Shoenfeld Y. Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies. Ann Rheum Dis 2001; 60:433-41. [PMID: 11302861 PMCID: PMC1753641 DOI: 10.1136/ard.60.5.433] [Citation(s) in RCA: 148] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVES To review the autoimmune and rheumatic manifestations of patients with malignancy. METHODS A Medline search of all published papers using keywords related to malignancies, autoimmunity, rheumatic diseases, and paraneoplastic syndromes. RESULTS Patients with malignant diseases may develop autoimmune phenomena and rheumatic diseases as a result of (a) generation of autoantibodies against various autoantigens, including oncoproteins (P185, 1-myc, c-myc, c-myb), tumour suppression genes (P53), proliferation associated antigens (cyclin A, B1, D1, E; CENP-F; CDK, U3-RNP), onconeural antigens (Hu, Yo, Ri, Tr), cancer/testis antigens (MAGE, GAGE, BAGE, SSX, ESO, SCP, CT7), and rheumatic disease associated antigens (RNP, Sm). The clinical significance of the various autoantibodies is not clear. Anti-oncoprotein and anti-tumour suppression gene antigens are detected before the diagnosis of the cancer or in the early stages of the malignant disease, suggesting a potential diagnostic or prognostic role. Anti-onconeural antibodies are pathogenic and are associated with specific clinical neurological syndromes (anti-Hu syndrome and others). (b) Paraneoplastic syndromes, a wide range of clinical syndromes, including classic autoimmune rheumatic diseases that develop among patients with cancer. (c) Rheumatism after chemotherapy, a clinical entity characterised by the development of musculoskeletal symptoms after combination chemotherapy for malignancy. CONCLUSION Autoimmune and rheumatic features are not rare among patients with malignancies. They are the result of various diverse mechanisms and occasionally they may be associated with serious clinical entities.
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Affiliation(s)
- M Abu-Shakra
- Department of Medicine and Rheumatic Diseases Unit, Soroka Medical Centre, and Ben-Gurion University, Beer-Sheva, Israel
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Weihrauch M, Benicke M, Lehnert G, Wittekind C, Wrbitzky R, Tannapfel A. Frequent k- ras -2 mutations and p16(INK4A)methylation in hepatocellular carcinomas in workers exposed to vinyl chloride. Br J Cancer 2001; 84:982-9. [PMID: 11286481 PMCID: PMC2363841 DOI: 10.1054/bjoc.2000.1675] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Vinyl chloride (VC) is a know animal and human carcinogen associated with liver angiosarcomas (LAS) and hepatocellular carcinomas (HCC). In VC-associated LAS mutations of the K- ras -2 gene have been reported; however, no data about the prevalence of such mutations in VC associated HCCs are available. Recent data indicate K- ras -2 mutations induce P16 methylation accompanied by inactivation of the p16 gene. The presence of K- ras -2 mutations was analysed in tissue from 18 patients with VC associated HCCs. As a control group, 20 patients with hepatocellular carcinoma due to hepatitis B (n = 7), hepatitis C (n = 5) and alcoholic liver cirrhosis (n = 8) was used. The specific mutations were determined by direct sequencing of codon 12 and 13 of the K- ras -2 gene in carcinomatous and adjacent non-neoplastic liver tissue after microdissection. The status of p16 was evaluated by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. All patients had a documented chronic quantitated exposure to VC (average 8883 ppmy, average duration: 245 months). K- ras -2 mutations were found in 6 of 18 (33%) examined VC-associated HCCs and in 3 cases of adjacent non-neoplastic liver tissue. There were 3 G --> A point mutations in the tumour tissue. All 3 mutations found in non-neoplastic liver from VC-exposed patients were also G --> A point mutations (codon 12- and codon 13-aspartate mutations). Hypermethylation of the 5' CpG island of the p16 gene was found in 13 of 18 examined carcinomas (72%). Of 6 cancers with K- ras -2 mutations, 5 specimens also showed methylated p16. Within the control group, K- ras -2 mutation were found in 3 of 20 (15%) examined HCC. p16 methylation occurred in 11 out of 20 (55%) patients. K- ras -2 mutations and p16 methylation are frequent events in VC associated HCCs. We observed a K- ras -2 mutation pattern characteristic of chloroethylene oxide, a carcinogenic metabolite of VC. Our results strongly suggest that K- ras -2 mutations play an important role in the pathogenesis of VC-associated HCC.
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Affiliation(s)
- M Weihrauch
- Institute of Occupational and Environmental Medicine, University of Hannover, Germany
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