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Jakovac H, Stašić N, Krašević M, Jonjić N, Radošević-Stašić B. Expression profiles of metallothionein-I/II and megalin/LRP-2 in uterine cervical squamous lesions. Virchows Arch 2020; 478:735-746. [PMID: 33084977 PMCID: PMC7990851 DOI: 10.1007/s00428-020-02947-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/18/2020] [Accepted: 10/09/2020] [Indexed: 12/29/2022]
Abstract
Metallothioneins (MTs) are phylogenetically old cysteine-rich proteins, which are implicated in a variety of physiological and pathological processes. Their growth-regulating, anti-apoptotic and anti-inflammatory functions have been attributed not only to intracellular free radical scavenging and to zinc and copper regulation but also to the ability of secreted MT to bind on surface lipoprotein receptor-megalin/LRP2, which enables the endocytosis of MT-I/II and a wide range of other functionally distinct ligands. In the present study, we analysed the expression pattern of both proteins in 55 cases of premalignant transformation of cervical squamous cells, i.e. in low- and high-grade squamous intraepithelial lesion (LSIL and HSIL). The data showed that in LSIL (cervical intraepithelial neoplasia CIN1; N = 25) MTs were present only in basal and parabasal cells and that megalin was only weakly expressed. In HSIL (CIN2; N = 15 and CIN 3/carcinoma in situ; N = 15), however, overexpression and co-localization of MT with megalin were found in the entire hyperplastic epithelium. Moreover, megalin immunoreactivity appeared on the glandular epithelium and vascular endothelium, as well as on lymphatic cells in stroma. Besides, multiple megalin-positive cells expressed phosphorylated Akt1, implying that MT- and/or megalin-dependent prosurvival signal transduction pathways might contribute to the development of severe cervical dysplasia. The data emphasize the diagnostic power of combined MT/megalin analysis in pre-cancer screening.
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Affiliation(s)
- Hrvoje Jakovac
- Department of Physiology and Immunology, Medical Faculty, University of Rijeka, B. Branchetta 20, 51 000 Rijeka, Croatia
| | - Nikola Stašić
- Teaching Institute of Public Health, Primorsko-goranska County, Medical Faculty, University of Rijeka, Rijeka, Croatia
| | - Maja Krašević
- Department of Pathology, Medical Faculty, University of Rijeka, Rijeka, Croatia
| | - Nives Jonjić
- Department of Pathology, Medical Faculty, University of Rijeka, Rijeka, Croatia
| | - Biserka Radošević-Stašić
- Department of Physiology and Immunology, Medical Faculty, University of Rijeka, B. Branchetta 20, 51 000 Rijeka, Croatia
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Mei C, Song PY, Zhang W, Zhou HH, Li X, Liu ZQ. Aberrant RNA Splicing Events Driven by Mutations of RNA-Binding Proteins as Indicators for Skin Cutaneous Melanoma Prognosis. Front Oncol 2020; 10:568469. [PMID: 33178596 PMCID: PMC7593665 DOI: 10.3389/fonc.2020.568469] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 08/14/2020] [Indexed: 12/29/2022] Open
Abstract
The worldwide incidence of skin cutaneous melanoma (SKCM) is increasing at a more rapid rate than other tumors. Aberrant alternative splicing (AS) is found to be common in cancer; however, how this process contributes to cancer prognosis still remains largely unknown. Mutations in RNA-binding proteins (RBPs) may trigger great changes in the splicing process. In this study, we comprehensively analyzed DNA and RNA sequencing data and clinical information of SKCM patients, together with widespread changes in splicing patterns induced by RBP mutations. We screened mRNA expression-related and prognosis-related mutations in RBPs and investigated the potential affections of RBP mutations on splicing patterns. Mutations in 853 RBPs were demonstrated to be correlated with splicing aberrations (p < 0.01). Functional enrichment analysis revealed that these alternative splicing events (ASEs) may participate in tumor progress by regulating the modification process, cell-cycle checkpoint, metabolic pathways, MAPK signaling, PI3K-Akt signaling, and other important pathways in cancer. We also constructed a prediction model based on overall survival-related AS events (OS-ASEs) affected by RBP mutations, which exhibited a good predict efficiency with the area under the curve of 0.989. Our work highlights the importance of RBP mutations in splicing alterations and provides effective biomarkers for prediction of prognosis of SKCM.
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Affiliation(s)
- Chao Mei
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Key Laboratory of Biological Nanotechnology of National Health Commission, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Pei-Yuan Song
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Key Laboratory of Biological Nanotechnology of National Health Commission, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Key Laboratory of Biological Nanotechnology of National Health Commission, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Key Laboratory of Biological Nanotechnology of National Health Commission, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Xi Li
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Key Laboratory of Biological Nanotechnology of National Health Commission, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Key Laboratory of Biological Nanotechnology of National Health Commission, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Institute of Clinical Pharmacology, Central South University, Changsha, China
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Filippini T, Malagoli C, Wise LA, Malavolti M, Pellacani G, Vinceti M. Dietary cadmium intake and risk of cutaneous melanoma: An Italian population-based case-control study. J Trace Elem Med Biol 2019; 56:100-106. [PMID: 31442947 DOI: 10.1016/j.jtemb.2019.08.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 07/31/2019] [Accepted: 08/01/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Exposure to the heavy metal cadmium has been associated with many adverse health effects, such as atherosclerosis, diabetes, and cancer, possibly melanoma. In non-occupationally exposed individuals, food intake is a major source of cadmium exposure, after smoking. We aimed to assess the risk of melanoma in relation to dietary cadmium intake. METHODS Using a population-based case-control study design, we recruited 380 incident cases of newly-diagnosed cutaneous melanoma and 719 matched controls in the Emilia-Romagna Region, Northern Italy in the years 2005-2006. We evaluated dietary intake using a semi-quantitative food frequency questionnaire. We used conditional logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs) for melanoma according to quintiles of dietary cadmium intake, adjusting for several potential confounders, and we modeled the association non-parametrically, using restricted cubic splines. RESULTS Median energy-adjusted intake of cadmium was 6.11 μg/day (interquartile range 5.38-6.91) among cases and 5.97 μg/day (5.15-6.79) among controls. For each 1 μg/day-increase in cadmium intake, the OR for melanoma was 1.11 (95% CI 1.00-1.24). Melanoma risk generally increased with increasing quintile of cadmium exposure, with ORs of 1.55 (95% CI 0.99-2.42), 1.54 (95% CI 0.99-2-40), 1.75 (95% CI 1.12-2.75), and 1.65 (95% CI 1.05-2.61) for the second through fifth quintiles, compared with the lowest quintile. Sex-stratified analysis showed ORs per 1 μg/day-increase in cadmium intake of 1.10 (95% CI 0.93-1-29) among men and 1.15 (95% CI 0.99-1.33) among women. Using spline regression analysis, we observed a generally linear increase in melanoma risk up to 6 μg/day of cadmium intake, after which the risk appeared to plateau. CONCLUSIONS We observed a positive non-linear association between dietary cadmium intake and risk of cutaneous melanoma in a Northern Italy population. However, further studies are needed to elucidate this association, due to concerns about exposure misclassification, unmeasured confounding, and the limited and conflicting evidence from epidemiological findings.
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Affiliation(s)
- Tommaso Filippini
- Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences - Section of Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | - Carlotta Malagoli
- Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences - Section of Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | - Lauren A Wise
- Department of Epidemiology, Boston University School of Public Health, Boston, USA
| | - Marcella Malavolti
- Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences - Section of Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | - Giovanni Pellacani
- Department of Dermatology, University of Modena and Reggio Emilia, Italy
| | - Marco Vinceti
- Environmental, Genetic and Nutritional Epidemiology Research Center, Department of Biomedical, Metabolic and Neural Sciences - Section of Public Health, University of Modena and Reggio Emilia, Modena, Italy; Department of Epidemiology, Boston University School of Public Health, Boston, USA.
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Matthews NH, Fitch K, Li WQ, Morris JS, Christiani DC, Qureshi AA, Cho E. Exposure to Trace Elements and Risk of Skin Cancer: A Systematic Review of Epidemiologic Studies. Cancer Epidemiol Biomarkers Prev 2019; 28:3-21. [PMID: 30297516 PMCID: PMC6324965 DOI: 10.1158/1055-9965.epi-18-0286] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 07/30/2018] [Accepted: 09/28/2018] [Indexed: 12/11/2022] Open
Abstract
Exposure to environmental trace elements has been studied in relation to many cancers. However, an association between exposure to trace elements and skin cancer remains less understood. Therefore, we conducted a systematic review of published epidemiologic literature examining the association between exposure to trace elements, and risk of melanoma and keratinocyte carcinoma in humans. We identified epidemiologic studies investigating exposure to arsenic, cadmium, chromium, copper, iron, selenium, and zinc and risk of skin cancer in humans. Among the minerals, arsenic, selenium, and zinc had more than five studies available. Exposure to arsenic was associated with increased risk of keratinocyte carcinoma, while too few studies existed on melanoma to draw conclusions. Exposure to selenium was associated with possible increased risk of keratinocyte carcinoma. Studies of zinc and skin cancer were case-control in design and were found to have inconsistent associations. The data on the association between cadmium, chromium, copper, and iron and risk of skin cancer remain too sparse to draw any conclusions. In summary, epidemiologic studies on exposure to trace elements and cutaneous malignancies are limited. Studies with larger sample sizes and prospective designs are warranted to improve our knowledge of trace elements and skin cancer.
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Affiliation(s)
- Natalie H Matthews
- Department of Dermatology, The Warren Alpert Medical School, Brown University, Providence, Rhode Island
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Katherine Fitch
- Department of Dermatology, The Warren Alpert Medical School, Brown University, Providence, Rhode Island
| | - Wen-Qing Li
- Department of Dermatology, The Warren Alpert Medical School, Brown University, Providence, Rhode Island
- Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island
| | - J Steven Morris
- Research Reactor Center, University of Missouri-Columbia and Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri
| | - David C Christiani
- Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
- Pulmonary and Critical Care Unit, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
| | - Abrar A Qureshi
- Department of Dermatology, The Warren Alpert Medical School, Brown University, Providence, Rhode Island
- Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Dermatology, Rhode Island Hospital, Providence, Rhode Island
| | - Eunyoung Cho
- Department of Dermatology, The Warren Alpert Medical School, Brown University, Providence, Rhode Island.
- Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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Eisenstein A, Gonzalez EC, Raghunathan R, Xu X, Wu M, McLean EO, McGee J, Ryu B, Alani RM. Emerging Biomarkers in Cutaneous Melanoma. Mol Diagn Ther 2018; 22:203-218. [PMID: 29411301 DOI: 10.1007/s40291-018-0318-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Earlier identification of aggressive melanoma remains a goal in the field of melanoma research. With new targeted and immune therapies that have revolutionized the care of patients with melanoma, the ability to predict progression and monitor or predict response to therapy has become the new focus of research into biomarkers in melanoma. In this review, promising biomarkers are highlighted. These biomarkers have been used to diagnose melanoma as well as predict progression to advanced disease and response to therapy. The biomarkers take various forms, including protein expression at the level of tissue, genetic mutations of cancer cells, and detection of circulating DNA. First, a brief description is provided about the conventional tissue markers used to stage melanoma, including tumor depth. Next, protein biomarkers, which provide both diagnostic and prognostic information, are described. This is followed by a discussion of important genetic mutations, microRNA, and epigenetic modifications that can provide therapeutic and prognostic material. Finally, emerging serologic biomarkers are reviewed, including circulating melanoma cells and exosomes. Overall the goal is to identify biomarkers that aid in the earlier identification and improved treatment of aggressive melanoma.
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Affiliation(s)
- Anna Eisenstein
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Estela Chen Gonzalez
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Rekha Raghunathan
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Xixi Xu
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Muzhou Wu
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Emily O McLean
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Jean McGee
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Byungwoo Ryu
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA.
| | - Rhoda M Alani
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA.
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Venza M, Visalli M, Biondo C, Oteri R, Agliano F, Morabito S, Caruso G, Caffo M, Teti D, Venza I. Epigenetic effects of cadmium in cancer: focus on melanoma. Curr Genomics 2015; 15:420-35. [PMID: 25646071 PMCID: PMC4311387 DOI: 10.2174/138920291506150106145932] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Revised: 11/07/2014] [Accepted: 11/17/2014] [Indexed: 01/01/2023] Open
Abstract
Cadmium is a highly toxic heavy metal, which has a destroying impact on organs. Exposure to cadmium causes severe health problems to human beings due to its ubiquitous environmental presence and features of the pathologies associated with pro-longed exposure. Cadmium is a well-established carcinogen, although the underlying mechanisms have not been fully under-stood yet. Recently, there has been considerable interest in the impact of this environmental pollutant on the epigenome. Be-cause of the role of epigenetic alterations in regulating gene expression, there is a potential for the integration of cadmium-induced epigenetic alterations as critical elements in the cancer risk assessment process. Here, after a brief review of the ma-jor diseases related to cadmium exposure, we focus our interest on the carcinogenic potential of this heavy metal. Among the several proposed pathogenetic mechanisms, particular attention is given to epigenetic alterations, including changes in DNA methylation, histone modifications and non-coding RNA expression. We review evidence for a link between cadmium-induced epigenetic changes and cell transformation, with special emphasis on melanoma. DNA methylation, with reduced expression of key genes that regulate cell proliferation and apoptosis, has emerged as a possible cadmium-induced epigenetic mechanism in melanoma. A wider comprehension of mechanisms related to this common environmental contaminant would allow a better cancer risk evaluation.
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Affiliation(s)
- Mario Venza
- Department of Experimental Specialistic Medical, Surgical and Odontostomatology Sciences, University of Messina, Messina, Italy
| | - Maria Visalli
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Carmelo Biondo
- Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, University of Messina, Messina, Italy
| | - Rosaria Oteri
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Federica Agliano
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Silvia Morabito
- Department of Experimental Specialistic Medical, Surgical and Odontostomatology Sciences, University of Messina, Messina, Italy
| | - Gerardo Caruso
- Department of Neurosciences, University of Messina, Messina, Italy
| | - Maria Caffo
- Department of Neurosciences, University of Messina, Messina, Italy
| | - Diana Teti
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Isabella Venza
- Department of Experimental Specialistic Medical, Surgical and Odontostomatology Sciences, University of Messina, Messina, Italy
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Gumulec J, Raudenska M, Adam V, Kizek R, Masarik M. Metallothionein - immunohistochemical cancer biomarker: a meta-analysis. PLoS One 2014; 9:e85346. [PMID: 24416395 PMCID: PMC3885711 DOI: 10.1371/journal.pone.0085346] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Accepted: 12/04/2013] [Indexed: 12/28/2022] Open
Abstract
Metallothionein (MT) has been extensively investigated as a molecular marker of various types of cancer. In spite of the fact that numerous reviews have been published in this field, no meta-analytical approach has been performed. Therefore, results of to-date immunohistochemistry-based studies were summarized using meta-analysis in this review. Web of science, PubMed, Embase and CENTRAL databases were searched (up to April 30, 2013) and the eligibility of individual studies and heterogeneity among the studies was assessed. Random and fixed effects model meta-analysis was employed depending on the heterogeneity, and publication bias was evaluated using funnel plots and Egger's tests. A total of 77 studies were included with 8,015 tissue samples (4,631 cases and 3,384 controls). A significantly positive association between MT staining and tumors (vs. healthy tissues) was observed in head and neck (odds ratio, OR 9.95; 95% CI 5.82-17.03) and ovarian tumors (OR 7.83; 1.09-56.29), and a negative association was ascertained in liver tumors (OR 0.10; 0.03-0.30). No significant associations were identified in breast, colorectal, prostate, thyroid, stomach, bladder, kidney, gallbladder, and uterine cancers and in melanoma. While no associations were identified between MT and tumor staging, a positive association was identified with the tumor grade (OR 1.58; 1.08-2.30). In particular, strong associations were observed in breast, ovarian, uterine and prostate cancers. Borderline significant association of metastatic status and MT staining were determined (OR 1.59; 1.03-2.46), particularly in esophageal cancer. Additionally, a significant association between the patient prognosis and MT staining was also demonstrated (hazard ratio 2.04; 1.47-2.81). However, a high degree of inconsistence was observed in several tumor types, including colorectal, kidney and prostate cancer. Despite the ambiguity in some tumor types, conclusive results are provided in the tumors of head and neck, ovary and liver and in relation to the tumor grade and patient survival.
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Affiliation(s)
- Jaromir Gumulec
- Department of Pathological Physiology, Masaryk University, Brno, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Martina Raudenska
- Department of Pathological Physiology, Masaryk University, Brno, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Vojtech Adam
- Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic
| | - Rene Kizek
- Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic
| | - Michal Masarik
- Department of Pathological Physiology, Masaryk University, Brno, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
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Owens SE, Summar ML, Ryckman KK, Haines JL, Reiss S, Summar SR, Aschner M. Lack of association between autism and four heavy metal regulatory genes. Neurotoxicology 2011; 32:769-75. [PMID: 21798283 PMCID: PMC3206176 DOI: 10.1016/j.neuro.2011.07.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Revised: 07/07/2011] [Accepted: 07/08/2011] [Indexed: 11/29/2022]
Abstract
Autism is a common neurodevelopmental disorder with genetic and environmental components. Though unproven, genetic susceptibility to high mercury (Hg) body burden has been suggested as an autism risk factor in a subset of children. We hypothesized that exposure to "safe" Hg levels could be implicated in the etiology of autism if genetic susceptibility altered Hg's metabolism or intracellular compartmentalization. Genetic sequences of four genes implicated in the transport and response to Hg were screened for variation and association with autism. LAT1 and DMT1 function in Hg transport, and Hg exposure induces MTF1 and MT1a. We identified and characterized 74 variants in MT1a, DMT1, LAT1 and MTF1. Polymorphisms identified through screening 48 unrelated individuals from the general and autistic populations were evaluated for differences in allele frequencies using Fisher's exact test. Three variants with suggestive p-values <0.1 and four variants with significant p-values <0.05 were followed-up with TaqMan genotyping in a larger cohort of 204 patients and 323 control samples. The pedigree disequilibrium test was used to examine linkage and association. Analysis failed to show association with autism for any variant evaluated in both the initial screening set and the expanded cohort, suggesting that variations in the ability of the four genes studied to process and transport Hg may not play a significant role in the etiology of autism.
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Affiliation(s)
- Sarah E. Owens
- Department of Pediatric Toxicology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Marshall L. Summar
- Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Kelli K. Ryckman
- Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Jonathan L. Haines
- Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Sara Reiss
- Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Samantha R. Summar
- Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Michael Aschner
- Department of Pediatric Toxicology, Vanderbilt University School of Medicine, Nashville, TN, USA
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McGee HM, Woods GM, Bennett B, Chung RS. The two faces of metallothionein in carcinogenesis: photoprotection against UVR-induced cancer and promotion of tumour survival. Photochem Photobiol Sci 2010; 9:586-96. [PMID: 20354655 DOI: 10.1039/b9pp00155g] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Metallothionein is a multi-functional protein that protects the host against toxic heavy metals. Under stressful situations it can protect against oxidative damage, contribute to tissue repair, modulate immune responses and limit inflammatory processes. Recently, metallothionein's role in ultraviolet radiation (UVR)-induced injury has been investigated. These studies have shown that when metallothionein is upregulated following exposure to UVR, it can protect against UVR-induced damage and the subsequent development of skin cancer. We propose that this initial protection is achieved through its anti-oxidant role resulting in reduced oxidative stress, reduced apoptosis, reduced NFkappaB activation and enhanced repair of DNA damage. However, once UVR-induced neoplasia has occurred, the cancer cells can hijack metallothionein's protective functions, resulting in increased tumour progression and malignancy. These two discordant sets of attributes are context-dependent, and represent the two faces of metallothionein.
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Affiliation(s)
- Heather M McGee
- Menzies Research Institute, University of Tasmania, Australia.
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Grabellus F, Sheu SY, Tötsch M, Lehmann N, Kaiser GM, Jasani B, Taeger G, Schmid KW. Overexpression of the drug resistance-associated protein metallothionein does not correlate with response of sarcomas to isolated limb perfusion treatment. J Surg Oncol 2010; 101:465-70. [DOI: 10.1002/jso.21513] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Immunohistochemical localization of metallothionein and p53 protein in pancreatic serous cystadenomas. Arch Immunol Ther Exp (Warsz) 2009; 57:295-301. [PMID: 19578815 DOI: 10.1007/s00005-009-0033-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2008] [Accepted: 01/30/2009] [Indexed: 12/27/2022]
Abstract
INTRODUCTION The objective of this study was to determine the expression levels of metallothionein (MT) and p53 protein, recognized neoplastic transformation markers, in pancreatic serous cystadenomas (SCA) and adenomocarcinomas. MATERIALS AND METHODS Neoplastic pancreatic tissue was taken from 20 patients with diagnosed benign (SCA: 5 cases) or malignant tumors (adenomocarcinomas: 15 cases) and control pancreatic tissue from healthy persons who had died in car accidents. Sections were stained with hematoxylin-eosin. Immunohistochemical localization of MT and p53 protein was carried out by LSAB2-HRP using specific antibodies against MT and p53. RESULTS Metallothionein expression was observed only in the epithelial cells of the neoplastic tissue of SCAs. MT expression in the cystadenomas was weaker than in the healthy pancreatic tissue. No tissue was found with p53 protein expression. In the adenomocarcinomas, positive staining for MT was observed in 67% and p53 was positive in the carcinoma cells. CONCLUSION The weak MT expression and lack of p53 protein expression in pancreatic SCAs confirms the lack of local invasive potential of the neoplastic lesion. Increased expressions of MT and p53 were observed in the less differentiated tumors. Thus the expression of MT may be a potential prognostic marker for tumors.
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Krizkova S, Fabrik I, Adam V, Kukacka J, Prusa R, Trnkova L, Strnadel J, Horak V, Kizek R. Effects of Reduced Glutathione, Surface Active Agents, and Ionic Strength on the Detection of Metallothioneins by Using of Brdicka Reaction. ELECTROANAL 2009. [DOI: 10.1002/elan.200804406] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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ROSSEN K, HAERSLEV T, HOU-JENSEN K, JACOBSEN G. Metallothionein expression in basaloid proliferations overlying dermatofibromas and in basal cell carcinomas. Br J Dermatol 2008. [DOI: 10.1046/j.1365-2133.1997.d01-1138.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Krizkova S, Fabrik I, Adam V, Kukacka J, Prusa R, Chavis GJ, Trnkova L, Strnadel J, Horak V, Kizek R. Utilizing of Adsorptive Transfer Stripping Technique Brdicka Reaction for Determination of Metallothioneins Level in Melanoma Cells, Blood Serum and Tissues. SENSORS (BASEL, SWITZERLAND) 2008; 8:3106-3122. [PMID: 27879868 PMCID: PMC3675534 DOI: 10.3390/s8053106] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2008] [Accepted: 05/09/2008] [Indexed: 11/16/2022]
Abstract
In the paper we utilized the adsorptive transfer stripping differential pulse voltammetry Brdicka reaction for the determination of metallothioneins (MT) in melanoma cells, animal melanoma tissues (MeLiM miniature pig) and blood serum of patients with malignant melanoma. Primarily we attempted to investigate the influence of dilution of real sample on MT electrochemical response. Dilution of samples of 1 000 times was chosen the most suitable for determination of MT level in biological samples. Then we quantified the MT level in the melanoma cells, the animal melanoma tissues and the blood serum samples. The MT content in the cells varied within the range from 4.2 to 11.2 μM. At animal melanoma tissues (melanomas localized on abdomen, back limb and dorsum) the highest content of MT was determined in the tumour sampled on the back of the animal and was nearly 500 μg of MTs per gram of a tissue. We also quantified content of MT in metastases, which was found in liver, spleen and lymph nodes. Moreover the average MT level in the blood serum samples from patients with melanoma was 3.0 ± 0.8 μM. MT levels determined at melanoma samples were significantly (p < 0.05) higher compared to control ones at cells, tissues and blood serum.
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Affiliation(s)
- Sona Krizkova
- Department of Chemistry and Biochemistry Faculty of Agronomy, Mendel University of Agriculture and Forestry, Zemedelska 1, CZ-613 00 Brno, Czech Republic
| | - Ivo Fabrik
- Department of Chemistry and Biochemistry Faculty of Agronomy, Mendel University of Agriculture and Forestry, Zemedelska 1, CZ-613 00 Brno, Czech Republic
| | - Vojtech Adam
- Department of Chemistry and Biochemistry Faculty of Agronomy, Mendel University of Agriculture and Forestry, Zemedelska 1, CZ-613 00 Brno, Czech Republic
- Department of Animal Nutrition and Forage Production, Faculty of Agronomy, Mendel University of Agriculture and Forestry, Zemedelska 1, CZ-613 00 Brno, Czech Republic
| | - Jiri Kukacka
- Department of Clinical Biochemistry and Pathobiochemistry, 2nd Faculty of Medicine, Charles University, V Uvalu 84, CZ-150 06 Prague 5, Czech Republic
| | - Richard Prusa
- Department of Clinical Biochemistry and Pathobiochemistry, 2nd Faculty of Medicine, Charles University, V Uvalu 84, CZ-150 06 Prague 5, Czech Republic
| | - Grace J Chavis
- Department of Chemistry, University of California, One Shields Avenue, CA-956 16 Davis, USA
| | - Libuse Trnkova
- Department of Chemistry, Faculty of Science, Masaryk University, Kotlarska 2, CZ-611 37 Brno, Czech Republic
| | - Jan Strnadel
- Laboratory of Tumour Biology, Department of Animal Embryology, Cell and Tissue Differentitation, Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, v.v.i., CZ-277 21 Libechov, Czech Republic
| | - Vratislav Horak
- Laboratory of Tumour Biology, Department of Animal Embryology, Cell and Tissue Differentitation, Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, v.v.i., CZ-277 21 Libechov, Czech Republic
| | - Rene Kizek
- Department of Chemistry and Biochemistry Faculty of Agronomy, Mendel University of Agriculture and Forestry, Zemedelska 1, CZ-613 00 Brno, Czech Republic.
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Weinlich G, Zelger B. Metallothionein overexpression, a highly significant prognostic factor in thin melanoma. Histopathology 2007; 51:280-3. [PMID: 17593214 DOI: 10.1111/j.1365-2559.2007.02744.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Weinlich G, Topar G, Eisendle K, Fritsch PO, Zelger B. Comparison of metallothionein-overexpression with sentinel lymph node biopsy as prognostic factors in melanoma. J Eur Acad Dermatol Venereol 2007; 21:669-77. [PMID: 17447982 DOI: 10.1111/j.1468-3083.2006.02051.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Metallothioneins (MT) are ubiquitous, intracellular small proteins with high affinity for heavy metal ions. Immunohistochemical MT overexpression in paraffin-embedded tissues of patients with primary melanoma is associated with poor prognosis. While sentinel lymph node (SLN) biopsy is an established surgical technique for high-risk melanoma patients with predictive value for progression, the benefit of this procedure for the individual patient's overall survival remains unclear. AIM AND METHODS We examined the role of MT overexpression in comparison with SLN biopsy in melanoma patients as a prognostic marker for progression and survival. One hundred and fifty-eight (158) patients underwent SLN biopsy due to high-risk melanoma. Primary melanoma specimens were investigated by using a monoclonal antibody against MT on routinely fixed, paraffin-embedded tissues. The patients were followed up (median 37 months); the data of disease free survival and overall survival were calculated with a broad panel of statistical analyses. RESULTS Twenty-eight (18%) out of 158 recruited melanoma patients developed metastases, 17 (11%) patients died due to widespread disease. Kaplan-Meier curves gave significant disadvantages for the MT-positive as well as the SLN-positive group for progression and survival. In the Fisher's exact test and Pearson's chi(2)-test MT overexpression was highly significant for progression, whereas SLN biopsy failed significance. In univariate as well as multivariate Cox regression analysis MT overexpression proved an excellent marker for progression (P=0.007 and P=0.009), although the P-values for survival were not significant. In contrast, while in the univariate analysis SLN biopsy did not show significant results for progression it did for survival, and in the multivariate analysis reached a P-value < 0.05 for both measured endpoints. CONCLUSION Results corroborate the validity of MT overexpression in primary melanoma as a useful prognostic marker in melanoma patients. Accuracy is comparable and to some degree supplementary to the results of SLN biopsy.
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Affiliation(s)
- G Weinlich
- Clinical Department of Dermatology and Venerology, Innsbruck Medical University, Innsbruck, Austria.
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Abstract
Metallothioneins (MTs) were discovered in 1957 by Margoshes and Vallee and identified as low-molecular weight and sulphydryl rich proteins. It is not surprising that most mammalian tissues contain age related basal levels of MTs since they are involved in metalloregulatory processes that include cell growth and multiplication. In an effort to understand the biology of this intriguing tumor, various biomarkers such as oncogenes, p53 tumor suppressor gene, waf 1 protein, proliferating cell nuclear antigen, telomerase, microsatellite markers and cytogenetic changes have been examined. One biomarker which has recently shown to be expressed in various human tumors but still less reported in carcinoma is MT. Immunohistochemical detection of MT proteins in cold acetone-fixed paraffin embedded liver sections was performed by the streptavidin-avidin-biotin immuno-peroxidase complex method.
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Affiliation(s)
- N Thirumoorthy
- College of Pharmacy, Kovai Estate, Kalapatti Road, Coimbatore 641035, Tamilnadu, India.
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Weinlich G, Eisendle K, Hassler E, Baltaci M, Fritsch PO, Zelger B. Metallothionein - overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients. Br J Cancer 2006; 94:835-41. [PMID: 16508630 PMCID: PMC2361379 DOI: 10.1038/sj.bjc.6603028] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Metallothioneins (MT) are ubiquitous, intracellular small proteins with high affinity for heavy metal ions. In the last decades, it was shown that MT overexpression in a variety of cancers is associated with resistance to anticancer drugs and is combined with a poor prognosis. In this prospective study, we examined the role of MT overexpression in melanoma patients as a prognostic factor for progression and survival. Between 1993 and 2004, 3386 patients with primary cutaneous melanoma were investigated by using a monoclonal antibody against MT on routinely fixed, paraffin-embedded tissues. In all, 1270 patients could be followed up for further statistical analysis (Fisher's exact test, Mantel-Haenszel chi2 test, Kaplan-Meier curves). The MT data of disease-free interval and overall survival were compared univariately and multivariately in Cox regression analysis. Immunohistochemical overexpression of MT in tumour cells of patients with primary melanoma (310 of 1270; 24.4%) was associated with a higher risk for progression (117 of 167; 70.1%) and reduced survival (80 of 110; 72.7%) of the disease (P<0.0001). Similarly, Kaplan-Meier curves gave highly significant disadvantages for the MT-positive group. Univariate analysis (relative risk 7.4; 95% confidence interval (CI) 5.2-10.2; P<0.0001 for progression; relative risk 7.1; 95% CI 4.7-10.9; P<0.0001 for survival), as well as multivariate analysis with other prognostic markers resulted in MT overexpression as a highly significant and independent factor for prognosis in primary melanoma.
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Affiliation(s)
- G Weinlich
- Clinical Department of Dermatology and Venerology, Innsbruck Medical University, Anichstrasse 35, Innsbruck A-6020, Austria.
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Yin X, Knecht DA, Lynes MA. Metallothionein mediates leukocyte chemotaxis. BMC Immunol 2005; 6:21. [PMID: 16164753 PMCID: PMC1262721 DOI: 10.1186/1471-2172-6-21] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2005] [Accepted: 09/15/2005] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Metallothionein (MT) is a cysteine-rich, metal-binding protein that can be induced by a variety of agents. Modulation of MT levels has also been shown to alter specific immune functions. We have noticed that the MT genes map close to the chemokines Ccl17 and Cx3cl1. Cysteine motifs that characterize these chemokines are also found in the MT sequence suggesting that MT might also act as a chemotactic factor. RESULTS In the experiments reported here, we show that immune cells migrate chemotactically in the presence of a gradient of MT. This response can be specifically blocked by two different monoclonal anti-MT antibodies. Exposure of cells to MT also leads to a rapid increase in F-actin content. Incubation of Jurkat T cells with cholera toxin or pertussis toxin completely abrogates the chemotactic response to MT. Thus MT may act via G-protein coupled receptors and through the cyclic AMP signaling pathway to initiate chemotaxis. CONCLUSION These results suggest that, under inflammatory conditions, metallothionein in the extracellular environment may support the beneficial movement of leukocytes to the site of inflammation. MT may therefore represent a "danger signal"; modifying the character of the immune response when cells sense cellular stress. Elevated metallothionein produced in the context of exposure to environmental toxicants, or as a result of chronic inflammatory disease, may alter the normal chemotactic responses that regulate leukocyte trafficking. Thus, MT synthesis may represent an important factor in immunomodulation that is associated with autoimmune disease and toxicant exposure.
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Affiliation(s)
- Xiuyun Yin
- Department of Molecular and Cell Biology, 91 North Eagleville Rd., U-3125, University of Connecticut, Storrs, CT USA 06269-3125
| | - David A Knecht
- Department of Molecular and Cell Biology, 91 North Eagleville Rd., U-3125, University of Connecticut, Storrs, CT USA 06269-3125
| | - Michael A Lynes
- Department of Molecular and Cell Biology, 91 North Eagleville Rd., U-3125, University of Connecticut, Storrs, CT USA 06269-3125
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Garrett SH, Park S, Sens MA, Somji S, Singh RK, Namburi VBRK, Sens DA. Expression of metallothoinein isoform 3 is restricted at the post-transcriptional level in human bladder epithelial cells. Toxicol Sci 2005; 87:66-74. [PMID: 15958653 DOI: 10.1093/toxsci/kfi231] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
This study was designed to define the effect that overexpression of MT-3 would have on a cell culture model of bladder urothelium. Stable and inducible transfection was used to achieve overexpression of the MT-3 gene in the UROtsa cell line. When the UROtsa cells were stably transfected with the MT-3 coding sequence, there was highly elevated expression of MT-3 mRNA, but no MT-3 protein. An inducible vector showed that low basal levels of MT-3 mRNA and protein could be produced, but that induction only increased MT-3 mRNA and not protein. The clones expressing low basal levels of MT-3 protein also had reduced growth rates compared to control cells. Site directed mutagenesis was used to produce an MT-3 coding sequence where the prolines in positions 7 and 9 were converted to threonines. When this altered MT-3 was stably transfected into the UROtsa cells, the cells were able to accumulate the mutated form of the MT-3 protein. These studies show that MT-3 protein expression is inhibited by post-transcriptional control in the urothelial cell. Modifying the MT-3 protein to resemble the MT-1 isoform removes this component of post-transcriptional control and allows accumulation of the mutated MT-3 protein. The altered sequence involved in post-transcriptional control of MT-3 protein expression is the same sequence implicated in the neuronal growth inhibitory activity associated specifically with the MT-3 isoform of the MT gene family.
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Affiliation(s)
- Scott H Garrett
- Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58202, USA
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Abstract
The metallothionein family is a class of low-molecular-weight, cysteine-rich proteins with high affinity for metal ions. Four major isoforms (metallothionein-1, -2, -3, and -4) have been identified in mammals, involved in many pathophysiological processes, including metal ion homeostasis and detoxification, protection against oxidative damage, cell proliferation and apoptosis, drug and radiotherapy resistance and several aspects of the carcinogenic process. In the present review we examine the expression of metallothionein in different human tumours and its correlation with histopathological variables, tumour cell proliferation or apoptosis, resistance to radiation or chemotherapy, patient survival and prognosis. A variable profile of metallothionein and its isoforms' expression has been observed in different cancer types. Although metallothionein expression has been implicated in carcinogenic evolution, its use as a marker of tumour differentiation, cell proliferation and prognosis predictor remains unclear. Detailed studies focused on the expression of metallothionein isoforms and isotypes in different tumour types could elucidate the role of this group of proteins in the carcinogenic process, delineating its possible clinical significance for the management of patients.
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Affiliation(s)
- S E Theocharis
- Department of Tumour Biology, Institut Curie, Paris, France.
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Abstract
Melanoma incidence is rising worldwide. Early diagnosis is very important, as the most effective treatment for melanoma still consists of excision of the tumour before onset of the metastatic growth phase. Immunohistochemistry is a valuable tool for (dermato)pathologists to aid establishing diagnosis. Melanoma markers can be classified into two main categories: melanocytic differentiation markers and melanoma progression markers. Melanocytic differentiation markers are mostly used to distinguish poorly differentiated melanomas from non-melanocytic tumours and for staging of melanocytic proliferative lesions. Melanoma progression markers are most suitable to determine the level of malignancy and/or aggressiveness of tumour cells. This review describes the classification of melanoma markers, including commonly used and recently identified antigens with potential marker function. We characterize their expression profile in melanocytic proliferative lesions and their potential usefulness for diagnosis, prognosis, microstaging, immunotherapeutic purposes and evaluation of therapies.
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Affiliation(s)
- N J W de Wit
- Department of Pathology, University Medical Centre St Radboud, Nijmegen, The Netherlands.
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Abstract
Two patients with metastatic melanoma, both with the same bizarre morphology and an unusual, comparatively benign course, are described: a 50-year-old female who more than 20 years after a primary melanoma on the right upper arm, Clark level III, maximum tumor thickness of 1.1 mm, developed multiple metastases in the deep soft tissue and a 62-year-old male with an acrolentiginous melanoma, Clark level III, maximum tumor thickness of 0.55 mm, who 6 months after the excision of the primary tumor developed metastasis in regional lymph nodes. Histology of all metastases revealed extensive central necrosis and hemorrhage with a demarcating granulomatous reaction imitating angiomatoid malignant fibrous histiocytoma but no obvious melanoma tissue. Although extensive immunohistochemistry and ultrastructural examination failed to solve the quandary, careful macroscopy revealed tiny foci of remnants from melanoma in the granulation center. The female developed multiple soft tissue metastases managed by surgery, immunochemotherapy, and autologous vaccination. Both patients are well without internal manifestations 9 and 5 years, respectively, after the first metastatic episode.
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Affiliation(s)
- Bettina G Zelger
- Department of Pathology Dermatology, University of Innsbruck, Innsbruck, Austria.
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Angiomatoid Metastatic Melanoma. Dermatol Surg 2004. [DOI: 10.1097/00042728-200402002-00018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Nixon JB, Kim KS, Lamb PW, Bottone FG, Eling TE. 15-Lipoxygenase-1 has anti-tumorigenic effects in colorectal cancer. Prostaglandins Leukot Essent Fatty Acids 2004; 70:7-15. [PMID: 14643174 DOI: 10.1016/j.plefa.2003.06.001] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The localization of 15-lipoxygenase-1 (15-LO-1) in human colorectal carcinoma and normal adjacent tissue was examined using immunohistochemistry. In normal tissues, 15-LO-1 was strongly localized in the mucosal epithelium. Conversely, in tumor tissues, staining for 15-LO-1 was dispersed throughout the tissue, weak in neoplastic epithelium, and strong in stromal inflammatory cells. The addition of 50 microM 13(S)-hydroxyeicosatetraenoic acid (HODE), resulted in decreased cell proliferation after 72 h, but lower concentrations (5 or 10 microM) had no effect compared to vehicle treated Caco-2 cells. In addition, 13(S)-HODE had no effect on apoptosis or differentiation of the Caco-2 cells. Microarray analyses of RNA from Caco-2 cells treated with 5 microM 13(S)-HODE revealed changes in 17 genes. HCT-116 colorectal cells were stably transfected with 15-LO-1. In athymic nude mice, transplantable tumors derived from 15-LO-1 HCT-116 cells were smaller than tumors derived from vector HCT-116 cells. These data demonstrate that 13(S)-HODE induces changes in gene expression and has anti-tumorigenic effects.
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Affiliation(s)
- Jennifer B Nixon
- Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Research Triangle Park, NC 27709, USA
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Cui YP, Wang JB, Zhang XY, Bi MX, Guo LP, Lu SH. Using yeast two-hybrid system to identify ECRG2 associated proteins and their possible interactions with ECRG2 gene. World J Gastroenterol 2003; 9:1892-6. [PMID: 12970870 PMCID: PMC4656638 DOI: 10.3748/wjg.v9.i9.1892] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify esophageal cancer related gene2 (ECRG2) associated proteins and their possible interactions with ECRG2 gene.
METHODS: In the yeast forward two-hybrid system, ECRG2 was fused with the DNA-binding domain (DBD) of Gal4 and human fetal liver cDNA library was fused with the transcriptional activation domain (AD) of Gal4. We performed a high-stringency scale procedure to screen ECRG2 against human fetal liver cDNA library and characterized positives by sequence analysis.
RESULTS: We found the following 9 putatively associated proteins. They were metallothionein2A, metallothionein1H, metallothionein1G, ferritin, erythrocyte membrane protein band4.2, mitochondrial ribosomal protein S12, hypothetical protein FLJ10101, and a novel gene whose cDNA was found to have no strong homology to any other previously characterized gene whose DDBJ/EMBL/GenBank accession number is AF422192 mapped to human chromosome 14q31.
CONCLUSION: MT, a potential interaction partner for ECRG2, might be involved in the regulation of cell proliferation and apoptosis, and in various physiological processes. Determination of a reliability score for each single protein-protein interaction, especially interaction of ECRG2 and MT, permits the assignment of ECRG2 and unannotated proteins to biological pathways. A further understanding of the association between ECRG2 and MT should facilitate the functions of ECRG2 gene.
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Affiliation(s)
- Yong-Ping Cui
- Department of Etiology and Carcinogenesis, Tumor Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, China
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Weinlich G, Bitterlich W, Mayr V, Fritsch PO, Zelger B. Metallothionein-overexpression as a prognostic factor for progression and survival in melanoma. A prospective study on 520 patients. Br J Dermatol 2003; 149:535-41. [PMID: 14510986 DOI: 10.1046/j.1365-2133.2003.05472.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Metallothioneins (MTs) are ubiquitous proteins with high affinity for heavy metal ions, e.g. zinc, copper and cadmium. In the last decade it has been shown that MT overexpression in a variety of cancers is associated with resistance to anticancer drugs and radiotherapy, and with a poor prognosis. OBJECTIVES To examine the role of MT overexpression in melanoma patients as a prognostic factor for progression and survival. METHODS In a prospective cohort study 760 patients with primary cutaneous melanoma were investigated over 5 years (1993-98) by using a monoclonal antibody (E9) against MT on routinely fixed and paraffin-embedded tissues. In total, 520 patients were able to be followed up for progression of their disease or death due to melanoma and were included for statistical analysis (Fisher's exact test, Mantel-Haenszel chi2 test, Kaplan-Meier curves). MT data, progress-free interval and overall survival were compared univariately and multivariately with other prognostic factors, e.g. Breslow thickness, Clark level, ulceration, localization, age and gender (Cox regression analysis). RESULTS The immunohistochemical overexpression of MT in tumour cells (cut-off level > 10% of all tumour cells) in patients with primary melanoma (156 of 520; 30%) was associated with a higher risk for progression of the disease (33 of 45; 73%) and reduced survival (24 of 30; 80%) than MT-negative lesions [364 of 520 (70%), 12 of 45 (27%) and six of 30 (20%), respectively (P < 0.0001)]. Similarly, Kaplan-Meier tumour-free survival and overall survival curves for the comparison of MT-positive and MT-negative tumours gave highly significant advantages for the MT-negative group. In a univariate analysis (comparison with Breslow thickness: relative risk 2.9, 95% confidence interval, CI 1.46-5.76, P = 0.0023 for progression; relative risk 4.19, 95% CI 1.73-10.19, P = 0.0015 for survival), as well as in a multivariate analysis with other prognostic markers, MT overexpression turned out to be a highly significant and independent factor for prognosis in primary melanoma. CONCLUSIONS MT overexpression in primary melanoma is associated with an increased risk for disease progression. This marker is independent from Breslow thickness and helps to identify those thin melanomas (< 1.5 mm) that are at increased risk of progression. Moreover, the immunohistochemical staining of paraffin material is a cheap, easy and widely available technique to gain these results.
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Affiliation(s)
- G Weinlich
- Department of Dermatology, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
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Li Y, Wo JM, Cai L, Zhou Z, Rosenbaum D, Mendez C, Ray MB, Jones WF, Kang YJ. Association of metallothionein expression and lack of apoptosis with progression of carcinogenesis in Barrett's esophagus. Exp Biol Med (Maywood) 2003; 228:286-92. [PMID: 12626773 DOI: 10.1177/153537020322800307] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Barrett's esophagus is the transformation of normal esophageal squamous epithelium to specialized intestinal metaplasia (SIM). Among the Barrett's specialized cells, those that can develop protective mechanisms against apoptosis may have potential to become malignant. Studies have shown that overexpression of metallothionein (MT), low molecular protein that protects cells from apoptotic stimuli, appears to be associated with more advanced, highly malignant tumors. We thus investigated the relationship between MT expression and apoptosis in different stages of Barrett's carcinogenesis. Terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling and immunohistochemical dual-staining assay were performed in human biopsy samples of normal, SIM, dysplasia, and adenocarcinoma. Apoptotic index and MT expression were quantified by using an image system to analyze the converted digital data. A negative correlation between MT expression and apoptotic index was found. MT expression was significantly increased along with the histologic progression towards adenocarcinoma. This study thus suggests that MT may contribute to cytoprotection, thereby inhibiting apoptosis and leading to carcinogenesis of Barrett's esophageal cells.
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Affiliation(s)
- Yan Li
- Division of Gastroenterology/Hepatology, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
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Dziegiel P, Suder E, Surowiak P, Kornafel J, Zabel M. Expression of metallothionein in synovial sarcoma cells. Appl Immunohistochem Mol Morphol 2002; 10:357-62. [PMID: 12607605 DOI: 10.1097/00129039-200212000-00012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Other authors have demonstrated earlier that cells of normal synovium contain metallothionein. The protein was also detected in several other normal cell types and in tumors derived from the cells. Metallothionein content is thought to reflect proliferative activity of neoplastic cells. Therefore, it was decided to demonstrate metallothionein expression in various types of synovial sarcoma. The present study aimed to determine metallothionein cellular expression by immunocytochemical techniques in nine cases of biphasic, six cases of monophasic (spindle cell), and five cases of poorly differentiated synovial sarcoma, and to compare the expression with those of vimentin and cytokeratin 19. Metallothionein expression was demonstrated in epithelioid cells in all cases of biphasic type sarcoma and in spindle cells in all cases of monophasic type tumors. In poorly differentiated tumors, metallothionein expression was detected in four of five cases (80%). Expression of cytokeratin 19 was typical for epithelioid cells and expression of vimentin for spindle cells of synovial sarcoma. A much less pronounced expression of the proteins was observed in poorly differentiated tumors. The results indicate that metallothionein expression may prove useful in differential diagnosis and for defining prognosis in cases of synovial sarcomas.
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Affiliation(s)
- P Dziegiel
- Department of Histology and Embryology, University Medical School, Wrocław, Poland.
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Kuroda K, Aoyama N, Tamura T, Sakashita M, Maekawa S, Inoue T, Wambura C, Shirasaka D, Minami R, Maeda S, Kuroda Y, Kasuga M. Variation in MT expression in early-stage depressed-type and polypoid-type colorectal tumours. Eur J Cancer 2002; 38:1879-87. [PMID: 12204670 DOI: 10.1016/s0959-8049(02)00233-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Metallothionein (MT) expression is observed in various carcinomas, but its role is not fully understood. To clarify the clinicopathological significance of MT, 87 colorectal adenomas and 128 early-stage carcinomas were immunohistochemically analysed for MT expression. The degree of MT immunostaining of a specimen was graded according to the proportion of MT-positive cells; negative (<5%) and positive (focally 5-50%, diffusely >50%). MT expression significantly decreased with tumour development. For carcinomas, MT-positivity was significantly associated with depth of invasion (T1 60% versus T2 33%; P<0.01), vascular involvement (positive 35% versus negative 61%; P<0.01) and morphology (polypoid 62% versus depressed 26%; P<0.01). Regarding MT-positive distribution, the diffuse-positive rate in MT-positive polypoid lesions was 28%, while MT-positive depressed lesions were all diffusely stained (P<0.01). In conclusion, our results suggested that decreasing MT expression is an early event in colorectal carcinogenesis and may reflect local invasion. Furthermore, MT-positive distribution may reflect genetic differences between the polypoid and depressed-type.
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Affiliation(s)
- K Kuroda
- Department of Clinical Molecular Medicine, Division of Diabetes, Digestive and Kidney Disease, Kobe University Graduate School of Medicine, Kobe, Japan
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Abstract
AIM: To investigate the expression of metallothioneins (MTs), which were recently thought to have close relationship with tumors, in human hepatocellular carcinoma.
METHODS: Histological specimens of 35 cases of primary human hepatocellular carcinoma with para-neoplastic liver tissue and 5 cases of normal liver were stained for MTs with monoclonal mouse anti-MTs serum (E9) by the immunohistochemical ABC technique.
RESULTS: MTs were stained in the 35 cases of HCC, including 6 cases negative (17.1%), 23 weakly positive (65.7%), and 6 strongly positive (17.1%). But MTs were stained strongly positive in all the five cases of normal liver and 35 cases of para-neoplastic liver tissue. The differences of MTs expression between HCC and normal liver tissue or para-neoplastic liver tissue were highly significant (P < 0.01). The rate of MTs expression in HCC grade I was 100 percent, higher than that in grade II (81%) and grade III and IV (78%). But the differences were not significant (P > 0.05). No obvious correlations between MTs expression in HCC and tumor size, clinical stage or serum alpha fetoprotein concentration were found (P > 0.05).
CONCLUSION: Decrease of MTs expression in HCC may play a role in carcinogenesis of HCC. MTs are stained heterogenously in HCC. We can choose the anticancer agents according to the MTs concentration in HCC, which may improve the results of chemotherapy for HCC.
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Affiliation(s)
- Geng-Wen Huang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China.
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32
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Bruewer M, Schmid KW, Krieglstein CF, Senninger N, Schuermann G. Metallothionein: early marker in the carcinogenesis of ulcerative colitis-associated colorectal carcinoma. World J Surg 2002; 26:726-31. [PMID: 12053227 DOI: 10.1007/s00268-002-6266-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Metallothioneins (MTs) are zinc-binding proteins whose overexpression may lead to sequestration of zinc ions and consequently to functional inactivation of the p53 tumor suppressor gene. The aim of the study was to investigate the potential role of MTs in the carcinogenesis of ulcerative colitis (UC) as well as possible effects on p53 function. The monoclonal antibodies E9 (anti-MT), DO-7, and 1801 (anti-p53) and the polyclonal antibody CM-1 (anti-p53) were used to stain formalin-fixed, paraffin-embedded colon specimens obtained from 14 patients with UC-associated colorectal carcinoma (CAC), 13 with high-grade dysplasia (HGD), 10 with low-grade dysplasia (LGD), and 30 with UC without dysplasia or carcinoma. Statistical significance (p <0.05) was assessed using Fisher's exact test. Positive MT staining (> 20% of tumor, dysplastic, or epithelial cells) was found in most UC and LGD but in only a small percentage of HGD and CAC (p <0.01 for CAC vs. UC and LGD vs. HGD). Positive p53 immunoreactivity was observed predominantly in HGD and CAC but not in LGD and UC (p <0.01 for CAC vs. UC and HGD vs. LGD). In histologically normal tissue neighboring CAC, significant MT expression was found in six of seven specimens with simultaneous lack of p53 expression. MT overexpression may represent an important early step in the development of CAC independent of p53 expression and should be investigated in the long term as an independent cancer risk factor in UC.
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Affiliation(s)
- Matthias Bruewer
- Department of General Surgery, University of Muenster, Waldeyerstrasse 1, D-48149 Muenster, Germany.
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33
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Theocharis S, Karkantaris C, Philipides T, Agapitos E, Gika A, Margeli A, Kittas C, Koutselinis A. Expression of metallothionein in lung carcinoma: correlation with histological type and grade. Histopathology 2002; 40:143-51. [PMID: 11952858 DOI: 10.1046/j.1365-2559.2002.01325.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIMS Over-expression of cellular metallothionein occurs frequently in human tumours but the underlying mechanism remains unknown. The aim of this study was to assess metallothionein expression in cases of lung carcinoma and to correlate it with histopathological parameters. METHODS AND RESULTS Tumour tissue samples from 89 patients with lung carcinoma were immunostained by the streptavidin-biotin-peroxidase technique, using a monoclonal antibody against both metallothionein-1 and -2 isoforms. Positive matallothionein immunostaining was prominent in 44 out of 89 (49%) and negative in 45 out of 89 (51%) cases of lung carcinoma examined. Metallothionein positivity was prominent in 32 out of 43 (74%) cases of squamous cell lung carcinoma, and in 12 out of 35 (34%) cases of adenocarcinoma, while it was negative in all 11 cases of small-cell lung carcinoma examined, presenting a statistically significant difference between the different histological types. The intensity of metallothionein staining revealed a statistically significant difference between the squamous cell and adenocarcinoma cases examined. The pattern and extent of metallothionein staining in tumour cells and the expression of metallothionein in stromal cells were not correlated with histopathological parameters (type and grade) in metallothionein-positive cases of lung carcinoma examined. No association was found between metallothionein expression and lymph node status in the examined cases of lung carcinoma. CONCLUSIONS Our findings indicate that expression of metallothionein was evident in squamous cell lung carcinoma and adenocarcinoma, but absent in small-cell lung carcinoma, supporting evidence for participation of this protein in the biological mechanisms underlying the carcinogenic evolution in the lung.
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Affiliation(s)
- S Theocharis
- Department of Histology and Embryology, University of Athens, Medical School, Athens, Greece.
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34
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McCluggage WG, Strand K, Abdulkadir A. Immunohistochemical localization of metallothionein in benign and malignant epithelial ovarian tumors. Int J Gynecol Cancer 2002; 12:62-5. [PMID: 11860537 DOI: 10.1046/j.1525-1438.2002.01081.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Metallothioneins (MTs) are a group of low-molecular-weight proteins that are overexpressed in a variety of human neoplasms and are related to differentiation and prognosis in some tumor types. This study investigated immunohistochemically detectable metallothionein expression in benign and malignant ovarian surface epithelial tumors of serous, mucinous, and endometrioid types. MT expression was observed in 56% of carcinomas (n = 139) and in 2% of benign neoplasms (n = 81). Of the malignant tumors, MT expression was found in 68% of endometrioid, 56% of mucinous, and 52% of serous neoplasms. There was increased MT expression in grade 3 carcinomas (64%) as compared with grade 2 (60%) and grade 1 (23%). The overexpression of MT in malignant as opposed to benign ovarian surface epithelial tumors may suggest a role in tumorigenesis. Analogous to the situation in endometrial carcinomas, there is a tendency toward higher expression in poorly differentiated tumors. Whether high MT expression is an independent prognostic factor and increased expression indicates chemotherapy resistance in ovarian cancer, as has been previously suggested, should be determined by further studies.
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Affiliation(s)
- W Glenn McCluggage
- Department of Pathology, Royal Group of Hospitals Trust, Grosvenor Road, Belfast BT12 6BL, Northern Ireland.
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35
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Yamamura Y, Tamano M, Iguchi T, Ohta Y. Metallothionein expression and tumor growth in the transplantable pregnancy-independent mouse mammary tumor. J Vet Med Sci 2001; 63:687-9. [PMID: 11459019 DOI: 10.1292/jvms.63.687] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
In various human tumors, a metal binding protein, metallothionein (MT) is reported to play an important role in carcinogenesis. In the present preliminary study, MT expression and tumor growth were investigated in transplantable pregnancy-independent mammary tumors (TPIMT) derived from pregnancy-independent mammary tumors (PIMT) in GR/A mice, in order to study the possible role of MT in mammary carcinogenesis. TPIMT as well as PIMT showed MT expression in tumor cells in all of the successive transplantations. A negative correlation was observed between MT expression in transplanted tumor tissues and their growth in the hosts (r=-0.53, p<0.05). The present study indicates that MT is a useful marker of tumor progression in TPIMT.
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Affiliation(s)
- Y Yamamura
- The United Graduate School of Veterinary Science, Yamaguchi University, Japan
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36
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Tsironi S, Ioachim E, Machera M, Aspiotis M, Agnanti N, Psilas K. Presence and possible significance of immunohistochemically demonstrable metallothionein expression in pterygium versus pinguecula and normal conjunctiva. Eye (Lond) 2001; 15:89-96. [PMID: 11318304 DOI: 10.1038/eye.2001.20] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
PURPOSE To investigate metallothionein (MT) expression in pterygium, pinguecula and normal conjunctiva and define its possible significance in this area of the eye. In order to further elucidate the mechanism of MT expression we correlated it with lymphocyte subpopulations (T4, T8), macrophages (CD68), Langerhans' cells (S100) and the proliferation-associated indices (PCNA, Ki67). METHODS Eighty-five surgically excised pterygia, 15 pingueculae and 20 normal conjunctivae were immunohistochemically studied by the avidin-biotin (ABC) method. A monoclonal antibody (E9) against a conserved epitope of I and II isoforms of MT was used on formalin-fixed, paraffin-embedded tissues. Statistical analysis was performed using the SPSS statistical package. RESULTS Epithelial MT expression was detected in all 120 cases examined and in most of them both nuclear and cytoplasmic immunoreactivity was present. Nevertheless no statistically significant difference of MT expression was found between the three types of tissue. A statistically significant positive correlation between MT expression and lymphocyte subsets, macrophages and Langerhans' cells was found in pterygium. On the contrary, we did not find any statistical correlation in pinguecula and normal conjunctiva. In all three types of tissues MT expression was also positively correlated with the proliferation-associated indices. CONCLUSION The data suggest that there is immunohistochemically demonstrable MT expression in the epithelium of pterygium, but also of normal conjunctiva and pinguecula. MT may serve a photoprotective role in this region. In pterygium in particular, the biochemical pathway of MT synthesis seems interestingly to cross the pathways of cell proliferation, inflammation and immune activation.
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Affiliation(s)
- S Tsironi
- Department of Ophthalmology, University of Ioannina, Medical School, Greece
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37
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Sugita K, Yamamoto O, Asahi M. Immunohistochemical analysis of metallothionein expression in malignant melanoma in Japanese patients. Am J Dermatopathol 2001; 23:29-35. [PMID: 11176049 DOI: 10.1097/00000372-200102000-00005] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Recently, Zelger et al. found that metallothionein expression in melanoma is a useful prognostic indicator in white patients. In this study, we evaluated metallothionein expression in patients with melanoma as a prognostic indicator. We studied the tumors of 44 patients with cutaneous melanoma seen in our clinic from July 1988 to August 1998. Twenty-five neoplasms were metallothionein-positive, and 19 were metallothionein-negative. Only 9 (37.5%) of 24 cases of level I through III melanoma were positive for metallothionein, but 16 (80%) of 20 level IV and V cases were positive. Eight (40%) of 20 cases of "thin" melanoma (thickness: < or = 1.5 mm) were metallothionein-positive, and 17 (70.8%) of 24 cases of "thick" melanoma (thickness: > 1.5 mm) were metallothionein-positive. These results indicate a strong correlation of metallothionein expression with the level of invasion and tumor thickness in melanoma. The survival distribution function curve (Kaplan-Meier) for metallothionein expression showed a much better survival rate in the metallothionein-negative group than in the metallothionein-positive group.
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Affiliation(s)
- K Sugita
- Department of Dermatology and Occupational Dermatopathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
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38
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Nguyen A, Jing Z, Mahoney PS, Davis R, Sikka SC, Agrawal KC, Abdel-Mageed AB. In vivo gene expression profile analysis of metallothionein in renal cell carcinoma. Cancer Lett 2000; 160:133-40. [PMID: 11053642 DOI: 10.1016/s0304-3835(00)00534-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The antiapoptotic and mitogenic responses of metallothionein (MT) have been well documented in vitro. While MT protein overexpression, frequently encountered in a number of human primary tumors, has been shown to be correlated with disease progression, little information is available on the in vivo isoform expression of MT. In this study we have demonstrated the occurrence of MT proteins and further defined their differential expression profile in human primary renal cell carcinoma (RCC). Pooled normal human kidney RNA and paired biopsy specimens (tumor and control) obtained from 11 patients diagnosed with RCC with tumor grade ranging from 1-3 and a pathological staging of T2-T3 (N0M0) were used for the study. Samples were analyzed for the presence of MT protein using immunohistochemical (IHC) analysis and for MT isoform-specific mRNA expression by reverse transcriptase polymerase chain reaction. Metallothionein protein assumed both cytoplasmic and nuclear staining in cancer cells and was detected in eight of 11 samples (72%) with polyclonal antibodies. The immunoreactivity of MT protein, but not its cellular localization, in RCC specimens suggests a relationship between and advanced disease. While alterations in the basal level of expression of MT-1E, MT-1F and MT-1X genes remained unchanged, significant up-regulation of MT-2A and down-regulation of MT-1A and MT-1G transcripts was observed in RCC tissue specimens when compared with controls. Intriguingly, the paired RCC biopsy specimens had lower MT-1H transcripts than pooled normal human controls. We here provide the first report of the differential expression of MT isoforms in human RCC and that this data further support the role of MT-2A in tumorigenesis.
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Affiliation(s)
- A Nguyen
- Department of Urology, SL-42, Tulane University School of Medicine, New Orleans, LA 70112, USA
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39
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Janssen AM, van Duijn W, Oostendorp-Van De Ruit MM, Kruidenier L, Bosman CB, Griffioen G, Lamers CB, van Krieken JH, van De Velde CJ, Verspaget HW. Metallothionein in human gastrointestinal cancer. J Pathol 2000; 192:293-300. [PMID: 11054711 DOI: 10.1002/1096-9896(2000)9999:9999<::aid-path712>3.0.co;2-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Metallothionein (MT) is a small thiol-rich metalloprotein with antioxidant properties, involved in tumour pathophysiology and therapy resistance. In order to assess the contribution of MT in gastrointestinal carcinogenesis, this study examined both the MT content by radioimmunoassay and the MT localization by immunohistochemistry in pairs of neoplastic and normal-appearing human gastrointestinal tissues. In addition, the relationship between MT expression and major clinicopathological parameters was assessed. The MT concentration of gastric carcinomas and of colorectal adenomas, carcinomas, and liver metastases was found to be significantly lower than that of corresponding normal-appearing tissue. A relatively high MT content, however, was found to be associated with the villous character of colorectal adenomas and with the Dukes' stage of colorectal carcinomas, indicating a relationship between MT level and malignant potential. Immunohistochemical evaluation showed a fairly good correlation with these quantitative data. MT was found to be expressed at a low level and in a patchy pattern in the gastrointestinal neoplastic and metastatic tissues, whereas in normal-appearing gastrointestinal mucosa MT was uniformly distributed in the cytoplasm and/or nucleus of apical cells. Although in the gastric cancer patients no association was found between the MT concentration and the clinicopathological parameters, the strong MT expression in areas with intestinal metaplasia, known to have neoplastic potential, further points to a relationship between this antioxidant metalloprotein and the malignant character of cells. Gastrointestinal neoplasms are apparently accompanied by a low level and decreased expression of MT, but those with a relatively high level seem to have an increased malignant potential. Further studies will be required to determine the clinical relevance of these observations.
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Affiliation(s)
- A M Janssen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, The Netherlands
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40
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Tuccari G, Fedele F, Giuffrè G, Trombetta CJ, Barresi G. Immunohistochemical demonstration of metallothionein in eyes with choroidal melanomas. Eur J Ophthalmol 2000; 10:312-7. [PMID: 11192839 DOI: 10.1177/112067210001000407] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
PURPOSE The since immunohistochemically detectable metallothionein (MT) overexpression has been described in a variety of human tumours, including skin melanomas, in relation to different stages of tumour development and progression. MATERIALS AND METHODS We used a monoclonal antibody to investigate the distribution of MT in 18 formalin-fixed, paraffin-embedded, surgically enucleated eyes with choroidal melanomas, from 18 patients (8 male, 10 female; age range 30-83 years, mean 58.7). Clinico-pathological details and follow-up data (2-124 months, mean 36.1) were also available. MT immunoreactivity was recorded and the percentage of stained cells was graded for semiquantitative purposes. Correlations between immunohistochemical data and morphological characteristics of melanomas were investigated using non-parametric methods; survival analysis was done by the Kaplan-Meier method and the survival curves were compared by the Mantel-Cox log-rank test. RESULTS MT immunoexpression was found in 15/18 cases (83.3%) with staining scores from 1 to 3; MT staining varied in intensity and was mainly localized in the cytoplasm, although a combined nuclear/cytoplasmic reactive pattern was seen in neoplastic elements. No differences in MT immunostaining were seen in relation to age or sex, tumour size, histotype and amount of pigment; univariate analysis of survival data showed no prognostic significance regarding MT expression. CONCLUSIONS The immunohistochemical evidence of MT in neoplastic elements could be related to the production of this scavenging protein in the tumour for cell defense mechanisms against hydroxyl free radicals, and to act as a Zn donor, since Zn is required for the synthesis of DNA and DNA-repair enzymes.
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Affiliation(s)
- G Tuccari
- Department of Human Pathology, University of Messina, Italy.
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41
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Ioachim EE, Kitsiou E, Carassavoglou C, Stefanaki S, Agnantis NJ. Immunohistochemical localization of metallothionein in endometrial lesions. J Pathol 2000; 191:269-73. [PMID: 10878548 DOI: 10.1002/1096-9896(2000)9999:9999<::aid-path616>3.0.co;2-q] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Metallothioneins (MTs) are a group of ubiquitous low-molecular-weight proteins essential for the protection of cells against heavy metal ion toxicity. The immunohistochemical expression of MT was studied by immunohistochemistry using a monoclonal antibody (E9) against a conserved epitope of I and II isoforms in a series of 89 endometrial carcinomas, 34 cases of hyperplasia, and 32 samples of normal endometrium. In secretory phase endometrium, extensive MT expression was detected in most cases (92.4%). In contrast, MT immunoreactivity was confined to small foci in 22.2% of proliferative phase cases. The MT values in normal endometrium were inversely correlated with oestrogen receptor (ER) content (p<0.0001), progesterone receptor (PgR) content and with PCNA (p<0.0001) and MIB1 (p=0.001) scores. In hyperplastic lesions, MT expression was detected only in 3.3% of cases, while in the group of carcinomas it was observed in 23.1%. A statistically significant difference of MT expression was observed between carcinomas and simple hyperplasias (p=0.03). In carcinomas, MT expression was positively correlated with grade (p=0.0065), MIB1 (p=0.022), and p53 (p=0.006) expression, and inversely with PgR (p=0.03). A trend of inverse correlation between MT and ER receptor was also detected (p=0.07). These data suggest that MT expression seems to be under hormonal control in normal endometrium; that it may modify p53 expression; and that it could be used as an additional biological marker indicating aggressive behaviour in endometrial lesions.
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Affiliation(s)
- E E Ioachim
- Department of Pathology, Medical School, University of Ioannina, Greece
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42
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Abstract
Metallothioneins (MTs) are intracellular proteins that bind to metal ions and are involved in heavy metal homeostasis and detoxification. Pancreatic islets were shown to be positive for zinc-containing matrix metalloproteinase-2 and -9 by immunocytochemical staining. The immunolocalization of matrix metalloproteinases in pancreatic islets prompted us to study further the link between zinc and MT in 34 cases of pancreatic endocrine neoplasms, including insulinomas, glucagonomas, gastrinomas, pancreatic polypeptide-omas, and non-functioning endocrine neoplasms. Four types of islet cells were found to be positive for MT, whereas pancreatic endocrine neoplasms mostly were either weakly positive or negative for MT. The presence of MT in normal islet cells and pancreatic endocrine neoplasms is consistent with the notion that MTs modulate zinc homeostasis and metabolism in pancreatic islet cells and pancreatic endocrine neoplasms as those tissues contain zinc-containing matrix metalloproteinases.
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Affiliation(s)
- T Tomita
- Department of Pathology, University of Kansas Medical Center, Kansas City 66160, USA
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Jayasurya A, Bay BH, Yap WM, Tan NG. Correlation of metallothionein expression with apoptosis in nasopharyngeal carcinoma. Br J Cancer 2000; 82:1198-203. [PMID: 10735506 PMCID: PMC2363356 DOI: 10.1054/bjoc.1999.1063] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
The expression of metallothionein (MT), an intracellular ubiquitous low molecular weight protein thiol with antioxidant properties, was studied in nasopharyngeal cancer (NPC) and correlated with the apoptotic index. Immunohistochemical staining of randomly selected, formalin-fixed and paraffin-embedded normal and malignant nasopharyngeal tissues were analysed for the expression of MT using the commercially available E9 antibody directed against MT I and MT II isoforms. The corresponding apoptosis labelling indices were evaluated by the TUNEL method. Localization of MT at the ultrastructural level was studied by immunogold labelling. All the tumour sections (17 specimens) showed MT-immunopositivity. A direct correlation between the percentage of MT-positive cells and the staining intensity was noted (P < 0.001; Pearson's r = 0.95). There was absence of cytoplasmic staining and only nuclear staining (with localization in the nucleoplasm) was demonstrated in the tumour cells. In normal epithelium of the nasopharynx, the basal layer was stained. An inverse relationship was observed between the level of MT expression and the apoptotic index in the NPC tissues (P = 0.0059; Pearson's r = -0.6380). The results suggest that overexpression of MT in NPC may protect the tumour cells from entering into the apoptotic process and thereby contribute to tumour expansion. Preferential localization of MT in the nuclei of NPC cells may possibly enhance radioresistance since radiotherapy is known to eradicate tumour cells by free radical-induced apoptosis.
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Affiliation(s)
- A Jayasurya
- Department of Anatomy, Faculty of Medicine, National University of Singapore, Kent Ridge
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44
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Ioachim E, Assimakopoulos D, Peschos D, Zissi A, Skevas A, Agnantis NJ. Immunohistochemical expression of metallothionein in benign premalignant and malignant epithelium of the larynx: correlation with p53 and proliferative cell nuclear antigen. Pathol Res Pract 2000; 195:809-14. [PMID: 10631715 DOI: 10.1016/s0344-0338(99)80102-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In this study we evaluated the immunohistochemical expression of metallothionein (MT) in 44 squamous cell carcinomas, 14 cases of in situ carcinoma, 47 with epithelial dysplasia, 11 papillomas and 21 cases of keratosis. The MT expression was studied in correlation with p53 protein expression and the proliferative cell nuclear antigen (PCNA). The monoclonal antibodies E9 (anti-MT), DO-7 (which reacts with a denaturation-resistant epitope in wild-type and mutant p53) and PC10 (anti-PCNA) on formalin-fixed, paraffin-embedded tissue were used employing the immunoperoxidase (ABC) method. The immunohistochemical localization of MT has shown its rather ubiquitous presence in the cytoplasm and nucleus of both benign and malignant epithelial cells. In most cases the adjacent "normal" epithelium showed low positivity in the basal portion. The mean value of metallothionein expression was 35.73 in squamous cell carcinomas, 32.21 in in situ carcinomas, 11.86 in dysplastic epithelium, 5.10 in papillomas and 3.5 in keratosis. In carcinomas, low MT expression (< 10% of neoplastic cells) was observed in 20.5% of the cases, moderate (10%-50% of neoplastic cells) in 54.5% and extensive expression (> 50% of neoplastic cells) in 25% of the cases. We did not find any statistically significant difference of MT expression between in situ and infiltrating carcinomas, while we did observe a significant difference between carcinomas and the other groups. There was a statistically significant difference in the PCNA values in both benign and malignant lesions, while no statistically significant difference was observed in p53 protein expression in the above groups. A positive correlation between MT expression and the PCNA value (p < 0.0001) in the benign and malignant groups was detected. The PCNA value was also correlated with the p53 protein expression (p = 0.001). No correlation was found between MT and p53 protein expression. In conclusion, these results suggest that the MT expression may play a role in the development of malignant disease of the larynx, from the early phase of laryngeal carcinogenesis, independently from the p53 expression. It is also possible to contribute to tumour cell growth, as determined by the PCNA score.
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Affiliation(s)
- E Ioachim
- Pathology Department, Medical School, University of Ioannina, Greece
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45
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Ioachim EE, Goussia AC, Agnantis NJ, Machera M, Tsianos EV, Kappas AM. Prognostic evaluation of metallothionein expression in human colorectal neoplasms. J Clin Pathol 1999; 52:876-9. [PMID: 10711249 PMCID: PMC501652 DOI: 10.1136/jcp.52.12.876] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
AIM To investigate the role of metallothionein in colorectal tumours and the possible relation with other factors associated with tumour progression: expression of cathepsin D (CD), CD44, p53, Rb, bcl-2, c-erbB-2, epidermal growth factor receptor (EGFR), proliferation indices (Ki-67, proliferating cell nuclear antigen (PCNA)), and conventional clinicopathological variables. METHODS The immunohistochemical expression of metallothionein was investigated in 23 cases of colorectal adenoma and 94 adenocarcinomas. Metallothionein expression was examined by the avidinbiotin peroxidase immunoperoxidase (ABC) using the monoclonal mouse antibody E9, on formalin fixed, paraffin embedded tissue. RESULTS Positive metallothionein expression (> 5% of neoplastic cells) was observed in 30.4% of adenomas and 25.5% of adenocarcinomas, while 8.7% of adenomas and 14.9% carcinomas showed focal metallothionein positivity. In contrast, 60.9% of adenomas and 59.6% of carcinomas almost completely lacked metallothionein expression. In the series of adenocarcinomas, metallothionein expression was inversely correlated with CD44 in neoplastic cells (p = 0.01). There was no statistically significant difference of metallothionein expression, or the other variables examined, between adenocarcinomas and adenomas. CONCLUSIONS Metallothionein expression does not seem to indicate aggressive biological behaviour in colorectal adenocarcinomas, in comparison with the other types of carcinoma. The inverse correlation with CD44 could suggest that the decreased metallothionein expression may contribute to the metastatic spread of the lymph node involvement in colorectal cancer. Metallothionein expression does not seem to represent an independent prognostic marker in colorectal cancer.
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Affiliation(s)
- E E Ioachim
- Department of Pathology, University of Ioannina Medical School, Greece
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Hishikawa Y, Koji T, Dhar DK, Kinugasa S, Yamaguchi M, Nagasue N. Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus. Br J Cancer 1999; 81:712-20. [PMID: 10574261 PMCID: PMC2362883 DOI: 10.1038/sj.bjc.6690753] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The goal of this study is to clarify whether the expression of metallothionein (MT) could affect the prognosis and the metastatic potential of squamous cell carcinoma (SCC) of the oesophagus. In paraffin-embedded specimens resected from 57 patients, MT mRNA and protein expressions were detected by in situ hybridization and immunohistochemistry respectively. The expression of MT was evaluated in respect of clinicopathologic variables and patients' survival. MT mRNA expression was significantly associated with the proportion of lymph node metastasis (71% in MT mRNA-positive tumours vs 42% in MT mRNA-negative tumours; P = 0.0343) and that of distant metastasis (29% in MT mRNA-positive tumours vs 5% in MT mRNA-negative tumours; P = 0.0452). In respect of MT protein expression, the frequency of distant metastasis was more common in MT-positive tumours than in MT-negative tumours (30% in MT-positive tumours vs 8% in MT-negative tumours; P = 0.0446). The survival rate of the patients with MT protein-negative tumours was significantly better than that of the patients with MT protein-positive tumours (P = 0.0340). There was a positive correlation between the expression of MT protein and that of proliferating cell nuclear antigen (P = 0.0018). Therefore, we conclude that MT expression, both at the mRNA and protein levels, may be a potential marker predicting metastatic and proliferative activities of oesophageal SCC.
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Affiliation(s)
- Y Hishikawa
- Second Department of Surgery, Shimane Medical University, Izumo, Japan
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Goldmann T, Suter L, Ribbert D, Otto F. The expression of proteolytic enzymes at the dermal invading front of primary cutaneous melanoma predicts metastasis. Pathol Res Pract 1999; 195:171-5. [PMID: 10220797 DOI: 10.1016/s0344-0338(99)80030-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
The expression of three proteinases Cathepsin B (Cath. B), Cathepsin D (Cath. D) and Collagenase IV (Coll. IV) has been retrospectively analyzed within an immunohistochemical study on routinely fixed, paraffin embedded tissues from 147 primary cutaneous melanomas belonging to the classes pT3 and pT4. The development of these melanomas has been followed for at least five years. We compared the expression of these proteolytic enzymes in tumors that metastized during the follow-up-period with that in tumors that did not metastize. The expression at the dermal invading front of the tumors showed higher prognostic values (Cath. B chi 2 = 40.03, p < 0.001; Cath. D chi 2 = 90.95, p < 0.001; Coll. IV chi 2 = 44.46, p < 0.001) than the overall expression of these enzymes (Cath. B chi 2 = 5.63, p = 0.018; Cath. D chi 2 = 6.21, p = 0.010; Coll. IV chi 2 = 6.57, p = 0.010). The distribution of protease-expression inside the tumor turned out to be important for the prognostic value, which might also lead to higher prognostic confidence when applied to other tumors.
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Affiliation(s)
- T Goldmann
- Department of Pathology, Forschungszentrum Borstel, Germany
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Yamamura Y, Sayama K, Takeda Y, Matsuzawa A, Iguchi T, Ohta Y. Differences in metallothionein expression in transplantable mouse mammary tumor lines. Cancer Lett 1999; 138:167-74. [PMID: 10378789 DOI: 10.1016/s0304-3835(99)00002-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
In order to elucidate a possible role of metallothionein (MT) in mammary carcinogenesis, MT and sex hormone receptor (estrogen receptor, ER; progesterone receptor, PR) expressions were investigated immunohistochemically in a transplantable pregnancy-dependent mouse mammary tumor (TPDMT-4) and related autonomous tumor sublines (T4-OI96, T4-OI165 and T4-OI320CY) recovered from pregnant and virgin DDD mice. TPDMT-4 showed MT expression in tumor cells, while the expression was less evident in T4-OI165 and T4-OI96 among the autonomous tumor lines; in T4-OI320CY, the MT expression was similar to that in TPDMT-4. Chromatographic study of MT contents in the tumor lines confirmed the results of the immunohistochemical examination. PR and ER were localized in the tumor cells of TPDMT-4, but not in those of autonomous tumor sublines. In TPDMT-4, a significant correlation was observed between MT and ER expressions (r = 0.83, P < 0.01), but not between MT and PR expressions (r = 0.26, P > 0.4), also between MT expression and mitotic activity (r = -0.34, P > 0.3). Since T4-OI96 and T4-OI165 are known to be more malignant than T4-OI320CY, the present study indicates a negative correlation between the MT positivity and progression of the transplantable mammary tumor in mice.
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Affiliation(s)
- Y Yamamura
- The United Graduate School of Veterinary Science, Yamaguchi University, Japan
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McCluggage WG, Maxwell P, Hamilton PW, Jasani B. High metallothionein expression is associated with features predictive of aggressive behaviour in endometrial carcinoma. Histopathology 1999; 34:51-5. [PMID: 9934584 DOI: 10.1046/j.1365-2559.1999.00579.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
AIMS Metallothioneins (MTs) are a group of ubiquitous low molecular weight proteins with a high affinity for heavy metal ions. The aim of the present study was to investigate MT expression in a series of endometrial carcinomas. We wished to determine whether MT expression in endometrial carcinoma was related to established prognostic factors such as tumour grade, stage and histological type. We also wanted to establish if high MT expression in curettings of endometrial carcinoma was predictive of high expression in the subsequent hysterectomy specimen. METHODS AND RESULTS Sixty-three cases of endometrial carcinoma were included in the study. These comprised 57 endometrioid adenocarcinomas (15 grade 1, 25 grade 2, 17 grade 3), three papillary serous adenocarcinomas, two mucinous adenocarcinomas and one clear cell adenocarcinoma. Forty-five tumours were stage I, 10 were stage II and eight were stage III. In 28 cases, diagnostic endometrial curettings, performed prior to hysterectomy, were available for study. Immunohistochemical staining was performed using the anti-MT monoclonal antibody E9. The intensity and distribution of MT staining were assessed using a semiquantitative method. This resulted in an intensity distribution (ID) score out of a maximum of 300. The mean ID score of grade 1 and 2 endometrioid adenocarcinomas was 67 and 63, respectively, while for grade 3 tumours the mean ID score was 114. This was statistically significant (P = 0.05). The three papillary serous adenocarcinomas had high ID scores with a mean of 208. The mean ID score of stage I tumours was 69. This was lower than those of stage II and III tumours which had mean ID scores of 116 and 128, respectively. However, these differences were not statistically significant (P = 0.288). A significant correlation was observed between MT ID scores in endometrial curettings and in the subsequent hysterectomy (P = 0.013). CONCLUSIONS MT isoforms can be demonstrated in most endometrial adenocarcinomas. High MT ID scores are associated with high grade and high stage endometrial adenocarcinomas and with the aggressive papillary serous adenocarcinoma. Whether this is of value as an independent prognostic factor has yet to be established.
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Affiliation(s)
- W G McCluggage
- Department of Pathology, Royal Group of Hospitals Trust, Belfast, Northern Ireland
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Deng DX, Chakrabarti S, Waalkes MP, Cherian MG. Metallothionein and apoptosis in primary human hepatocellular carcinoma and metastatic adenocarcinoma. Histopathology 1998; 32:340-7. [PMID: 9602331 DOI: 10.1046/j.1365-2559.1998.00348.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIMS Differences in expression of metallothionein (MT) have been reported in various human tumours. MT is mainly expressed in proliferating epithelial tumour cells but in human hepatocellular carcinoma (HCC) there is only a minimal expression of MT. Since MT is a zinc binding protein and certain inducers of MT including zinc play a role in apoptosis, studies were undertaken to compare the expression of MT and the presence of apoptotic cells (APPC) in both primary HCC and metastatic adenocarcinoma. METHODS AND RESULTS Histological sections of 13 cases of primary HCC and eight cases of metastatic adenocarcinoma were obtained from archival samples. They were stained for MT using a polyclonal antibody which crossreacts readily with human MT and for APPC by the TUNEL technique. Normal human liver had consistent MT staining with no detectable APPC. The primary HCC showed moderate MT staining with a small number of APPC while metastatic adenocarcinoma showed no MT staining with a large number of APPC. CONCLUSIONS These results suggest a relationship between absence of MT and appearance of APPC in human liver tumours, especially in metastatic adenocarcinomas.
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Affiliation(s)
- D X Deng
- Department of Pathology, University of Western Ontario, London, Canada
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