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Stolzenberg-Solomon R, Jin D, Huang WY, Brockman J. Prediagnostic whole-blood cadmium and molybdenum associated with pancreatic cancer in an American cohort. Am J Epidemiol 2025; 194:1275-1284. [PMID: 38965764 DOI: 10.1093/aje/kwae165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 05/02/2024] [Accepted: 06/24/2024] [Indexed: 07/06/2024] Open
Abstract
Environmental exposures to elements such as cadmium might be contributing to the increasing incidence of pancreatic cancer. Few prospective studies have examined the association between trace elements and pancreatic ductal adenocarcinoma (PDAC). We conducted a nested case-control study in participants aged 55-74 years at baseline from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort to examine the association between 12 trace elements measured in prediagnostic whole-blood samples and PDAC. From May 1998 through December 2014, 318 incident PDAC cases were identified during follow-up to 16.7 years. Of 636 control participants, 2 who were alive when each case patient was diagnosed were selected and matched by age (±5 years), sex, calendar date of blood sample collection (2-month blocks), and race and ethnic group. We used multivariable adjusted conditional logistic regression to calculate odds ratios (ORs) and 95% CIs. Cadmium and molybdenum were associated with PDAC (highest compared with lowest quintile: for cadmium, OR = 1.81 [95% CI, 01.12-2.95], P = .03 for trend; for molybdenum, OR = 0.50 [95% CI, 0.32-0.80], P = .02 for trend). The inverse molybdenum association was only observed among ever smokers (OR = 0.31 [95% CI, 0.17-0.58]; P = .003 for trend, P = .03 for interaction) with no association in never smokers. Lead, arsenic, and other trace elements were not associated with PDAC. Our results support that an increasing prediagnostic whole-blood level of cadmium is associated with increased PDAS risk, whereas that for molybdenum reduces PDAC risk.
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Affiliation(s)
- Rachael Stolzenberg-Solomon
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, United States
| | - David Jin
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, United States
| | - Wen-Yi Huang
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, United States
| | - John Brockman
- Department of Chemistry, University of Missouri Research Reactor Center, Columbia, MO, United States
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Schilling K, Moore RET, Sullivan KV, Capper MS, Rehkämper M, Goddard K, Ion C, Coombes RC, Vesty-Edwards L, Lamb AD, Halliday AN, Larner F. Zinc stable isotopes in urine as diagnostic for cancer of secretory organs. Metallomics 2021; 13:mfab020. [PMID: 33877364 DOI: 10.1093/mtomcs/mfab020] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 03/09/2021] [Accepted: 04/16/2021] [Indexed: 12/31/2022]
Abstract
Breast, prostate, and pancreatic cancers alter the zinc (Zn) metabolism. Combined analyses of urinary Zn concentrations [Zn] and Zn stable isotope compositions (δ66Zn) may provide a non-invasive approach for tracing malignancy-induced Zn dyshomeostasis. In this study, we measured [Zn] and δ66Zn in urine from prostate (n = 22), breast (n = 16), and from women with benign breast disease (n = 14) and compared those with age-matched healthy controls (22-49 years or 50+ years) and published data for pancreatic cancer (n = 17). Our results show that cancer-induced changes are reflected in higher urinary [Zn] and lower urinary δ66Zn for pancreatic and prostate cancer and benign breast disease when compared with healthy controls. For prostate cancer, the progression of low [Zn] and high δ66Zn for patients of low-risk disease toward high [Zn] and low δ66Zn for the higher risk patients demonstrates that [Zn] and δ66Zn in urine could serve as a reliable prognostic tool. Urinary excretion of isotopically light Zn by patients with prostatic and pancreatic cancer is probably the result of increased reactive oxygen species in cancerous cells, which limits the scavenging of hydroxyl radicals and thus facilitates the oxidation of metalloproteins with sulfur-rich ligands. Urine from breast cancer patients shows undistinguishable δ66Zn to healthy controls, implying that the expression of metalloproteins with sulfur-rich ligands is stronger in breast cancer tissues. In conclusion, urinary δ66Zn may provide a non-invasive diagnostic tool for pancreatic cancer and support disease prognosis for prostate cancer. These findings should translate to comprehensive transverse and longitudinal cohort studies in future.
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Affiliation(s)
- Kathrin Schilling
- Lamont-Doherty Earth Observatory, Columbia University, Palisades, NY, USA
| | - Rebekah E T Moore
- Department of Earth Science and Engineering, Imperial College London, London, UK
| | - Kaj V Sullivan
- Department of Renewable Resources, University of Alberta, Alberta, Canada
| | - Miles S Capper
- Department of Earth Science and Engineering, Imperial College London, London, UK
| | - Mark Rehkämper
- Department of Earth Science and Engineering, Imperial College London, London, UK
| | - Kate Goddard
- Imperial College Healthcare NHS Trust, London, UK
| | | | | | - Lois Vesty-Edwards
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Alastair D Lamb
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | | | - Fiona Larner
- Department of Earth Sciences, University of Oxford, South Parks Road, Oxford, UK
- St Catherine's College, University of Oxford, Manor Road, Oxford, UK
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Zhu B, Huo R, Zhi Q, Zhan M, Chen X, Hua ZC. Increased expression of zinc transporter ZIP4, ZIP11, ZnT1, and ZnT6 predicts poor prognosis in pancreatic cancer. J Trace Elem Med Biol 2021; 65:126734. [PMID: 33631610 DOI: 10.1016/j.jtemb.2021.126734] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 02/11/2021] [Accepted: 02/15/2021] [Indexed: 01/19/2023]
Abstract
INTRODUCTION Zinc homeostasis is regulated by SLC39A/ZIP, SLC30A/ZnT, and metallothionein (MT) families in human cells. Zinc dyshomeostasis may affect or be affected by the abnormal behavior of cancer cells. Although decreased serum zinc levels are observed in patients with pancreatic adenocarcinoma (PAAD), limited information is available regarding the expression pattern and prognostic roles of zinc homeostasis-related genes in PAAD. OBJECTIVES The primary objective of this study was to explore the expression pattern and prognostic roles of zinc homeostasis-related genes in PAAD. METHODS The expression pattern of 35 known zinc homeostasis-related genes in PAAD was systemically explored based on RNA-sequencing data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) projects. The association between the expression levels of zinc homeostasis-related genes and survival of PAAD patients was evaluated using the Kaplan-Meier method and the log-rank test. Expressional correlation between zinc homeostasis-related genes with potential prognostic value in PAAD and normal pancreatic controls was evaluated using Pearson's correlation analysis. Functional enrichment analyses were performed to elucidate possible mechanisms for the potential prognostic and therapeutic roles of these zinc homeostasis-related genes in PAAD. Effects of ZIP11, ZnT1, or ZnT6 knockdown on the proliferation and the migration of Capan-1 pancreatic cancer cells were assessed by the CCK-8 assay and the wound healing assay respectively. RESULTS We demonstrated that the expression levels of ZIP1, ZIP3, ZIP4, ZIP6, ZIP7, ZIP9, ZIP10, ZIP11, ZIP13, ZnT1, ZnT5, ZnT6, ZnT7, and ZnT9 were increased, whereas the expression levels of ZIP5, ZIP14, ZnT2, MT1 G, MT1H, and MT1X were decreased in PAAD tumors compared with normal pancreatic controls. Among these differentially-expressed genes related to zinc homeostasis, higher expression of ZIP4, ZIP11, ZnT1 or ZnT6 predicted poorer prognosis with the possible involvement of several cancer-related processes and pathways in PAAD patients. We further demonstrated that knockdown of ZIP11 attenuated Capan-1 cell proliferation with decreased activation of ERK1/2 pathway; knockdown of ZnT1 attenuated Capan-1 cell proliferation with decreased activation of ERK1/2, p38 MAPK, NF-kB, and mTOR pathways; knockdown of ZnT6 attenuated Capan-1 cell proliferation with decreased activation of ERK1/2, p38 MAPK, and NF-kB pathways. CONCLUSIONS Higher expression of the zinc transporter ZIP4, ZIP11, ZnT1 or ZnT6 predicted poorer prognosis in patients with PAAD. These findings provide new clues for understanding the complex relationship between zinc homeostasis and pancreatic cancer.
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Affiliation(s)
- Bo Zhu
- School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, PR China; School of Medicine and Holistic Integrative Medicine and Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210023, PR China; School of Life Sciences, Nanjing University, Nanjing 210023, PR China.
| | - Ruwei Huo
- School of Medicine and Holistic Integrative Medicine and Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Qi Zhi
- School of Medicine and Holistic Integrative Medicine and Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Mingjie Zhan
- School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, PR China
| | - Xiao Chen
- School of Medicine and Holistic Integrative Medicine and Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210023, PR China; School of Life Sciences, Nanjing University, Nanjing 210023, PR China
| | - Zi-Chun Hua
- School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, PR China; School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Changzhou High-Tech Research Institute of Nanjing University and Jiangsu Target Pharma Laboratories Inc., Changzhou 213164, PR China.
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Merlos Rodrigo MA, Jimenez Jimemez AM, Haddad Y, Bodoor K, Adam P, Krizkova S, Heger Z, Adam V. Metallothionein isoforms as double agents - Their roles in carcinogenesis, cancer progression and chemoresistance. Drug Resist Updat 2020; 52:100691. [PMID: 32615524 DOI: 10.1016/j.drup.2020.100691] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/25/2020] [Accepted: 03/01/2020] [Indexed: 02/06/2023]
Abstract
Metallothioneins (MTs) are small cysteine-rich intracellular proteins with four major isoforms identified in mammals, designated MT-1 through MT-4. The best known biological functions of MTs are their ability to bind and sequester metal ions as well as their active role in redox homeostasis. Despite these protective roles, numerous studies have demonstrated that changes in MT expression could be associated with the process of carcinogenesis and participation in cell differentiation, proliferation, migration, and angiogenesis. Hence, MTs have the role of double agents, i.e., working with and against cancer. In view of their rich biochemical properties, it is not surprising that MTs participate in the emergence of chemoresistance in tumor cells. Many studies have demonstrated that MT overexpression is involved in the acquisition of resistance to anticancer drugs including cisplatin, anthracyclines, tyrosine kinase inhibitors and mitomycin. The evidence is gradually increasing for a cellular switch in MT functions, showing that they indeed have two faces: protector and saboteur. Initially, MTs display anti-oncogenic and protective roles; however, once the oncogenic process was launched, MTs are utilized by cancer cells for progression, survival, and contribution to chemoresistance. The duality of MTs can serve as a potential prognostic/diagnostic biomarker and can therefore pave the way towards the development of new cancer treatment strategies. Herein, we review and discuss MTs as tumor disease markers and describe their role in chemoresistance to distinct anticancer drugs.
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Affiliation(s)
- Miguel Angel Merlos Rodrigo
- Central European Institute of Technology, Brno University of Technology, Purkynova 123, CZ-612 00 Brno, Czech Republic; Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic.
| | - Ana Maria Jimenez Jimemez
- Central European Institute of Technology, Brno University of Technology, Purkynova 123, CZ-612 00 Brno, Czech Republic; Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic
| | - Yazan Haddad
- Central European Institute of Technology, Brno University of Technology, Purkynova 123, CZ-612 00 Brno, Czech Republic; Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic
| | - Khaldon Bodoor
- Department of Applied Biology, Jordan University of Science and Technology, 3030, Irbid, Jordan
| | - Pavlina Adam
- Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic
| | - Sona Krizkova
- Central European Institute of Technology, Brno University of Technology, Purkynova 123, CZ-612 00 Brno, Czech Republic; Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic
| | - Zbynek Heger
- Central European Institute of Technology, Brno University of Technology, Purkynova 123, CZ-612 00 Brno, Czech Republic; Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic
| | - Vojtech Adam
- Central European Institute of Technology, Brno University of Technology, Purkynova 123, CZ-612 00 Brno, Czech Republic; Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic.
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Schilling K, Larner F, Saad A, Roberts R, Kocher HM, Blyuss O, Halliday AN, Crnogorac-Jurcevic T. Urine metallomics signature as an indicator of pancreatic cancer. Metallomics 2020; 12:752-757. [DOI: 10.1039/d0mt00061b] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Urine metallomics as potential diagnostic tool for PDAC, one of the deadliest types of cancer.
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Affiliation(s)
- Kathrin Schilling
- Department of Earth Sciences
- University of Oxford
- UK
- Lamont-Doherty Earth Observatory
- Columbia University
| | - Fiona Larner
- Department of Earth Sciences
- University of Oxford
- UK
- St Catherine's College
- Oxford
| | - Amina Saad
- Centre for Tumour Biology
- Barts Cancer Institute
- Queen Mary University of London
- London
- UK
| | - Rhiannon Roberts
- Centre for Tumour Biology
- Barts Cancer Institute
- Queen Mary University of London
- London
- UK
| | - Hemant M. Kocher
- Centre for Tumour Biology
- Barts Cancer Institute
- Queen Mary University of London
- London
- UK
| | - Oleg Blyuss
- Wolfson's Institute for Cancer Prevention
- Queen Mary University of London
- London
- UK
- Department of Paediatrics and Paediatric Infectious Diseases
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Abstract
Metallothioneins (MTs) are small cysteine-rich proteins that play important roles in metal homeostasis and protection against heavy metal toxicity, DNA damage, and oxidative stress. In humans, MTs have four main isoforms (MT1, MT2, MT3, and MT4) that are encoded by genes located on chromosome 16q13. MT1 comprises eight known functional (sub)isoforms (MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X). Emerging evidence shows that MTs play a pivotal role in tumor formation, progression, and drug resistance. However, the expression of MTs is not universal in all human tumors and may depend on the type and differentiation status of tumors, as well as other environmental stimuli or gene mutations. More importantly, the differential expression of particular MT isoforms can be utilized for tumor diagnosis and therapy. This review summarizes the recent knowledge on the functions and mechanisms of MTs in carcinogenesis and describes the differential expression and regulation of MT isoforms in various malignant tumors. The roles of MTs in tumor growth, differentiation, angiogenesis, metastasis, microenvironment remodeling, immune escape, and drug resistance are also discussed. Finally, this review highlights the potential of MTs as biomarkers for cancer diagnosis and prognosis and introduces some current applications of targeting MT isoforms in cancer therapy. The knowledge on the MTs may provide new insights for treating cancer and bring hope for the elimination of cancer.
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Affiliation(s)
- Manfei Si
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730 China
| | - Jinghe Lang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730 China
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Cadmium Exposure as a Putative Risk Factor for the Development of Pancreatic Cancer: Three Different Lines of Evidence. BIOMED RESEARCH INTERNATIONAL 2017; 2017:1981837. [PMID: 29349066 PMCID: PMC5733953 DOI: 10.1155/2017/1981837] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 10/31/2017] [Indexed: 12/11/2022]
Abstract
Although profoundly studied, etiology of pancreatic cancer (PC) is still rather scant. Exposure to cadmium (Cd), a ubiquitous metal associated with well-established toxic and carcinogenic properties, has been hypothesized to one putative cause of PC. Hence, we analyzed recently published observational studies, meta-analyses, and experimental animal and in vitro studies with the aim of summarizing the evidence of Cd involvement in PC development and describing the possible mechanisms. Consolidation of epidemiological data on PC and exposure to Cd indicated a significant association with an elevated risk of PC among general population exposed to Cd. Cadmium exposure of laboratory animals was showed to cause PC supporting the findings suggested by human studies. The concordance with human and animal studies is buttressed by in vitro studies, although in vitro data interpretation is problematic. In most instances, only significant effects are reported, and the concentrations of Cd are excessive, which would skew interpretation. Previous reports suggest that oxidative stress, apoptotic changes, and DNA cross-linking and hypermethylation are involved in Cd-mediated carcinogenesis. Undoubtedly, a significant amount of work is still needed to achieve a better understanding of the Cd involvement in pancreatic cancer which could facilitate prevention, diagnosis, and therapy of this fatal disease.
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Dziegiel P, Pula B, Kobierzycki C, Stasiolek M, Podhorska-Okolow M. The Role of Metallothioneins in Carcinogenesis. ADVANCES IN ANATOMY EMBRYOLOGY AND CELL BIOLOGY 2016. [DOI: 10.1007/978-3-319-27472-0_4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Luckett BG, Su LJ, Rood JC, Fontham ETH. Cadmium exposure and pancreatic cancer in south Louisiana. JOURNAL OF ENVIRONMENTAL AND PUBLIC HEALTH 2012; 2012:180186. [PMID: 23319964 PMCID: PMC3540786 DOI: 10.1155/2012/180186] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Accepted: 11/04/2012] [Indexed: 01/21/2023]
Abstract
Cadmium has been hypothesized to be a pancreatic carcinogen. We test the hypothesis that cadmium exposure is a risk factor for pancreatic cancer with a population-based case-control study sampled from a population with persistently high rates of pancreatic cancer (south Louisiana). We tested potential dietary and nondietary sources of cadmium for their association with urinary cadmium concentrations which reflect long-term exposure to cadmium due to the accumulation of cadmium in the kidney cortex. Increasing urinary cadmium concentrations were significantly associated with an increasing risk of pancreatic cancer (2nd quartile OR = 3.34, 3rd = 5.58, 4th = 7.70; test for trend P ≤ 0.0001). Potential sources of cadmium exposure, as documented in the scientific literature, found to be statistically significantly associated with increased risk of pancreatic cancer included working as a plumber, pipefitter or welder (OR = 5.88) and high consumption levels of red meat (4th quartile OR = 6.18) and grains (4th quartile OR = 3.38). Current cigarette smoking, at least 80 pack years of smoking, occupational exposure to cadmium and paints, working in a shipyard, and high consumption of grains were found to be statistically significantly associated with increased concentrations of urinary cadmium. This study provides epidemiologic evidence that cadmium is a potential human pancreatic carcinogen.
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Affiliation(s)
- Brian G Luckett
- Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier Street, 3rd Floor, New Orleans, LA 70112, USA.
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Zamirska A, Matusiak Ł, Dziegiel P, Szybejko-Machaj G, Szepietowski JC. Expression of metallothioneins in cutaneous squamous cell carcinoma and actinic keratosis. Pathol Oncol Res 2012; 18:849-55. [PMID: 22407324 PMCID: PMC3448047 DOI: 10.1007/s12253-012-9513-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 02/28/2012] [Indexed: 12/13/2022]
Abstract
Metallothioneins (MT) are low-molecular weight proteins implicated in heavy metal detoxification, zinc and cooper homeostasis and cell protection against free radicals. In variety of cancers MT-overexpression was shown, but there are just a few studies on the role of MT in skin carcinogenesis. Current study was undertaken to evaluate MT and Ki-67 expression in pre-cancerous skin lesions as well as in fully developed skin cancers. 73 squamous cell carcinomas (SCC), 23 actinic keratoses (AK) and 20 normal skin samples were included in the study. In obtained paraffin sections immunohistochemical reactions were performed. MT-expression in SCC (mean 2.89 ± 1.83) was significantly higher than in AK (mean 1.69 ± 1.26)(p = 0.006) and higher than in normal skin (mean 2 ± 0.79) (p = 0.0075). The MT-expression positively correlated with Ki-67 expression (R = 0.28; p = 0.017) in SCC and in AK (R = 0.49; p = 0.018). Various clinico-pathological variables, e.g. morphology, size of lesions and the depth of neoplastic infiltration were not associated to MT-expression in both SCC and AK. The grade of histological differentiation of SCC correlated positively with Ki-67 antigen (p < 0.001) and did not correlate with MT-expression (p = 0.06). Ki-67 expression was higher in SCC and in AK than in healthy skin (p = 0,003). In SCC and in AK expression of Ki-67 antigen correlated positively with MT-expression (respectively p = 0.017 and p = 0.018). MT may serve as a good markers of proliferation in SCC and AK. MT-overexpression in SCC may suggest a potential role of MT in skin carcinogenesis.
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Affiliation(s)
- Aleksandra Zamirska
- Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Chałubińskiego 1, 50-368 Wrocław, Poland
| | - Łukasz Matusiak
- Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Chałubińskiego 1, 50-368 Wrocław, Poland
| | - Piotr Dziegiel
- Department of Histology and Embryology, Wroclaw Medical University, Wroclaw, Poland
- Department of Histology and Embryology, Poznan Medical University, Poznan, Poland
| | - Grażyna Szybejko-Machaj
- Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Chałubińskiego 1, 50-368 Wrocław, Poland
| | - Jacek C. Szepietowski
- Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Chałubińskiego 1, 50-368 Wrocław, Poland
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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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Pedersen MØ, Larsen A, Stoltenberg M, Penkowa M. The role of metallothionein in oncogenesis and cancer prognosis. ACTA ACUST UNITED AC 2008; 44:29-64. [PMID: 19348910 DOI: 10.1016/j.proghi.2008.10.001] [Citation(s) in RCA: 140] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2008] [Accepted: 10/02/2008] [Indexed: 12/12/2022]
Abstract
The antiapoptotic, antioxidant, proliferative, and angiogenic effects of metallothionein (MT)-I+II has resulted in increased focus on their role in oncogenesis, tumor progression, therapy response, and patient prognosis. Studies have reported increased expression of MT-I+II mRNA and protein in various human cancers; such as breast, kidney, lung, nasopharynx, ovary, prostate, salivary gland, testes, urinary bladder, cervical, endometrial, skin carcinoma, melanoma, acute lymphoblastic leukemia (ALL), and pancreatic cancers, where MT-I+II expression is sometimes correlated to higher tumor grade/stage, chemotherapy/radiation resistance, and poor prognosis. However, MT-I+II are downregulated in other types of tumors (e.g. hepatocellular, gastric, colorectal, central nervous system (CNS), and thyroid cancers) where MT-I+II is either inversely correlated or unrelated to mortality. Large discrepancies exist between different tumor types, and no distinct and reliable association exists between MT-I+II expression in tumor tissues and prognosis and therapy resistance. Furthermore, a parallel has been drawn between MT-I+II expression as a potential marker for prognosis, and MT-I+II's role as oncogenic factors, without any direct evidence supporting such a parallel. This review aims at discussing the role of MT-I+II both as a prognostic marker for survival and therapy response, as well as for the hypothesized role of MT-I+II as causal oncogenes.
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Affiliation(s)
- Mie Ø Pedersen
- Section of Neuroprotection, Department of Neuroscience and Pharmacology, Faculty of Health Sciences, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
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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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Hinkel A, Schmidtchen S, Palisaar RJ, Noldus J, Pannek J. Identification of bladder cancer patients at risk for recurrence or progression: an immunohistochemical study based on the expression of metallothionein. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2008; 71:954-959. [PMID: 18569601 DOI: 10.1080/15287390801989101] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Despite similarities in tumor stage and grade the individual outcome of bladder cancer patients is not predictable. The ideal tool for treatment stratification has not yet been found. Metallothionein (MT) overexpression is correlated with poor tumor differentiation, resistance to chemotherapy, and impaired survival in different malignancies. The clinical relevance of MT expression for defining patients at high risk for recurrence or progression was assessed. MT was detected immunohistochemically and evaluated semiquantitively in tumor specimens of 103 male and 19 female patients (transsurethral resection: n = 94, cystectomy: n = 28). Mean age of the patients was 68 (38-87) yr. According to histopathological features, three groups were distinguished for further analysis (pTa-1G1-2, pTis/pT1G3, and muscle invasive tumors). A cutoff value of 50% immunoreactive cells was used for further analysis. The 5-yr tumor specific survival rate was significantly lower in patients with high MT expression (32 vs. 72%). Accordingly, impaired 5-yr recurrence (90 vs. 58%), and progression rates (78 vs. 54%) were associated with high MT expression. All patients suffering from pTis and pT1G3 tumors with MT expression above the cutoff value showed recurrence within less than 40 mo, whereas 26% of those patients with MT expression below the cutoff value remained long-term recurrence free. Long term progression free survival was detected in 75% of pT1G3 patients with MT expression below the cutoff value. In contrast, 68% of pT1G3 tumor patients with MT expression above the cutoff value progressed, all within the first 12 mo after initial tumor resection. A correlation between high MT expression and prognosis was demonstrated especially in pT1G3 and pTis tumors, where >50% MT expression was linked to shorter tumor-specific survival and increased recurrence/progression rates. Thus, MT expression seems to be a promising marker for further risk stratification in the clinical treatment of bladder cancer patients.
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Affiliation(s)
- Andreas Hinkel
- Department of Urology and Neurourology, Ruhr-Universitat Bochum, Marienhospital Herne, Germany
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15
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Ostrakhovitch EA, Olsson PE, von Hofsten J, Cherian MG. P53 mediated regulation of metallothionein transcription in breast cancer cells. J Cell Biochem 2007; 102:1571-83. [PMID: 17477370 DOI: 10.1002/jcb.21381] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Recent studies have shown that only breast cancer epithelial cells with intact p53 can induce metallothionein (MT) synthesis after exposure to metals. In this study, the potential role of p53 on regulation of MT was investigated. Results demonstrate that zinc and copper increased metal response elements (MREs) activity and MTF-1 expression in p53 positive MN1 and parental MCF7 cells. However, inactivation of p53 by treatment with pifithrin-alpha or the presence of inactive p53 inhibited MRE-dependent reporter gene expression in response to metals. MTF-1 levels remained unchanged after treatment with zinc in cells with nonfunctional p53. The introduction of wild-type p53 in MDD2 cells, containing nonfunctional p53, enhanced the ability of zinc to increase MRE-dependent reporter gene expression. The cellular level of p21Cip1/WAF1 was increased in MDD2 cells after p53 transfection, confirming the presence of active p53. The treatment of MN1 and parental MCF7 with trichostatin A led to a sixfold increase in the MRE activity in response to zinc. On the contrary, MRE activity remained unaltered in MDD2 cells with inactive p53. The above results demonstrate that activation of p53 is an important factor in metal regulation of MT.
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Affiliation(s)
- Elena A Ostrakhovitch
- Department of Pathology, University of Western Ontario, London, Ontario N6A 5C1, Canada.
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16
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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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18
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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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20
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Yamasaki Y, Smith C, Weisz D, van Huizen I, Xuan J, Moussa M, Stitt L, Hideki S, Cherian MG, Izawa JI. Metallothionein expression as prognostic factor for transitional cell carcinoma of bladder. Urology 2006; 67:530-5. [PMID: 16504266 DOI: 10.1016/j.urology.2005.09.033] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2005] [Revised: 08/28/2005] [Accepted: 09/23/2005] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To determine whether metallothionein (MT) protein expression is associated with clinical outcomes in patients with transitional cell carcinoma (TCC) of the bladder. METHODS Archival pathologic radical cystectomy and transurethrally resected specimens and medical charts were reviewed for 123 patients with TCC. Patients were divided into groups based on the TNM stage, tumor grade, and MT protein expression in the primary tumor. Survival and disease progression were correlated with MT expression. RESULTS The mean patient age was 66 years (range 41 to 92). Of the 123 tumors, 21, 13, 18, 24, 17, and 30 were pathologically staged as pTa, pT1, pT2, pT3, pT4, and pTis, respectively; 28, 15, 14, and 66 tumors had a histologic grade of X, 1, 2, and 3, respectively. On univariate analysis, TNM stage and tumor grade predicted survival and progression outcomes. MT expression was detected in 69 (56.9%) of 123 bladder cancer specimens. Greater MT protein expression was associated with worse overall survival, disease-specific survival, disease-free survival, and disease-free progression (P = 0.0004, P = 0.05, P = 0.0008, and P = 0.0005, respectively). CONCLUSIONS MT protein expression in the primary tumor of TCC specimens appeared to be associated with overall survival, disease-specific survival, disease-free survival, and disease-free progression. This finding requires additional validation using other data sets.
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Affiliation(s)
- Yasuto Yamasaki
- Division of Urology, Department of Surgery, University of Western Ontario, London, Ontario, Canada
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21
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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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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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Mitsuhashi M, Wanibuchi H, Morimura K, Doi K, Wei M, Wada S, Nakatani T, Fukushima S. Significance of overexpression of metallothionein in mouse urinary bladder focal lesions induced by treatment with N-butyl-N-(4-hydroxybutyl)-nitrosamine. Cancer Sci 2003; 94:1052-8. [PMID: 14662020 PMCID: PMC11160210 DOI: 10.1111/j.1349-7006.2003.tb01400.x] [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: 01/19/2023] Open
Abstract
Metallothionein (MT) is expressed in various types of human tumors, including transitional cell carcinomas of the urinary bladder, but its biological significance remains unclear. In the present study, the role of MT in urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) treatment was investigated using C57BL/6 mice. One hundred 5-week-old male C57BL/6 mice were divided into two groups, which were given drinking water with or without 0.05% BBN throughout the experimental period. Subgroups of ten animals from each group were sacrificed at weeks 5, 10, 15, 20 and 25, and urinary bladder samples were examined immunohistochemically for MT, proliferating cell nuclear antigen (PCNA) and apoptosis. MT was found to be abundant in normal-looking mucosa, but decreased with progression from precancerous lesions to invasive carcinoma in the urinary bladder obtained from BBN-treated mice. Lesions could be divided into MT-positive and negative. There was a tendency for greater MT expression in PCNA-positive lesions, while apoptosis was rather associated with MT-negativity. These data suggest that the overexpression of MT may play a role in mouse urinary bladder carcinogenesis.
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Affiliation(s)
- Makoto Mitsuhashi
- Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585
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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; 228:286-292. [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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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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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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29
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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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30
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Jin R, Bay BH, Chow VT, Tan PH. Metallothionein 1F mRNA expression correlates with histological grade in breast carcinoma. Breast Cancer Res Treat 2001; 66:265-72. [PMID: 11510698 DOI: 10.1023/a:1010658907462] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Immunohistochemical expression of metallothioneins (MTs), a group of intracellular metal-binding proteins, is well documented in breast cancer. However, there is a paucity of information on the expression of the different MT isoforms in breast cancer tissues. The dichotomous association of MT overexpression with tumour types and progression led us to examine the role of the MT-1F mRNA isoform in breast cancer. We evaluated MT expression in 48 primary invasive ductal breast cancer tissues by immunohistochemistry, and the corresponding MT-1F mRNA expression via a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay. The specificity of the RT-PCR products was confirmed by direct cycle sequencing and restriction enzyme digestion. Immunohistochemical analysis of MT revealed a significantly higher MT expression in histological grade 3 tumours as compared to grade 1 and 2 tumours (p = 0.021). Similarly, MT-1F mRNA expression was found to be significantly higher in grade 3 tumours (p < 0.001). The results suggest that the MT-1F isoform influences histological differentiation in invasive ductal breast cancer. The converse is also true in that the histological grade may determine the level of MT-1F expression in breast cancer.
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Affiliation(s)
- R Jin
- Department of Anatomy, Faculty of Medicine, National University of Singapore
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31
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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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32
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Bay BH, Jin R, Jayasurya A. Analysis of Metallothionein Expression in Human Cancers. Acta Histochem Cytochem 2001. [DOI: 10.1267/ahc.34.171] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Affiliation(s)
- Boon-Huat Bay
- Department of Anatomy, National University of Singapore
| | - Rongxian Jin
- Department of Anatomy, National University of Singapore
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33
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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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34
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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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35
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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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36
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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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37
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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: 44] [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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Stenram U, Ohlsson B, Tranberg KG. Immunohistochemical expression of metallothionein in resected hepatic primary tumors and colorectal carcinoma metastases. APMIS 1999; 107:420-4. [PMID: 10230697 DOI: 10.1111/j.1699-0463.1999.tb01575.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Metallothionein is a protein with affinity for metals and is present in several tumors. We examined its immunohistochemical expression in 37 resected primary liver tumors and 117 colorectal metastases. The reaction was intense in the two fibrolamellar hepatocellular carcinomas and in many of the hepatocytes of the pseudotumor case of focal nodular hyperplasia. The reaction was low or moderate in 5 of 17 ordinary hepatocellular carcinomas and in 4 of 14 cholangiocellular carcinomas. There was no reaction in one case each of spindle cell hepatocellular carcinoma, oncocytic adenoma and hemangioendothelial sarcoma. In the metastases, the reaction was low or moderate in 14 cases and negative in 103. Surrounding hepatocytes and stromal cells were more or less positive in all cases.
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Affiliation(s)
- U Stenram
- Department of Pathology, Lund University, Sweden
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40
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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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41
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Hiura T, Khalid H, Yamashita H, Tokunaga Y, Yasunaga A, Shibata S. Immunohistochemical analysis of metallothionein in astrocytic tumors in relation to tumor grade, proliferative potential, and survival. Cancer 1998. [DOI: 10.1002/(sici)1097-0142(19981201)83:11<2361::aid-cncr16>3.0.co;2-n] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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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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