MUC1 IN THE DIAGNOSIS AND PATHOGENESIS OF MALIGNANT MESOTHELIOMA

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1 MUC1 IN THE DIAGNOSIS AND PATHOGENESIS OF MALIGNANT MESOTHELIOMA Alina Miranda BSc (Hons) This thesis is presented for the degree of Doctor of Philosophy At The University of Western Australia School Of Medicine and Pharmacology 2011

2 SUMMARY Malignant mesothelioma is a highly aggressive tumour arising from the serosal surfaces of the pleural, peritoneal and occasionally pericardial cavities. Despite the universal ban of asbestos use in mining and in many industries, the incidence of mesothelioma is expected to increase in Australia until 2020, mainly because of the long latency period between initial asbestos exposure to development of disease, making it an extremely important health issue for our society. The new wave of asbestos related disease is now seen from individuals in the construction industries and the everyday home handy man. The diagnosis of mesothelioma is an extremely difficult process and is usually made in conjunction with clinical, radiological and pathological findings. It is therefore understandable that the interest to identify a technique to aid in the early diagnosis of mesothelioma is extensive. Several biomarkers and combinations of biomarkers have been evaluated to aid in the non-invasive diagnosis of malignant mesothelioma. Pleural effusion is one of the earliest signs and symptoms that patients present with, however, despite recurrent pleural effusions and serial chest x-rays including computed tomography (CT) scans, it is not unusual that a definite diagnosis is not possible until tumour burden increases where it is more visible on radiology while the patient s symptoms become more debilitating and the overall prognosis becomes worse. One of the main diagnostic difficulties is the ability to differentiate between benign reactive mesothelial proliferation and mesothelioma. Currently, the gold standard for a diagnosis of mesothelioma requires a histological biopsy specimen with invasion being the only reliable marker between benign reactive mesothelial proliferation and malignant Page i

3 mesothelioma. Unlike epithelial adenocarcinomas, there are no sensitive and specific tumour markers available to detect mesothelioma. Although pleural effusion is readily drained and easily collected for cytological investigation, the cytological diagnosis of mesothelioma is highly controversial and unacceptable at an international level. However, some centres have been successfully diagnosing mesothelioma on cytological effusion samples for more than 30 yrs and one of the main reasons for this success is the use of the anti-muc1 antibody epithelial membrane antigen (EMA). The anti-muc1 EMA antibody has been used extensively as a differential marker between reactive mesothelial cells and mesothelioma; however, internationally there has been less confidence in its ability to equivocally differentiate between these two processes, mainly due to inconsistent results. This is the first study designed on a prospective patient cohort with reviewers blinded to clinical, surgical, radiological and previous pathology results to examine the performance of EMA as a diagnostic marker in the cytological diagnosis of mesothelioma. The results demonstrate the sensitivity and specificity of five anti-muc1 EMA antibodies highlighting that the EMA E29 clone has the highest sensitivity and specificity for a final diagnosis of mesothelioma. Several previous studies have implicated that MUC1 plays a vital role in the pathogenesis of epithelial malignancies including breast, lung, prostate and pancreatic tumours however this is the first time that MUC1 has shown a functional role in cell migration, invasion and tumorigenesis of mesothelioma. Understanding these molecular differences seen in the malignant phenotype enables us to understand the pathway to tumour progression and ultimately it enables us to design specific immunotherapies targeted towards treating aggressive tumours such as mesothelioma. Page ii

4 ACKNOWLEDGEMENTS Whatever possessed me to do this at my age I will never know, but it was certainly one of the most challenging experiences that I have had to face to date. I would sincerely like to thank my two principal supervisors Professor Jenette Creaney and Professor Anna Nowak for their continuous support, encouragement and understanding. I know it must be hard to teach an old dog new tricks and I thank you both for your patience, encouragement and persistence especially towards the end. To the PathWest research committee, thank you for providing me with the opportunity to reach this goal. I sincerely thank all the staff within the Histology and Cytology departments, especially Mike Platten, Chris, Felicia, Fran, Tara, John, Hendrica and Matt, for all your help in preparing and collecting the material. A special thank you goes to Dr Sterrett and Dr Segal for the valuable hours that they have contributed and to Dr DeBoer, Dr Amanuel, Dr Frost, Dr Kumarasinghe and Dr Williams for all their continuous encouragement and support. A special thank you goes to Deborah Yeoman who guided me through the early days, thanks for keeping me driven and focused. Thanks to all the staff from the Biomarker and Discovery area, Ian, Hanne, Justine, Sarah, David and Crystal. Thanks to all other TIG staff who kept me entertained on a daily basis in the labs, Bruce, Richard, Cleo, Amanda, Ali, Dozi, Amy, Joanne, Sam, Ann, Karen and Kelly. Sincere thanks go to Scott for your molecular assistance and to Mel for her continued support and encouragement while trying to put this thesis together. Thanks to the LIWA staff for their assistance, AiLing, Baharah, Sally, Hui Ling, Cecilia and Steve. I would like to thank Lisa and Marie for their help and support while I was working with them at SJOG research. To my family and friends, in particular, Cath who initially encouraged me to take this challenge, David, Alice, Shane and Sandy, thanks guys for being there continually for my kids and for me. To all the mums and teachers from Kindy to Year 3 at JTC primary thanks for keeping me informed with all the kids activities, excursions, school drop offs and school pickups. Sincere thanks goes to Linda for being there for me during my most difficult moments. Finally, to my beloved family and especially to my dedicated husband Sunil, thank you for your unconditional love, continued support and encouragement. To my three beautiful children, Aimee, Shaila and Kanan, I know it has been a rough ride for all of us but I hope that somehow I can repay those lost days? I love and thank you all for helping me to survive this journey and for your continued love, hugs and kisses that kept me sane through this extremely difficult process. Page iii

5 DECLARATION All experiments presented in this thesis were performed by the PhD candidate, except as stated below. This thesis has not been previously accepted for any other degree at this, or any other institution, and contains fewer than 100, 000 words. Mrs Hanne Dare, performed the CA15-3 assays required for Chapter 4, results. Ms Sarah Wong performed most of the FACS experiments of cell lines described in Chapter 5. Signature:. Date:... Page iv

6 TABLE OF CONTENTS Summary i Acknowledgments...iii Declaration...iv Table of Contents..v List of Figures...xi List of Tables...xiv List of Abbreviations..xvi CHAPTER 1: 1 LITERATURE REVIEW MALIGNANT MESOTHELIOMA Asbestos History of Asbestos use in Australia Other aetiological agents Simian Virus 40 (SV-40) Radiation Erionite Genetic Predisposition Clinical presentation of mesothelioma Establishing a diagnosis of malignant mesothelioma Histological assessment of malignant mesothelioma Cytological diagnosis of malignant mesothelioma Histochemistry analysis of malignant mesothelioma Immunohistochemistry of malignant mesothelioma Ultrastructural analysis of malignant mesothelioma Therapeutic options for mesothelioma Surgery Chemotherapy 21 Page v

7 Radiotherapy Multimodality approach to treatment MUC Structure of MUC Gene structure of MUC Protein structure of MUC Alternatively spliced variants of MUC Soluble MUC Function of MUC MUC1 in protection of cells and as an adhesion molecule MUC1 in reproduction MUC1 mediated immunoregulatory mechanisms The role of MUC1 in signal transduction MUC1 antibodies MUC1 EXPRESSION IN MALIGNANCY MUC1 protein expression in malignancy CA15-3 levels in malignancy MUC1 mrna expression in malignancy MUC1 cytoplasmic tail in malignancy MUC1 as an adhesion molecule in malignancy MUC1 resistance to apoptosis Why is MUC1 disregulated in cancer? THESIS OVERVIEW 44 CHAPTER 2 47 MATERIALS AND METHODS TISSUE CULTURE 48 Page vi

8 2.1.1 Maintenance of cell lines Splitting cells Viable cell counting Freezing cells Cell blocks from cell lines PATIENT SAMPLES Cell block microarray (CBMA) Immunohistochemistry staining of CBMA Manual immunohistochemistry staining of CBMA Automated immunohistochemistry staining of CBMA ANALYSIS OF CBMA Immunohistochemical scoring of CBMA Statistical Analysis of CBMA Immunohistochemical Staining CA15-3 ASSAY MESOTHELIN ASSAY HOMOGENISATION OF CELL LINES IN ULTRASPEC RNA ISOLATION REAGENT RNA EXTRACTION AND REVERSE TRANSCRIPTION QUANTITATIVE POLYMERASE CHAIN REACTION (PCR) IMMUNOHISTOCHEMISTRY STAINING OF CELL LINES SOFT AGAR ASSAY CyQUANT CELL PROLIFERATION ASSAY WST-1 CELL PROLIFERATION ASSAY TRANSWELL MIGRATION ASSAY 63 Page vii

9 2.14 WOUND HEALING ASSAY FLOW CYTOMETRY SH-RNA MUC1 STABLE CELL LINE TRANSFECTION Transformation of plasmids in competent cells Quick plasmid mini preparation Restriction digest of plasmid Amplification and maxipreparation of purified plasmid Selection for antibiotic resistance Plasmid DNA transfection GENERAL STATISTICAL ANALYSIS 69 CHAPTER 3 70 SENSITIVITY AND SPECIFICITY OF MUC1 IN THE CYTOLOGICAL DIAGNOSIS OF EPITHELIAL MALIGNANACY AND MALIGNANT MESOTHELIOMA INTRODUCTION RESULTS Description of patient cohort Description of sample scoring Dichotomisation of samples based upon epithelial cellularity Categorisation of samples based on cellular morphology Scoring of immunoperoxidase staining Immunoreactivity of anti-muc1 monoclonal antibodies Anti-MUC1 antibody EMA (E29) on interim diagnosis Anti-MUC1 antibody (Mc5) on interim diagnosis Anti-MUC1 antibody (VU4H5) on interim diagnosis 89 Page viii

10 Anti-MUC1 antibody (SM3) on interim diagnosis Anti-MUC1 antibody (BC2) on interim diagnosis Summary of Anti-MUC1 antibody staining related to interim diagnosis Summary of Anti-MUC1 antibody staining related to Final Diagnosis Sensitivity and Specificity of anti-muc1 monoclonal antibodies determined on a subset of 35 mesothelioma patients Comparison of the sensitivity of MUC1 for mesothelioma diagnosis Diagnosing mesothelioma without the anti-muc1 antibody EMA (E29) DISCUSSION CHAPTER SUMMARY 120 CHAPTER SENSITIVITY AND SPECIFICITY OF SOLUBLE MUC1 CONCENTRATIONS IN SUPERNATANT SAMPLES OF PLEURAL MALIGNANCIES INTRODUCTION RESULTS Patient characteristics Sensitivity and Specificity of CA15-3 in effusion supernatant samples Concordance of MUC1 cell surface expression and effusion CA15-3 levels Sensitivity and specificity of mesothelin in effusion supernatant samples Correlation of CA15-3 and mesothelin levels in effusions Comparing and combining the performance of CA15-3 and mesothelin Relationship between the CA15-3 levels in effusions with survival in patients with mesothelioma DISCUSSION CHAPTER SUMMARY 147 Page ix

11 CHAPTER EFFECT OF MUC1 ON MALIGNANT MESOTHELIOMA CELL FUNCTION AND CHARACTERISTICS INTRODUCTION RESULTS Characterising MUC1 in mesothelioma cell lines mrna levels of MUC1 in mesothelioma cell lines Protein expression of MUC1 on mesothelioma cell lines using immunohistochemistry Protein expression of MUC1 on normal mesothelial cell lines using immunohistochemistry ShRNA MUC1 knockdown in mesothelioma cell lines MUC1 mrna expression in mesothelioma cell lines following shrna MUC1 knockdown Cell surface expression of MUC1 in mesothelioma cell lines following shrna MUC1 knockdown using flow cytometry Protein expression of MUC1 in mesothelioma cell lines following shrna MUC1 knockdown using chamber slide immunohistochemistry Effect of reduced MUC1 expression on in vitro mesothelioma cell proliferation Effect of reduced MUC1 expression level on in vitro mesothelioma cell migration Invitro scratch assays on mesothelioma and shrna MUC1 knockdown cell lines Cell migration assays on mesothelioma and shrna MUC1 knockdown cell lines Effect of reduced MUC1 expression on in vitro mesothelioma tumourigenic potential Cell migration assays on parental and shrna MUC1 knockdown cell lines DISCUSSION CHAPTER SUMMARY 187 CHAPTER Page x

12 FINAL DISCUSSION GENERAL DISCUSSION CONCLUSIONS 196 BIBLIOGRAPHY 198 APPENDIX 220 Page xi

13 LIST OF FIGURES Figure Page 1.1 Histological sections of mesothelioma stained with H and E Cytological smears of mesothelioma stained with Papanicolaou stain Schematic representation of MUC Tissue morphology divided into low and high cellularity A H and E section of a case diagnosed as malignant B H and E section of a case diagnosed as malignant possibly adenocarcinoma C H and E section of a case diagnosed as benign D H and E section of a case diagnosed as atypical/equivocal Optimisation of cell block microarray Comparison between anti-muc1 antibodies Cell block microarray stained with the manual E29 antibody Cell block microarray stained with the Mc5 antibody Cell block microarray stained with the VU4H5 antibody Cell block microarray stained with the SM3 antibody Cell block microarray stained with the BC2 antibody Characteristics of patient cohort determined from interim pathology diagnosis Hypothetical analysis of the patient cohort in the absence of the EMA (E29) antibody Hypothetical analysis of the patient cohort in the presence of the EMA (E29) antibody Page xii

14 Figure Page 3.12A Hypothetical analysis of the patient cohort in the presence of the EMA (E29) antibody distinguishing between mesothelioma and other malignancy B Hypothetical analysis of the patient cohort in the presence of the EMA (E29) antibody distinguishing equivocal cell morphology CA15-3 concentrations determined in effusions from individual patients ROC analysis to determine the ability of CA15-3 to distinguish between mesothelioma, benign and malignant cases Mesothelin concentrations determined in effusions from individual patients ROC analysis to determine the ability of Mesothelin to distinguish between mesothelioma, benign and all malignant cases Spearman correlation of CA15-3 and mesothelin values in effusion samples from patients with mesothelioma ROC analysis for all epithelial malignancies ROC analysis for differentiating mesothelioma from all other samples Relationship between CA15-3 levels in effusions and survival of patients with mesothelioma Innate levels of MUC1 expression on cell lines Normal mesothelial cells stained with anti-muc1 antibodies mrna confirmation of shrna MUC1 knockdown in stably transfected cell line FACS cell surface expression of anti-muc1 E29 antibody on the VGE62 shrna cell line Comparison of FACS cell surface expression on five mesothelioma cell lines Innate levels of MUC1 expression of shrna MUC1 cell line VGE

15 Figure Page 5.7 Cell proliferation of shrna MUC1 in VGE62 cell line Cell proliferation of shrna MUC1 cell lines and parental control Wound scratch assay of VGE62 shrna MUC1 transfectants and parental control Wound scratch assay of all shrna MUC1 transfectants and parental control Transwell migration of all shrna MUC1 transfectants and parental control cell lines Anchorage independent growth of STY51 and normal mesothelial cells Anchorage independent growth shrna MUC1 transfectant and parental cell lines Matrigel cell invasion of shrna MUC1 cell lines and parental cell lines Diagnostic algorithm for the proposed utility of MUC1 immunocytochemistry and CA15-3 in the differential diagnosis of reactive mesothelial cells, malignant mesothelioma and epithelial malignancy...193

16 LIST OF TABLES Table Page 1.1 Summary of markers used in the differential diagnosis of mesothelioma and adenocarcinoma Summary of the major differences between the MUC1 variants Panel of antibodies used for diagnosis of cell block microarray Patient characteristics grouped by Interim pathology diagnosis Characteristics of samples categorized as benign Summary of immunohistochemical staining of 266 patients A A summary of the anti-muc1 antibody staining on control tissue sections Correlation of immunoperoxidase scoring of all cases using EMA clone (E29) Correlation of immunoperoxidase scoring of all mesothelioma cases using EMA clone (E29) Correlation of immunoperoxidase scoring of epithelial malignancies using EMA clone (E29) Summary of sensitivity and specificity of anti-muc1 antibodies for an interim diagnosis of epithelioid malignancy Summary of sensitivity and specificity of anti-muc1 antibodies for an interim diagnosis of mesothelioma Summary of the sensitivity and specificity of anti-muc1 antibodies for a final diagnosis of epithelioid malignancy Summary of the sensitivity and specificity of anti-muc1 antibodies for a final diagnosis of mesothelioma Page xv

17 Table Page 3.11 Compilation of data relevant to mesothelioma diagnosis from tables 3.8 and Comparison of study characteristics for anti-muc1 antibody for a diagnosis of mesothelioma Patient demographics of effusion supernatant samples collected CA15-3 concentrations from the interim diagnosis category CA15-3 concentrations in effusions from the final diagnosis category Mesothelin levels from interim diagnosis category Mesothelin levels from the final diagnosis category Combined performance of CA15-3 and mesothelin Characteristics of all cell lines used in this study and relative to MUC1 mrna Immunohistochemistry scores of tested anti-muc1 antibodies in cell lines Percentage of cells expressing MUC1 on cells surface relative to isotype control Page xvi

18 LIST OF ABBREVIATIONS A ATCC AUC Bcl-XL Ampicillan American Type Culture Collection Area under the curve B cell lymphoma extra large transmembrane molecule BFS Buffered formal saline 10% bp BSA C CBMA cdna CEA CK c-src Ct CT datp DC dctp dgtp dntp dttp ddh 2 O DDT DMSO Base pairs Bovine serum Albumin Celsius Cell block microarray Complementary DNA Carcinoembryonic antigen Cytokeratin Cellular proto oncogene tyrosine kinase Threshold cycle Computed tomography Deoxyadenosine-5 -triphosphate Dendritic cells Deoxycytidine-5 triphosphate Deoxyguanosine-5 triphosphate Deoxynucleotide Triphosphate Deoxythymidine-5 -triphosphate Double deionised water Dithiothreitol Dimethylsulphoxide Page xvii

19 DNA DPX ECL EDTA EGFR EMA EPP ErbB EtOH FCS FNA G GAPDH H 2 O 2 H and E HBBS HCl HEPES HMFG HREC HRP IASLC ISOBM Deoxyribonucleic acid Distyrene, Plasticizer and Xylene mounting media Enhanced Chemiluminescence Ethylenediamine tetra-acetic acid Epidermal growth factor receptor Epithelial membrane antigen Extra pleural pneumonectomy Erythrocyte leukaemia viral oncogene Ethanol Fetal calf serum Fine needle aspiration Gleason grade Glyceraldehyde 3-phosphate dehydrogenase Hydrogen peroxide Haematoxylin and Eosin Hanks Buffered salt solution Hydrochloric acid 4-(2-Hydroxyl)-1-piperazineethanesulfonic acid Human milk fat globulin Human Research Ethics Committee Horse radish peroxidase International association for the study of lung cancer International Society for Oncodevelopmental Biology and Medicine kbp Kilo base pairs Page xviii

20 kda Lck LDR M Kilo Dalton Lymphocyte specific tyrosine kinase Length to diameter ratio Molar MAP2K1 Mitogen activated protein kinase 1 MM mab Mc5 MeOH μg μl mg min ml mrna MUC NaN3 Na 2 CO 3 NaCl NCARD NaOH NPV NSCLC OD PAS Malignant mesothelioma Monoclonal antibody anti-muc1 antibody Methanol Microgram Microlitre Milligram Minute Millilitre Messenger RNA Mucin Sodium azide Sodium bicarbonate Sodium chloride National Centre for Asbestos Related Disease Sodium hydroxide Negative predictive value Non small cell lung cancer Optical density Periodic acid Schiff Page xix

21 PBL PBS PC PCAM P/D PDGF-A PEFL PEM PHA PLFL PMSF PO PPV PUM PVDF RB RNA RPMI ROC RT-PCR SEA sec SCGH SJOG SDS Peripheral blood lymphocyte Phosphate buffered saline Pericardial cells Intercellular cell adhesion molecule Pleurectomy and decortication Platelet derived growth factor Peritoneal fluid Polymorphic epithelial mucin Phytohaemagglutinin Pleural fluid Phenylmethylsulfonyl fluoride Periodate oxidation Positive predictive value Peanut reactive urinary mucin Polyvinylidene difluoride Retinoblastoma Ribonucleic acid Roswell Park Memorial Institute Receiver operating characteristics Reverse transcription polymerase chain reaction Sea urchin sperm protein enterokinase and agrin Second Sir Charles Gairdner Hospital, Nedlands St John of God Hospital, Subiaco Sodium dodecyl sulphate Page xx

22 SNOP STAT Systematized Nomenclature of Pathology Signal transducer and activator of transcription SV-40 Simian virus 40 TAA TACE TE Tm TMA TN TP Tumour associated antigen Tumour necrosis α converting enzyme Trypsin-EDTA Melting temperature Tissue microarray Total negative Total positive TTF-1 Thyroid transcription factor 1 VATS VNTR Video assisted thoracoscopic surgery Variable number of tandem repeats Page xxi

23 CHAPTER 1: LITERATURE REVIEW 1

24 1.1 MALIGNANT MESOTHELIOMA This chapter will discuss the incidence and aetiology of malignant mesothelioma (hereafter mesothelioma ), including the diagnostic algorithms and clinical management currently available, before addressing in more detail the topic of this thesis. Malignant mesothelioma is a highly aggressive malignancy involving the pleural, peritoneal and occasionally the pericardial cavity. Mesothelioma is a fatal disease with a median survival from initial diagnosis between 9 and 12 months, even with optimal evidence-based therapy (Vogelzang, NJ, Rusthoven, JJ et al. 2003; Nowak, AK and Bydder, S 2007). Australia has one of the highest incidence of mesothelioma in the world, with approximately 600 cases per annum (SafeWorkAustralia 2010). Approximately 90% of cases occur in the pleura with the remaining cases involving the peritoneum and isolated cases occurring in the pericardium or testis. The major causative agent of mesothelioma is exposure to asbestos. Mesothelioma has an extremely long latency period and usually takes 20 to 40 years to become clinically apparent after asbestos exposure. Incidence patterns of this disease therefore reflect the production and use of asbestos in any given region, and currently in Australia are reflecting a period just before regulatory mechanisms were put in place to minimise asbestos exposure. In Australia the incidence of mesothelioma has been estimated to peak in the next 10 years (Clements, M, Berry, G et al. 2007). More males than females develop mesothelioma as a result of the greater use of asbestos in male dominated industries. Incidence rates for Australian males and females aged >20yrs were 53.3/million and 10.2/million respectively (Leigh, J and Driscoll, T 2003). In Great 2

25 Britain, the occurrence of mesothelioma is predicted to peak in 2016 with an approximate number of 2040 mesothelioma related deaths per annum (Tan, E, Warren, N et al. 2010). The peak incidence of mesothelioma in the United States of America may have already occurred, currently there are between 2500 and 3000 cases diagnosed annually (Yang, H, Testa, JR et al. 2008). Significant restrictions have been put in place on the mining and use of asbestos in many industrialised countries over the last 30 years (Kazan-Allen, L 2005; Bianchi, C and Bianchi, T 2007; Yang, H, Testa, JR et al. 2008). However, asbestos manufacturers have found alternative markets for the use of asbestos in the Asia-Pacific region, targeting underdeveloped countries with minimal regulations limiting asbestos use. This has resulted in an increased number of mesothelioma cases diagnosed in countries such as; Brazil, China, Japan, Korea, Malaysia, Thailand, Vietnam, India, Indonesia and The Philippines. Several of these countries have already consumed more than tonnes of asbestos since 2000 (Kazan-Allen, L 2005) Asbestos Asbestos has been used for thousands of years for household items from the wicks of oil lamps to pottery. Its widespread use began in Canada in 1880, when serpentine asbestos was used for the construction of heat resistant fabrics. Asbestos has many properties that make it a good industrial product including extreme flexibility, with high tensile strength and heat resistance (Rom, WN and Palmer, PE 1974). Asbestos has been known to cause disease since 1906, when Montague Murray first described a case of asbestosis in England (Lemen, R, Dement, J et al. 1980). This 3

26 report was followed in 1927 by a more detailed account of asbestosis by Cooke and McDonald who described curious bodies originating from asbestos fibres that had reached the lungs (McDonald, S 1927). In 1930, the first case of asbestos bodies found in sputum samples of asbestos workers in the United States was described (Lynch, KM 1955). These early studies formed the basis of the hypotheses that individuals exposed to the asbestos dust develop asbestosis, especially if the exposure was high or over an extended period of time. However, subsequent authors found that asbestosis was also occurring in individuals working in industries such as pipe insulation and ship building. Cases of extensive pleural calcification were also observed in workers from sand asphalt and vinyl tile flooring industries (Rom, WN and Palmer, PE 1974). Further studies into the mechanical trades highlighted that 25% of individuals exposed to asbestos had x-ray abnormalities consistent with asbestosis and restricted pulmonary function (Rom, WN and Palmer, PE 1974; Wagner, JC, Berry, G et al. 1974). There are two major forms of asbestos, serpentine or chrysotile (white asbestos) and amphibole which include both crocidolite (blue asbestos) and amosite (brown asbestos). Crocidolite is an extremely fine, thin, straight fibre which is generally less than 0.1μm in diameter. In animal models inhaled crocidolite fibres align towards the centre of airflow and have been shown to extend to the distal alveolar spaces. In comparison, chrysotile is spiral in structure and adheres to the respiratory mucous membranes via the ciliary tufts of the bronchial epithelial cells. Chrysotile can be eliminated from the body more readily than crocidolite or amosite (Bernstein, DM, Rogers, RA et al. 2010). 4

27 A meta-analysis of over 29 epidemiological studies concluded that amphibole types of asbestos (such as crocidolite and amosite) have much greater oncogenic potential than chrysotile for the development of asbestos related diseases (Berman, DW and Crump, KS 2008). The authors hypothesised that fibres longer than 10μm are more potent than shorter fibres for inducing mesothelioma (Berman, DW and Crump, KS 2008) History of Asbestos use in Australia In Australia, there were two main asbestos mining operations. Chrysotile was mined in Baryulgil in northern New South Wales from 1939 to Crocidolite asbestos was mined in Wittenoom, in northwest Western Australia from 1937 until Asbestos fibre was also imported from Canada (chrysotile) and South Africa (crocidolite and amosite) and asbestos containing products were imported from the United Kingdom, United States of America, Germany and Japan (Bianchi, C and Bianchi, T 2007). In Australia, the consumption of crocidolite began to be phased out in 1967, although the use of amosite continued until the mid 1980 s. Regulations prohibiting the importation, use or sale of chrysotile came into place on December 31 st 2003 (Jamrozik, E, de Klerk, N et al. 2011). However, asbestos is still present in many Australian homes and can be found in a range of products including brake pads, clutch linings, insulation, asbestos cement sheeting, gaskets and adhesives Other aetiological agents Aetiological agents in addition to asbestos have been linked to the development of mesothelioma, including simian virus 40 (SV-40), radiation and erionite and these will be discussed below in more detail. 5

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