Aldieri E, Riganti C, Silvagno F, Orecchia S, Betta PG, Doublier S, Gazzano E, Polimeni M, Bosia A, Ghigo D.

Genetics, Biology and Biochemistry, University of Turino, Turino, Italy; University of Torino, Interdepartmental Center "G. Scansetti" for Studies on Asbestos and Other Toxic Particulates, Torino, Italy; University of Torino, Research Center on Experimental Medicine (CeRMS), Torino, Italy.

Abstract

Rationale: Asbestos is a naturally occurring fibrous silicate, whose inhalation is highly related to the risk of developing malignant mesothelioma (MM), and crocidolite is one of its most oncogenic types. The mechanism by which asbestos may cause MM is still unclear. We have previously observed that crocidolite in human MM cells (HMM) induces NF-kB activation and stimulates the synthesis of nitric oxide by inhibiting the RhoA signaling pathway.

Methods: In primary human mesothelial cells (HMC) and HMM cells exposed to crocidolite asbestos, co-incubated or not with antioxidants, we evaluated both cytotoxicity and oxidative stress induction (lipid peroxidation), then the effect of asbestos on the RhoA signaling pathway (RhoA GTP binding, Rho kinase activity, RhoA prenylation, hydroxy-3-methylglutharyl-CoA reductase activity). Results. In this paper we show that the reactive oxygen species generated by the incubation of crocidolite with both primary HMC and three human MM cell lines mediate the inhibition of 3-hydroxy-3-methylglutharyl-CoA reductase (HMGCR). Indeed the co-incubation of HMC and HMM cells with crocidolite together with antioxidants, such as Tempol, Mn-porphyrin and the association of superoxide dismutase and catalase, completely prevented the cytotoxicity and lipoperoxidation caused by crocidolite alone, as well as the decrease of HMGCR activity, and restored the RhoA/ROCK activity and the RhoA prenylation. The same effect was observed when the oxidizing agent menadione was administrated to the cells in place of crocidolite.

Conclusions: Such a mechanism could at least partly explain the effects exerted by crocidolite fibers in mesothelial cells.

Lee HE, Kim HR.

Occupational Safety and Health Research Institute, KOSHA, Inchoen, Korea.

Abstract

Malignant mesothelioma and lung cancer are representative examples of occupational cancer. Lung cancer is the leading cause of cancer death, and the incidence of malignant mesothelioma is expected to increase sharply in the near future. Although information about lung carcinogen exposure is limited, it is estimated that the number of workers exposed to carcinogens has declined. The first official case of occupational cancer was malignant mesothelioma caused by asbestos exposure in the asbestos textile industry in 1992. Since then, compensation for occupational respiratory cancer has increased. The majority of compensated lung cancer was due to underlying pneumoconiosis. Other main causative agents of occupational lung cancer included asbestos, hexavalent chromium, and crystalline silica. Related jobs included welders, foundry workers, platers, plumbers, and vehicle maintenance workers. Compensated malignant mesotheliomas were associated with asbestos exposure. Epidemiologic studies conducted in Korea have indicated an elevated risk of lung cancer in pneumoconiosis patients, foundry workers, and asbestos textile workers. Occupational respiratory cancer has increased during the last 10 to 20 yr though carcinogen-exposed population has declined in the same period. More efforts to advance the systems for the investigation, prevention and management of occupational respiratory cancer are needed.

Baumann F, Maurizot P, Mangeas M, Ambrosi JP, Douwes J, Robineau B.

University of New Caledonia.

Abstract

Background: High incidences of malignant mesothelioma (MM) have been observed in New Caledonia. Previous work showed an association between MM and soil containing serpentinite.

Objectives: To study the spatial and temporal variation of MM and its association with environmental factors.

Methods: All 109 MM cases recorded in the Cancer Registry of New Caledonia between 1984 and 2008 were investigated. Spatial, temporal and space-time cluster analyses were performed. We conducted an ecological analysis involving 100 tribes over a large area including those with the highest incidence rates. Associations with environmental factors were assessed using logistic and Poisson regression analyses.

Results: The highest incidence was observed in the Houaïlou area with a world age standardised rate of 128.7 per 100,000 person-years; 95%CI: 70.41–137.84. A significant spatial cluster grouped 18 tribes (31 observed cases vs 8.12 expected cases, p=0.001), but no significant temporal clusters were identified. The ecological analyses identified serpentinite on roads as the greatest environmental risk factor: odds ratio = 495.0, 95%CI: 46.2–4679.7; multivariate incidence rate ratio = 13.0, 95%CI: 10.2-16.6. The risk increased with serpentinite surface, proximity to serpentinite quarries and distance to the peridotite massif. The association with serpentines was stronger than for amphiboles. Living on a slope and close to dense vegetation appeared protective. The use of whitewash, previously suggested to be a risk factor, was not associated with MM incidence.

Conclusions: Presence of serpentinite on roads is a major environmental risk factor for mesothelioma in New Caledonia.

Méndez-Vargas MM, López-Rojas P, Campos-Pujal GA, Marín-Cotoñieto IA, Salinas-Tovar S, Fernández-Muñoz Mde J.

Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Distrito Federal, México. medmakika1915@yahoo.com.mx

Abstract

Objective: To identify the characteristics of pleural mesothelioma in patients exposed to asbestos.

Methods: A transverse study in 3700 cases of lung cancer was conducted. There were identified 21 cases with mesothelioma. Age, gender, smoking history, cancer development, dissemination, cytohistochemistry, lethality and total lung capacity were studied. ANOVA test was used.

Results: The incidence was of 0.45/100,000 patients. Four (19%) corresponded to occupational exposure (OE), seven (33%) para-occupational (PE) and ten (48%) environmental (EE). The mean age at detection was 50 years for PE, 55 years for EE and 64 years for OE. Twenty cases were male. Thirteen patients (62%) were active cigarette smokers. The latency time in PE mesothelioma was 34.5 years, in OE 40 years, and in EE more than 40 years. In 19 (90%) cases the tumor was disseminated. Diagnosis was confirmed by cytohistochemistry. Malignant mesothelioma was reported in 19 (90%) cases. The survival period was 5 months for OE patients, 10 in PE and 16 in EE.

Conclusions: There is a low incidence of malignant mesothelioma in our population. Male was the predominant group. Occupational and paraoccupational exposure predominated in patients.

Christensen BC, Houseman EA, Godleski JJ, Marsit CJ, Longacker JL, Roelofs CR, Karagas MR, Wrensch MR, Yeh RF, Nelson HH, Wiemels JL, Zheng S, Wiencke JK, Bueno R, Sugarbaker DJ, Kelsey KT.

Department of Community Health, Center for Environmental Health and Technology, Brown University, 70 Ship Street, Providence, RI 02903, USA.

Abstract

Mechanisms of action of nonmutagenic carcinogens such as asbestos remain poorly characterized. As pleural mesothelioma is known to have limited numbers of genetic mutations, we aimed to characterize the relationships among gene-locus-specific methylation alterations, disease status, asbestos burden, and survival in this rapidly fatal asbestos-associated tumor. Methylation of 1505 CpG loci associated with 803 cancer-related genes were studied in 158 pleural mesotheliomas and 18 normal pleura. After false-discovery rate correction, 969 CpG loci were independently associated with disease status (Q < 0.05). Classifying samples based on CpG methylation profile with a mixture model approach, methylation classes discriminated tumor from normal pleura (permutation P < 0.0001). In a random forests classification, the overall misclassification error rate was 3.4%, with <1% (n = 1) of tumors misclassified as normal (P < 0.0001). Among tumors, methylation class membership was significantly associated with lung tissue asbestos body burden (P < 0.03), and significantly predicted survival (likelihood ratio P < 0.01). Consistent with prior work, asbestos burden was associated with an increased risk of death (hazard ratio, 1.4; 95% confidence interval, 1.1-1.8). Our results have shown that methylation profiles powerfully differentiate diseased pleura from nontumor pleura and that asbestos burden and methylation profiles are independent predictors of mesothelioma patient survival. We have added to the growing body of evidence that cellular epigenetic dysregulation is a critical mode of action for asbestos in the induction of pleural mesothelioma. Importantly, these findings hold great promise for using epigenetic profiling in the diagnosis and prognosis of human cancers.

Archimandriti DT, Dalavanga YA, Cianti R, Bianchi L, Manda-Stachouli C, Armini A, Koukkou AI, Rottoli P, Constantopoulos SH, Bini L.

Department of Pneumonology, Medical School, University of Ioannina, Ioannina, Greece.

Abstract

Inhabitants of Metsovo, NW Greece, have been exposed to an asbestos whitewash, resulting in malignant pleural mesothelioma (MPM) and pleural calcifications (PCs). Interestingly, those with PCs (PC⁺) are less prone to MPM. They also have lymphocytic alveolitis, and differences in bronchoalveolar lavage (BAL) proteins, compared with those without pleural calcifications (PC^-). This may mean a different response to the fiber leading to different susceptibility to neoplasia. To further evaluate this, a proteomic analysis of BAL proteins was performed. Proteomic analysis (2D-electrophoresis/Mass Spectrometry) of BAL in Metsovites nonoccupationally exposed to asbestos revealed increased albumin fragments, alpha1-antitrypsin, S100-A9 and HSP27, suggesting ongoing inflammation. In those without pleural calcifications, increased expression of acid ceramidase, glutathione-S-transferase and presence of calcyphosin, all involved in cell cycle regulation and death as well as in the detoxification of mutagenic and toxic agents, lend further support to our thesis of possible “protection against neoplasia” in Metsovites with pleural calcifications.

Moore AJ, Parker RJ, Wiggins J.

Department of Respiratory Medicine, Wexham Park Hospital, Wexham, Slough, Berkshire, UK. a.moore@ic.ac.uk

Abstract

Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10-20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational “environmental” exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis.

Sherwood AL, Mutsaers SE, Peeva VK, Robinson C, deSilva CJ, Swanson NR, Lake RA.

National Centre for Asbestos Related Diseases, University of Western Australia, Perth, Australia.

Abstract

Objectives: Mesotheliomas occur in occult serous cavities after chronic exposure of mesothelial cells to asbestos fibres. Molecular events that contribute to the development of this cancer are therefore not readily accessible for study. We have used in vitro culture systems to study and compare induced and spontaneous transformation events in primary mouse mesothelial cells.

Materials and Methods: Mouse mesothelial cells were cultivated until small populations of proliferating cells emerged from senescing cultures. Spontaneously transformed cultures of cells were characterized and compared to malignantly transformed cells.

Results: Human mesothelial cells had a finite lifespan of 10-15 population doublings when cultured in vitro; mouse mesothelial cells typically exhibit this same pattern. Here, we show that mouse mesothelial cells can be cultured for extended periods and that these cells can transform spontaneously. Lines of spontaneously transformed cells generated in this study are immortal and growth factor-independent. They display the salient characteristic features of transformation, including increased proliferation rate, lack of contact inhibition, aneuploidy and ability to grow in anchorage-independent conditions. A subset of these cell lines developed into tumours in syngeneic mice. Comparative gene expression analysis demonstrated that spontaneously transformed cell lines were more closely related to neoplastic cells than to primary cells.

Conclusion: These findings have implications for interpretation of in vitro transformation studies, demonstrating broad similarity between spontaneous and induced genetic changes.

Park EK, Hannaford-Turner KM, Hyland RA, Johnson AR, Yates DH.

Research and Education Unit, Workers’ Compensation Dust Diseases Board of NSW, Sydney, Australia.

Abstract

Asbestos is a fibrous silicate which is recognized as causing a variety of lung disorders including malignant mesothelioma of the pleura, lung cancer and asbestosis. Asbestos use has been banned in most developed countries but exposure still occurs under strict regulation in occupational settings and also occasionally in domestic settings. Although the hazards of asbestos are well known in developed countries, awareness of its adverse health effects is less in other parts of the world, particularly when exposure occurs in non-occupational settings. Experience of asbestos use and its adverse heath effects in developed countries such as Australia have resulted in development of expertise in the diagnosis and treatment of asbestos-related diseases as well as in screening and this can be used to help developing countries facing the issue of asbestos exposure.

Keywords: Asbestos, Mesothelioma, Asbestos-related diseases, Occupational exposure, Public health

Pancaldi C, Balatti V, Guaschino R, Vaniglia F, Corallini A, Martini F, Mutti L, Tognon M.

Department of Morphology and Embryology, Section of Cell Biology and Molecular Genetics, University of Ferrara, Ferrara, Italy.

Abstract

Objective: Asbestos is considered the main agent in causing the onset of the malignant pleural mesothelioma (MM), a fatal cancer of increasing incidence worldwide. Other factors may contribute to the onset/progression of MM, such as genetic predisposition and infection by oncogenic viruses, like simian virus 40 (SV40). SV40 was administered to human populations mainly with SV40-contaminated anti-polio vaccines. SV40 footprints have been detected in specific human tumours, including MM, and in healthy blood donors. The aim of this study was to verify the presence of SV40 sequences in buffy coats of healthy blood donors, inhabitants of Casale Monferrato, where MM is 10 times more prevalent compared to other areas.

Methods: DNA from 148 buffy coats of healthy blood donors were qualitatively and quantitatively PCR analyzed for SV40 sequences.

Results: SV40 sequences were detected in 24 out of 148 (16%) samples. Quantitative real time PCR analyses carried out in SV40-positive samples indicated a viral copy number in the range of 10-10,000 per 100,000 cells.

Conclusions: SV40 sequences are present in blood samples of healthy donors from Casale Monferrato with a prevalence similar to that reported in previous investigations of healthy donors from asbestos-free areas. Altogether these data suggest that SV40 is circulating in the human population.