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.

Weiner SJ, Neragi-Miandoab S.

Cleveland Clinic Lerner College of Medicine, 9500 Euclid Avenue, Cleveland, OH, USA.

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor for which no effective therapy exists despite the discovery of many possible molecular and genetic targets. The late stage of MPM diagnosis and the long latency that exist between some exposures and diagnosis have made it difficult to comprehensively evaluate the role of risk factors and their downstream molecular effects.

Methods: This manuscript is a review of current literature about the pathogenesis of malignant mesothelioma. In this overview, current published studies concerning pathogenesis of malignant mesothelioma are reviewed, with insights into its etiology and pathogenesis. We searched pubmed using the following subjects: mesothelioma, radiation, genetics, pediatric malignant mesothelioma, SV40 virus, and growth factors. We selected 350 valuable articles of which 152 sources were used to complete this review.

Conclusion: Many risk factors for MPM development have been recognized including environmental exposures, genetic susceptibility, viral contamination, and radiation. In this review, we discuss the current molecular and genetic contributors to MPM pathogenesis and the risk factors associated with these carcinogenic processes.

Keywords: Radiation – Genetics – Pediatric malignant mesothelioma – SV40 virus – Growth factors

Sarić M, Curin K, Varnai VM.

Institute for Medical Research and Occupational Health, Zagreb, Croatia. marko@imi.hr

Abstract

From the Croatian Cancer Registry (period 1991-1997) 194 malignant pleural mesothelioma patients were collected. According to participation in polio vaccination mass campaign in 1961 that covered the entire Croatian population aged 3 months to 20 years, mesothelioma patients were divided in vaccinated (N=58), and non-vaccinated (N=136) subjects. Significantly higher percentage of those with a history of occupational exposure to asbestos was found in vaccinated (79%) compared to non-vaccinated group (63%). This is the opposite to what would be expected if potential SV40 contamination of polio vaccine used had a causative role in the development of the tumour. On the other hand, shorter latency period reflected by very high percentage of 45-year-old or younger mesothelioma patients in vaccinated group (15 out of 58), with all of them having a history of occupational asbestos exposure, raises a question for a possible enhancing effect of the vaccine used to asbestos exposure, if it was contaminated with SV40.

Yang H, Testa JR, Carbone M.

Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI, 96813, USA.

Abstract

Opinion Statement: The incidence of mesothelioma has gone from almost none to the current 2500-3000 cases per year in the USA. This estimate is an extrapolation based on information available from the Surveillance, Epidemiology and End Results (SEER) Program that collects information on approximately 12% of the US population. Mesothelioma is a cancer that is linked to exposure to carcinogenic mineral fibers. Asbestos and erionite have a proven causative role; the possible role of other mineral fibers in causing mesothelioma is being investigated. Asbestos is considered the main cause of mesothelioma in the US and in the Western world. The capacity of asbestos to induce mesothelioma has been linked to its ability to cause the release of TNF-alpha (that promotes mesothelial cells survival), other cytokines and growth factors, and of mutagenic oxygen radicals from exposed mesothelial cells and nearby macrophages. Some investigators proposed that as a consequence of the regulations to prevent exposure and to forbid and/or limit the use of asbestos, the incidence of mesothelioma in the US (and in some European countries) should have started to decline before or around the year 2000, and sharply decline thereafter. Unfortunately, there are no data available yet to support this optimistic hypothesis. Simian virus 40 (SV40) infection and radiation exposure are additional causes, although their contribution to the overall incidence of mesothelioma is unknown. Recent data from several laboratories indicate that asbestos exposure and SV40 infection are co-carcinogens in causing mesothelioma in rodents and in causing malignant transformation of human mesothelial cells in tissue culture. An exciting new development comes from the discovery that genetic susceptibility to mineral fiber carcinogenesis plays a critical role in the incidence of this cancer in certain families. It is hoped that the identification of this putative mesothelioma gene will lead to novel mechanistically driven preventive and therapeutic approaches.

Coleman S, Gibbs A, Butchart E, Mason MD, Jasani B, Tabi Z.

Velindre Hospital, Velindre NHS Trust, Cardiff, United Kingdom.

Abstract

The continued presence of simian virus 40 (SV40), a monkey polyomavirus, in man is confirmed by the regular detection of SV40-specific antibodies in 5-10% of children who are unlikely to have received contaminated polio-vaccines. The aim of our experiments was to find cellular immunological evidence of SV40 infection in humans by testing memory T cell responses to SV40 large T antigen (Tag). As there is some indication that the virus may be present in malignant pleural mesothelioma (MPM) cells, we analyzed T cell responses in MPM patients and in healthy donors. The frequencies of responding T cells to overlapping Tag peptides were tested by cytokine flow cytometry. CD8⁺ T cells from 4 of 32 MPM patients responded (above twofold of control) to SV40 Tag peptides, while no positive responses were detected in 12 healthy donors. Within SV40 Tag we identified three 15 amino acid-long immunogenic sequences and one 9 amino acid-long T cell epitope (p138) (138FPSELLSFL146), the latter including a HLA-B7-restriction motif. T cell responses to p138 were SV40-specific as T cells stimulated with p138 did not cross-react with the corresponding sequences of Tag of human polyomaviruses BKV and JCV. Similarly, the relevant BKV and JCV Tag peptides did not generate T cell responses against SV40 TAg p138. Peptide-stimulated T cells also killed SV40 Tag-transfected target cells. This article demonstrates the presence, and provides a detailed analysis, of SV40-specific T cell memory in man.

Keywords: polyomavirus, T cell memory, epitope search, SV40.

Zervos MD, Bizekis C, Pass HI.

Department of Cardiothoracic Surgery, Division of Thoracic Surgery, New York University School of Medicine, New York, USA. zervom01@med.nyu.edu

Abstract

Purpose of review: Mesothelioma is an aggressive malignancy of the pleura with poor survival. There will be approximately 3000 cases of mesothelioma in the United States annually. Multimodality treatment including neoadjuvant chemotherapy in selected individuals followed by extrapleural pneumonectomy and radiation has been studied in recent trials for its effects on disease free and overall survival This review provides a general overview of malignant mesothelioma with a summary of the most significant articles from within the past year as well as from the past.

Recent findings: Areas of recent interest include the evaluation of osteopontin and mesothelin as new tumor markers for mesothelioma. New phase III trials have been performed to evaluate the use of combined chemotherapy regimens.

Summary: Malignant mesothelioma is a very difficult malignancy to treat. Patients with the disease usually have an occupational asbestos exposure, and in some, viral exposure with SV40. There have been many historical treatments including combinations of local control with surgery and radiation as well as attempts to prevent systemic failure with chemotherapy. Novel therapies including intrapleural chemotherapy, photodynamic therapy and hyperthermic perfusion have also been used with some success. Finally there are several attempts at immunomodulating and targeted treatments, which are in phase I/II trials.

Rivera Z, Strianese O, Bertino P, Yang H, Pass H, Carbone M.

Cancer Research Center of Hawaii and Department of Pathology, University of Hawaii, Honolulu, Hawaii, USA .

Abstract

Purpose of review: Simian virus 40 is present in some human malignant mesotheliomas. The evidence in favor and against a pathogenic role of simian virus 40 in malignant mesothelioma is discussed in this review.

Recent findings: When simian virus 40 is injected intracardially into hamsters, 60% develop and die of malignant mesothelioma. Moreover, some human malignant mesotheliomas contain and express simian virus 40 DNA and proteins. To date, over 50 laboratories have detected simian virus 40 in malignant mesotheliomas and in other tumors; however, the variability of the percentage of positivity led to a controversy about the role and significance of simian virus 40 in malignant mesotheliomas. Compared with other cell types, human mesothelial cells are unusually susceptible to simian virus 40-induced malignant transformation. The presence of simian virus 40 in malignant mesothelioma has been associated with the activation of specific oncogene pathways. Cocarcinogenesis between simian virus 40 and asbestos in causing malignant mesotheliomas has been demonstrated in three separate research laboratories using different experimental approaches. Epidemiological data possibly linking simian virus 40 and malignant mesothelioma is lacking owing to unattainable identification of infected from noninfected cohorts.

Summary: Available evidence appears sufficient to link simian virus 40 either alone or in conjunction with asbestos in causing malignant mesotheliomas; however, it is still insufficient to speculate about the contribution of simian virus 40 to the overall incidence of malignant mesotheliomas.

Dikensoy O.

Department of Pulmonary Diseases, Gaziantep University, Gaziantep, Turkey. dikensoy@yahoo.com

Abstract

Purpose of review: The prevalence of malignant mesothelioma due to erionite exposure in Central Anatolia is very high. In this report, we review the recent developments on this epidemic on the basis of previous literature.

Recent findings: Recently, it has been shown that erionite is poorly cytotoxic, induces proliferating signals and high growth rate in human mesothelial cells. Additionally, long-term exposure to erionite transforms human mesothelial cells in vitro, regardless of the presence of Simian Virus 40 sequences, leading to foci formation in cultured monolayers. It has also been confirmed that a genetic predisposition to erionite carcinogenesis is the cause of the mesothelioma epidemic in Cappadocia.

Summary: The data obtained recently on the epidemiology, etiology, and pathogenesis of the mesothelioma due to erionite exposure in Turkey are described.

Kobayashi M, Takeuchi T, Ohtsuki Y.

Department of Respiratory Medicine, Hosogi Hospital, 37 Daizen-cho, Kochi, Kochi 780-8535, Japan. kmakoto@jinseikai-group.or.jp

Abstract

Introduction: The incidence of mesothelioma is estimated to rise sharply worldwide, including Japan, in the next two decades. Molecular and proteomic studies are urgently required to elucidate the pathobiology of malignant mesothelioma. This paper describes the characterization of novel human malignant pleural mesothelioma cell lines representing the sarcomatoid, epithelioid and biphasic subtypes.

Materials and Methods: Established pleural effusion fluid cell lines were observed using phase-contrast microscopy and transmission electron microscopy. The immunoreactivity of the cells was evaluated using immunohistochemistiy, FACS analysis and Western blotting. The expression of SV40 large cell antigen and the EGFR mutation status were also analyzed.

Results: The cell lines had different morphological and immunophenotypic characteristics. All cell lines showed immunophenotypic marker expression of vimentin, mesothelin and N-cadherin, but no expression of CEA or E-cadherin. At the electron microscopic level, a cell surface rich in microvilli confirmed mesothelial origin of the cell lines. Karyotype analyses showed complex abnormalities in all cell lines. Neither EGFR mutations relevant to tyrosine kinase inhibitor responsiveness nor the expression of SV40 large cell antigen was detected in any of the cell lines.

Conclusion: FACS analysis is more sensitive for evaluating mesothelin expression than immunohistochemistry of cut specimens. Irrespective of the expression of EGFR on FACS analysis, no EGFR mutation was detected. These three cell lines may be useful for studying cellular, molecular and genetic aspects of mesothelioma.

Toyooka S, Kishimoto T, Date H.

Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan. toyooka@md.okayama-u.ac.jp

Abstract

Malignant mesothelioma (MM) is a highly aggressive tumor with a dismal prognosis. The incidence of MM is increasing as a result of widespread exposure to asbestos. As for the molecular alterations that occur in MM, chromosome alterations including homo-deletion of the P16 and P14 genes located in the 9p21 are well known. Mutations are rare in the P53 and Ras genes, which are frequently present in epithelial solid tumors. However, mutations are frequently present in the neurofibromatosis type 2 gene. Epigenetic alterations including DNA methylation have been found in the MM, the profile of which is different from that of lung cancer, although differential diagnosis is sometimes clinically difficult. As in other malignant tumors, genes that are related to immortalization, proliferation, metastasis, angiogenesis, and anti-apoptosis are also overexpressed in MM, contributing to its malignant phenotype. It is of interest that simian virus 40 has been implicated to be one of the causative factors of MM in western countries. Although the causative role of asbestos is well-known in MM, much less information is available for MM than for other malignant tumors regarding the molecular alterations that occur in the disease. In terms of future tasks, it will be necessary to apply the knowledge that is learned about molecular alterations to clinical practice and to further elucidate the pathogenesis of MM with extensive research.

Keywords: malignant mesothelioma, P16, methylation