Skip to main content
SpringerLink
Log in

Malignant Mesothelioma: Mechanism of Carcinogenesis

  • Chapter
  • First Online:
Occupational Cancers

Abstract

Our present knowledge of the mechanism of mesothelial carcinogenesis results from pathophysiological and toxicological research carried out in vivo in rodents and in mammalian cells in culture and from biological and molecular studies of malignant mesothelioma (MM) tissue samples and cell lines from humans and experimental animals. In this latter context, most experimental studies have been based on the cellular and/or animal responses to asbestos fibers and in genetically modified mice. These investigations have provided a body of data on the cellular and molecular effects of asbestos fibers on mesothelial cells and the mesothelium, including genomic and genetic changes and alterations of regulatory and signaling pathways. Human MM has been characterized at the genomic, genetic, epigenetic, and physiological levels, with the development of large-scale analyses allowing global integration of the networks involved in the transformation of the mesothelial cell. The aim of the present work is to propose a potential mechanism of mesothelial carcinogenesis by integrating data based on cellular and molecular effects of asbestos fibers on mesothelial cells, with altered physiological and molecular features of malignant mesothelioma cells.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Lippmann M, Yeates DB, Albert RE. Deposition, retention and clearance of inhaled particles. Br J Industr Med. 1980;37:337–62.

    CAS  Google Scholar 

  2. Oberdorster G. Evaluation and use of animal models to assess mechanisms of fibre carcinogenicity. IARC Sci Publ.1996;107–25.

    Google Scholar 

  3. Miserocchi GA, Sancini GA, Mantegazza F, Chiappino G. Translocation pathways for inhaled asbestos fibers. Environ Health. 2008;7:4.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Donaldson K, Murphy FA, Duffin R, Poland CA. Asbestos, carbon nanotubes and the pleural mesothelium: a review and the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma. Part Fibre Toxicol. 2010;7:5.

    PubMed Central  PubMed  Google Scholar 

  5. Wang NS. Anatomy of the pleura. Clin Chest Med. 1998;19:229–40.

    CAS  PubMed  Google Scholar 

  6. Wang NS. The preformed stomas connecting the pleural cavity and the lymphatics in the parietal pleura. Am Rev Respir Dis. 1975;111:12–20.

    CAS  PubMed  Google Scholar 

  7. Hammar SP. The pathology of benign and malignant pleural disease. Chest Surg Clin N Am. 1994;4:405–30.

    CAS  PubMed  Google Scholar 

  8. Holt PF. Transport of inhaled dust to extrapulmonary sites. J Pathol. 1981;133:123–9.

    CAS  PubMed  Google Scholar 

  9. Muller KM, Schmitz I, Konstantinidis K. Black spots of the parietal pleura: morphology and formal pathogenesis. Respiration. 2002;69:261–7.

    PubMed  Google Scholar 

  10. Mitchev K, Dumortier P, De Vuyst P. ‘Black Spots’ and hyaline pleural plaques on the parietal pleura of 150 urban necropsy cases. Am J Surg Pathol. 2002;26:1198–206.

    PubMed  Google Scholar 

  11. Pooley FD. Proceedings: the recognition of various types of asbestos as minerals, and in tissues. Clin Sci Mol Med. 1974;47:11P–2.

    CAS  PubMed  Google Scholar 

  12. Dodson RF, O’Sullivan MF, Huang J, Holiday DB, Hammar SP. Asbestos in extrapulmonary sites: omentum and mesentery. Chest. 2000;117:486–93.

    CAS  PubMed  Google Scholar 

  13. Boffetta P. Epidemiology of peritoneal mesothelioma: a review. Ann Oncol. 2007;18:985–90.

    CAS  PubMed  Google Scholar 

  14. Price B, Ware A. Time trend of mesothelioma incidence in the United States and projection of future cases: an update based on SEER data for 1973 through 2005. Crit Rev Toxicol. 2009;39:576–88.

    PubMed  Google Scholar 

  15. Albin M, Magnani C, Krstev S, Rapiti E, Shefer I. Asbestos and cancer: an overview of current trends in Europe. Environ Health Perspect. 1999;107 Suppl 2:289–98.

    PubMed Central  PubMed  Google Scholar 

  16. Kishimoto T, Ozaki S, Kato K, Nishi H, Genba K. Malignant pleural mesothelioma in parts of Japan in relationship to asbestos exposure. Ind Health. 2004;42:435–9.

    PubMed  Google Scholar 

  17. Goldberg M, Imbernon E, Rolland P, et al. The French national mesothelioma surveillance program. Occup Environ Med. 2006;63:390–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Park EK, Hannaford-Turner KM, Hyland RA, Johnson AR, Yates DH. Asbestos-related occupational lung diseases in NSW, Australia and potential exposure of the general population. Ind Health. 2008;46:535–40.

    CAS  PubMed  Google Scholar 

  19. Bernstein D, Castranova V, Donaldson K, et al. Testing of fibrous particles: short-term assays and strategies. Inhal Toxicol. 2005;17:497–537. of an ILSI Risk Science Institute Working Group.

    CAS  PubMed  Google Scholar 

  20. Wagner JC, Berry G. Mesotheliomas in rats following inoculation with asbestos. Br J Cancer. 1969;23:567–81.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Davis JM. Structural variations between pleural and peritoneal mesotheliomas produced in rats by the injection of crocidolite asbestos. Ann Anat Pathol (Paris). 1976;21:199–210.

    CAS  Google Scholar 

  22. Davis JM. The histopathology and ultrastructure of pleural mesotheliomas produced in the rat by injections of crocidolite asbestos. Br J Exp Pathol. 1979;60:642–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Fleury-Feith J, Lecomte C, Renier A, et al. Hemizygosity of Nƒ2 is associated with increased susceptibility to asbestos-induced peritoneal tumours. Oncogene. 2003;22:3799–805.

    CAS  PubMed  Google Scholar 

  24. Adamson IYR, Bakowska J. KGF and HGF are growth factors for mesothelial cells in pleural lavage fluid after intratracheal asbestos. Exp Lung Res. 2001;27:605–16.

    CAS  PubMed  Google Scholar 

  25. Gelzleichter TR, Bermudez E, Mangum JB, Wong BA, Moss OR, Everitt JI. Pulmonary and pleural responses in Fischer 344 rats following short-term inhalation of a synthetic vitreous fiber. 2. Pathobiologic responses. Fund Appl Toxicol. 1996;30:39–46.

    CAS  Google Scholar 

  26. Everitt JI, Gelzleichter TR, Bermudez E, et al. Comparison of pleural responses of rats and hamsters to subchronic inhalation of refractory ceramic fibers. Environ Health Perspect. 1997;105 Suppl 5:1209–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Boutin C, Dumortier P, Rey F, Viallat JR, Devuyst P. Black spots concentrate oncogenic asbestos fibers in the parietal pleura: thoracoscopic and mineralogic study. Am J Respir Crit Care Med. 1996;153:444–9.

    CAS  PubMed  Google Scholar 

  28. Libbus BL, Craighead JE. Chromosomal translocations with specific breakpoints in asbestos-induced rat mesotheliomas. Cancer Res. 1988;48:6455–61.

    CAS  PubMed  Google Scholar 

  29. Ni Z, Liu YQ, Keshava N, Zhou G, Whong WZ, Ong TM. Analysis of K-ras and p53 mutations in mesotheliomas from humans and rats exposed to asbestos. Mutat Res. 2000;468:87–92.

    CAS  PubMed  Google Scholar 

  30. Unfried K, Kociok N, Roller M, Friemann J, Pott F, Dehnen W. P53 mutations in tumours induced by intraperitoneal injection of crocidolite asbestos and benzo[a]pyrene in rats. Exp Toxicol Pathol. 1997;49:181–7.

    CAS  PubMed  Google Scholar 

  31. Unfried K, Schürkes C, Abel J. Distinct spectrum of mutations induced by crocidolite asbestos: clue for 8-hydroxydeoxyguanosine-dependent mutagenesis in vivo. Cancer Res. 2002;62:99–104.

    CAS  PubMed  Google Scholar 

  32. Schurkes C, Brock W, Abel J, Unfried K. Induction of 8-hydroxydeoxyguanosine by man made vitreous fibres and crocidolite asbestos administered intraperitoneally in rats. Mutat Res. 2004;553:59–65.

    CAS  PubMed  Google Scholar 

  33. Vaslet CA, Messier NJ, Kane AB. Accelerated progression of asbestos-induced mesotheliomas in heterozygous p53 (+/−) mice. Toxicol Sci. 2002;68:331–8.

    CAS  PubMed  Google Scholar 

  34. Altomare DA, Vaslet CA, Skele KL, et al. A mouse model recapitulating molecular features of human mesothelioma. Cancer Res. 2005;65:8090–5.

    CAS  PubMed  Google Scholar 

  35. Lecomte C, Andujar P, Renier A, et al. Similar tumor suppressor gene alteration profiles in asbestos-induced murine and human mesothelioma. Cell Cycle. 2005;4:1862–9.

    CAS  PubMed  Google Scholar 

  36. Altomare DA, Menges CW, Pei J, et al. Activated TNF-alpha/NF-kappaB signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice. Proc Natl Acad Sci U S A. 2009;106:3420–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Jaurand MC. Use of in-vitro genotoxicity and cell transformation assays to evaluate potential carcinogenicity of fibres. In: Kane AB, Boffetta P, Sarracci R, Wilbourn JD, editors. Mechanisms in fiber carcinogenesis, vol. 140. 1996. p. 55–72.

    Google Scholar 

  38. Huang SXL, Jaurand MC, Kamp DW, Whysner J, Hei T. Role of mutagenicity in asbestos fiber-induced carcinogenicity and other diseases. J Toxicol Environ Health Part B. 2011;14:1–67.

    CAS  Google Scholar 

  39. Jaurand MC. Mechanisms of fiber-induced genotoxicity. Environ Health Perspect. 1997;105:1073–84.

    PubMed Central  PubMed  Google Scholar 

  40. Ruosaari ST, Nymark PE, Aavikko MM, et al. Aberrations of chromosome 19 in asbestos-associated lung cancer and in asbestos-induced micronuclei of bronchial epithelial cells in vitro. Carcinogenesis. 2008;29:913–7.

    CAS  PubMed  Google Scholar 

  41. Lechner JF, Tokiwa T, LaVeck M, et al. Asbestos-associated chromosomal changes in human mesothelial cells. Proc Natl Acad Sci U S A. 1985;82:3884–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Olofsson K, Mark J. Specificity of asbestos-induced chromosomal aberrations in short-term cultures human mesothelial cells. Cancer Genet Cytogenet. 1989;41:33–9.

    CAS  PubMed  Google Scholar 

  43. Pelin K, Hirvonen A, Taavitsainen M, Linanainmaa K. Cytogenetic response to asbestos fibers in cultured human primary mesothelial cells from 10 different donors. Mutat Res. 1995;334:225–33.

    CAS  PubMed  Google Scholar 

  44. Burmeister B, Schwerdtle T, Poser I, et al. Effects of asbestos on initiation of DNA damage, induction of DNA-strand breaks, P53-expression and apoptosis in primary, SV40-transformed and malignant human mesothelial cells. Mutat Res. 2004;558:81–92.

    CAS  PubMed  Google Scholar 

  45. Poser I, Rahman Q, Lohani M, et al. Modulation of genotoxic effects in asbestos-exposed primary human mesothelial cells by radical scavengers, metal chelators and a glutathione precursor. Mutat Res. 2004;559:19–27.

    CAS  PubMed  Google Scholar 

  46. Chen Q, Marsh J, Ames B, Mossman B. Detection of 8-oxo-2′-deoxyguanosine, a marker of oxidative DNA damage, in culture medium from human mesothelial cells exposed to crocidolite asbestos. Carcinogenesis. 1996;17:2525–7.

    CAS  PubMed  Google Scholar 

  47. Fung H, Kow YW, Van Houten B, Mossman BT. Patterns of 8-hydroxydeoxyguanosine formation in DNA and indications of oxidative stress in rat and human pleural mesothelial cells after exposure to crocidolite asbestos. Carcinogenesis. 1997;18:825–32.

    CAS  PubMed  Google Scholar 

  48. Jensen CG, Watson M. Inhibition of cytokinesis by asbestos and synthetic fibres. Cell Biol Intl. 1999;23:829–40.

    CAS  Google Scholar 

  49. Nygren J, Suhonen S, Norppa H, Linnainmaa K. DNA damage in bronchial epithelial and mesothelial cells with and without associated crocidolite asbestos fibers. Environ Mol Mutagen. 2004;44:477–82.

    CAS  PubMed  Google Scholar 

  50. Jaurand MC, Kheuang L, Magne L, Bignon J. Chromosomal changes induced by chrysotile fibres or benzo(3–4)pyrene in rat pleural mesothelial cells. Mutat Res. 1986;169:141–8.

    CAS  PubMed  Google Scholar 

  51. Achard S, Perderiset M, Jaurand MC. Sister chromatid exchanges in rat pleural mesothelial cells treated with crocidolite, attapulgite or benzo 3–4 pyrene. Br J Ind Med. 1987;44:281–3.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Wang NS, Jaurand MC, Magne L, Kheuang L, Pinchon MC, Bignon J. The interactions between asbestos fibers and metaphase chromosomes of rat pleural mesothelial cells in culture. A scanning and transmission electron microscopic study. Am J Pathol. 1987;126:343–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Renier A, Levy F, Pilliere F, Jaurand MC. Uncheduled DNA synthesis in rat pleural mesothelial cells treated with mineral fibres or benzo[a]pyrene. Mutat Res. 1990;241:361–7.

    CAS  PubMed  Google Scholar 

  54. Yegles M, Saint-Etienne L, Renier A, Janson X, Jaurand MC. Induction of metaphase and anaphase/telophase abnormalities by asbestos fibers in rat pleural mesothelial cells in vitro. Am J Respir Cell Mol Biol. 1993;9:186–91.

    CAS  PubMed  Google Scholar 

  55. Dong HY, Buard A, Renier A, Levy F, Saint-Etienne L, Jaurand MC. Role of oxygen derivatives in the cytotoxicity and DNA damage produced by asbestos on rat pleural mesothelial cells in vitro. Carcinogenesis. 1994;15:1251–5.

    CAS  PubMed  Google Scholar 

  56. Dong HY, Buard A, Levy F, Renier A, Laval F, Jaurand MC. Synthesis of poly(ADP-ribose) in asbestos treated rat pleural mesothelial cells in culture. Mutat Res. 1995;331:197–204.

    CAS  PubMed  Google Scholar 

  57. Yegles M, Janson X, Dong HY, Renier A, Jaurand MC. Role of fibre characteristics on cytotoxicity and induction of anaphase/telophase aberrations in rat pleural mesothelial cells in vitro. Correlations with in vivo animal findings. Carcinogenesis. 1995;16:2751–8.

    CAS  PubMed  Google Scholar 

  58. Levresse V, Renier A, Fleury-Feith J, et al. Analysis of cell cycle disruptions in cultures of rat pleural mesothelial cells exposed to asbestos fibres. Am J Respir Cell Mol Biol. 1997;17:660–71.

    CAS  PubMed  Google Scholar 

  59. Fung H, Kow YW, Van Houten B, et al. Asbestos increases mammalian AP-endonuclease gene expression, protein levels, and enzyme activity in mesothelial cells. Cancer Res. 1998;58:189–94.

    CAS  PubMed  Google Scholar 

  60. Liu W, Ernst JD, Broaddus VC. Phagocytosis of crocidolite asbestos induces oxidative stress, DNA damage, and apoptosis in mesothelial cells. Am J Respir Cell Mol Biol. 2000;23:371–8.

    CAS  PubMed  Google Scholar 

  61. Janssen YMW, Heintz NH, Marsh JP, Borm PJA, Mossman BT. Induction of c-fos and c-jun proto-oncogenes in target cells of the lung and pleura by carcinogenic fibers. Am J Respir Cell Mol Biol. 1994;11:522–30.

    CAS  PubMed  Google Scholar 

  62. Timblin CR, Janssen YWM, Mossman BT. Transcriptional activation of the proto-oncogene c-jun by asbestos and H2O2 is directly related to increased proliferation and transformation of tracheal epithelial cells. Cancer Res. 1995;55:2723–6.

    CAS  PubMed  Google Scholar 

  63. Zanella CL, Timblin CR, Cummins A, et al. Asbestos-induced phosphorylation of epidermal growth factor receptor is linked to c-fos and apoptosis. Am J Physiol. 1999;277:L684–93.

    CAS  PubMed  Google Scholar 

  64. Berken A, Abel J. Unfried K. beta1-integrin mediates asbestos-induced phosphorylation of AKT and ERK1/2 in a rat pleural mesothelial cell line. Oncogene. 2003;22:8524–8.

    CAS  PubMed  Google Scholar 

  65. Zanella CL, Posada J, Tritton TR, Mossman BT. Asbestos causes stimulation of the extracellular signal-regulated kinase 1 mitogen-activated protein kinase cascade after phosphorylation of the epidermal growth factor receptor. Cancer Res. 1996;56:5334–8.

    CAS  PubMed  Google Scholar 

  66. Faux SP, Houghton CE, Hubbard A, Patrick G. Increased expression of epidermal growth factor receptor in rat pleural mesothelial cells correlates with carcinogenicity of mineral fibres. Carcinogenesis. 2001;12:2275–80.

    Google Scholar 

  67. Kopnin PB, Kravchenko IV, Furalyov VA, Pylev LN, Kopnin BP. Cell type-specific effects of asbestos on intracellular ROS levels, DNA oxidation and G1 cell cycle checkpoint. Oncogene. 2004;23:8834–40.

    CAS  PubMed  Google Scholar 

  68. Levresse V, Renier A, Levy F, Broaddus VC, Jaurand MC. DNA breakage in asbestos-treated normal and transformed (TSV40) rat pleural mesothelial cells. Mutagenesis. 2000;15:239–44.

    CAS  PubMed  Google Scholar 

  69. Puhakka A, Ollikainen T, Soini Y, et al. Modulation of DNA single-strand breaks by intracellular glutathione in human lung cells exposed to asbestos fibers. Mutat Res. 2002;514:7–17.

    CAS  PubMed  Google Scholar 

  70. Pietruska JR, Kane AB. SV40 oncoproteins enhance asbestos-induced DNA double-strand breaks and abrogate senescence in murine mesothelial cells. Cancer Res. 2007;67:3637–45.

    CAS  PubMed  Google Scholar 

  71. Pelin K, Kivipensas P, Linnainmaa K. Effects of asbestos and man-made vitreous fibers on cell division in cultured human mesothelial cells in comparison to rodent cells. Environ Mol Mutag. 1995;25:118–25.

    CAS  Google Scholar 

  72. Broaddus VC. Asbestos, the mesothelial cell and malignancy: a matter of life or death. Am J Respir Cell Mol Biol. 1997;17:657–9.

    CAS  PubMed  Google Scholar 

  73. Marsella JM, Liu BL, Vaslet CA, Kane AB. Susceptibility of p53-deficient mice to induction of mesothelioma by crocidolite asbestos fibers. Environ Health Perspect. 1997;105(supp 5):1069–72.

    PubMed Central  PubMed  Google Scholar 

  74. Jongsma J, van Montfort E, Vooijs M, et al. A conditional mouse model for malignant mesothelioma. Cancer Cell. 2008;13:261–71.

    CAS  PubMed  Google Scholar 

  75. Merchant JA. Human epidemiology: a review of fiber type and characteristics in the development of malignant and nonmalignant disease. Environ Health Perspect. 1990;88:287–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Baris YI, Grandjean P. Prospective study of mesothelioma mortality in Turkish villages with exposure to fibrous zeolite. J Natl Cancer Inst. 2006;98:414–7.

    CAS  PubMed  Google Scholar 

  77. Coin PG, Roggli VL, Brody AR. Persistence of long, thin chrysotile asbestos fibers in the lungs of rats. Environ Health Perspect. 1994;102 Suppl 5:197–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Greillier L, Astoul P. Mesothelioma and asbestos-related pleural diseases. Respiration. 2008;76:1–15.

    CAS  PubMed  Google Scholar 

  79. IOM. Asbestos: selected cancers. Washington, DC: The National Academies Press; 2006.

    Google Scholar 

  80. Fubini B. Surface reactivity in the pathogenic response to particulates. Environ Health Perspect. 1997;105:1013–20.

    PubMed Central  PubMed  Google Scholar 

  81. McDonald JC. Epidemiology of malignant mesothelioma – an outline. Ann Occup Hyg. 2010;54:851–7.

    PubMed  Google Scholar 

  82. McDonald JC, Harris J, Armstrong B. Mortality in a cohort of vermiculite miners exposed to fibrous amphibole in Libby, Montana. Occup Environ Med. 2004;61:363–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  83. IARC. Silica and some silicates. In: IARC Press G, editors. Monographs on the evaluation of carcinogenic risk of chemical to humans. vol. 42. 1987. p. 39–143.

    Google Scholar 

  84. Hamilton RF, Wu N, Porter D, Buford M, Wolfarth M, Holian A. Particle length-dependent titanium dioxide nanomaterials toxicity and bioactivity. Part Fibre Toxicol. 2009;6:35.

    PubMed Central  PubMed  Google Scholar 

  85. Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320:674–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Poland CA, Duffin R, Kinloch I, et al. Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat Nanotechnol. 2008;3:423–8.

    CAS  PubMed  Google Scholar 

  87. Mercer RR, Scabilloni J, Wang L, et al. Alteration of deposition pattern and pulmonary response as a result of improved dispersion of aspirated single-walled carbon nanotubes in a mouse model. Am J Physiol Lung Cell Mol Physiol. 2008;294:L87–97.

    CAS  PubMed  Google Scholar 

  88. Ryman-Rasmussen JP, Tewksbury EW, Moss OR, Cesta MF, Wong BA, Bonner JC. Inhaled multiwalled carbon nanotubes potentiate airway fibrosis in murine allergic asthma. Am J Respir Cell Mol Biol. 2009;40:349–58.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Porter DW, Hubbs AF, Mercer RR, et al. Mouse pulmonary dose- and time course-responses induced by exposure to multi-walled carbon nanotubes. Toxicology. 2010;269:136–47.

    CAS  PubMed  Google Scholar 

  90. Mercer RR, Hubbs AF, Scabilloni JF, et al. Distribution and persistence of pleural penetrations by multi-walled carbon nanotubes. Part Fibre Toxicol. 2010;7:28.

    PubMed Central  PubMed  Google Scholar 

  91. Takagi A, Hirose A, Nishimura T, et al. Induction of mesothelioma in p53+/− mouse by intraperitoneal application of multi-wall carbon nanotube. J Toxicol Sci. 2008;33:105–16.

    CAS  PubMed  Google Scholar 

  92. Sakamoto Y, Nakae D, Fukumori N. Induction of mesothelioma by a single intrascrotal administration of multi-wall carbon nanotube in intact male Fischer 344 rats. J Toxicol Sci. 2009;34:65–76.

    CAS  PubMed  Google Scholar 

  93. Muller J, Delos M, Panin N, Rabolli V, Huaux F, Lison D. Absence of carcinogenic response to multiwall carbon nanotubes in a 2-year bioassay in the peritoneal cavity of the rat. Toxicol Sci. 2009;110:442–8.

    CAS  PubMed  Google Scholar 

  94. Fubini B, Otero-Arean C. Clinical aspects of the toxicity of inhaled mineral dusts. Chem Soc Rev. 1999;28:373–81.

    CAS  Google Scholar 

  95. Fubini B, Mollo L. Role of iron in the reactivity of mineral fibers. Toxicol Lett. 1995;82–3:951–60.

    Google Scholar 

  96. Hardy JA, Aust AE. The effect of iron binding on the ability of crocidolite asbestos to catalyze DNA single-strand breaks. Carcinogenesis. 1995;16:319–25.

    CAS  PubMed  Google Scholar 

  97. Shukla A, Ramos-Nino M, Mossman B. Cell signaling and transcription factor activation by asbestos in lung injury and disease. Intl J Biochem Cell Biol. 2003;35:1198–209.

    CAS  Google Scholar 

  98. Upadhyay D, Kamp DW. Asbestos-induced pulmonary toxicity: role of DNA damage and apoptosis. Exp Biol Med (Maywood). 2003;228:650–9.

    CAS  Google Scholar 

  99. Brown DM, Fisher C, Donaldson K. Free radical activity of synthetic vitreous fibers: iron chelation inhibits hydroxyl radical generation by refractory ceramic fiber. J Toxicol Environ Health A. 1998;53:545–61.

    CAS  PubMed  Google Scholar 

  100. Okayasu R, Wu L, Hei TK. Biological effects of naturally occurring and man-made fibres: in vitro cytotoxicity and mutagenesis in mammalian cells. Br J Cancer. 1999;79:1319–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Fenoglio I, Tomatis M, Lison D, et al. Reactivity of carbon nanotubes: free radical generation or scavenging activity? Free Radic Biol Med. 2006;40:1227–33.

    CAS  PubMed  Google Scholar 

  102. Galano A, Francisco-Marquez M, Martinex A. Influence of point defects on the free-radical scavenging capability of single-walled carbon nanotubes. J Phys Chem C. 2010;114:8302.

    CAS  Google Scholar 

  103. Di Sotto A, Chiaretti M, Carru GA, Bellucci S, Mazzanti G. Multi-walled carbon nanotubes: lack of mutagenic activity in the bacterial reverse mutation assay. Toxicol Lett. 2009;184:192–7.

    PubMed  Google Scholar 

  104. Wirnitzer U, Herbold B, Voetz M, Ragot J. Studies on the in vitro genotoxicity of baytubes (R), agglomerates of engineered multi-walled carbon-nanotubes (MWCNT). Toxicol Lett. 2009;186:160–5.

    CAS  PubMed  Google Scholar 

  105. Yamashita K, Yoshioka Y, Higashisaka K, et al. Carbon nanotubes elicit DNA damage and inflammatory response relative to their size and shape. Inflammation. 2010;33:276–80.

    CAS  PubMed  Google Scholar 

  106. Muller J, Decordier I, Hoet PH, et al. Clastogenic and aneugenic effects of multi-wall carbon nanotubes in epithelial cells. Carcinogenesis. 2008;29:427–33.

    CAS  PubMed  Google Scholar 

  107. Kisin ER, Murray AR, Sargent L, et al. Genotoxicity of carbon nanofibers: are they potentially more or less dangerous than carbon nanotubes or asbestos? Toxicol Appl Pharmacol. 2011;252:1–10.

    CAS  PubMed  Google Scholar 

  108. Lindberg HK, Falck GC, Suhonen S, et al. Genotoxicity of nanomaterials: DNA damage and micronuclei induced by carbon nanotubes and graphite nanofibres in human bronchial epithelial cells in vitro. Toxicol Lett. 2009;186:166–73.

    CAS  PubMed  Google Scholar 

  109. Pacurari M, Yin XJ, Ding M, et al. Oxidative and molecular interactions of multi-wall carbon nanotubes (MWCNT) in normal and malignant human mesothelial cell. Nanotoxicology. 2008;2:155–70.

    CAS  Google Scholar 

  110. Pacurari M, Yin XJ, Zhao J, et al. Raw single-wall carbon nanotubes induce oxidative stress and activate MAPKs, AP-1, NF-kappaB, and Akt in normal and malignant human mesothelial cells. Environ Health Perspect. 2008;116:1211–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Sanchez VC, Pietruska JR, Miselis NR, Hurt RH, Kane AB. Biopersistence and potential adverse health impacts of fibrous nanomaterials: what have we learned from asbestos? Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2009;1:511–29.

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Manning CB, Vallyathan V, Mossman BT. Diseases caused by asbestos: mechanisms of injury and disease development. Int Immunopharmacol. 2002;2:191–200.

    CAS  PubMed  Google Scholar 

  113. Park SH, Aust A. Participation of iron and nitric oxide in the mutagenicity of asbestos in hgprt-, gpt + chines hamster V79 cells. Cancer Res. 1998;58:1144–8.

    CAS  PubMed  Google Scholar 

  114. Hei T, Louie D, Zhao YL. Genotoxicity versus carcinogenicity: implications from fiber toxicity studies. Inhal Toxicol. 2000;12:141–7.

    CAS  Google Scholar 

  115. MacCorkle RA, Slattery SD, Nash DR, Brinkley BR. Intracellular protein binding to asbestos induces aneuploidy in human lung fibroblasts. Cell Motil Cytoskeleton. 2006;63:646–57.

    CAS  PubMed  Google Scholar 

  116. Sargent LM, Reynolds SH, Castranova V. Potential pulmonary effects of engineered carbon nanotubes: in vitro genotoxic effects. Nanotoxicology. 2010;4:396–408.

    CAS  PubMed  Google Scholar 

  117. Berman DW, Crump KS. A meta-analysis of asbestos-related cancer risk that addresses fiber size and mineral type. Crit Rev Toxicol. 2008;38 Suppl 1:49–73.

    CAS  PubMed  Google Scholar 

  118. Suzuki Y, Yuen SR, Ashley R. Short, thin asbestos fibers contribute to the development of human malignant mesothelioma: pathological evidence. Int J Hyg Environ Health. 2005;208:201–10.

    CAS  PubMed  Google Scholar 

  119. Dodson RF, Hammar SP. Pleural mesothelioma in a woman whose documented past exposure to asbestos was from smoking asbestos-containing filtered cigarettes: the comparative value of analytical transmission electron microscopic analysis of lung and lymph-node tissue. Inhal Toxicol. 2006;18:679–84.

    CAS  PubMed  Google Scholar 

  120. Hesterberg TW, Chase G, Axten C, et al. Biopersistence of synthetic vitreous fibers and amosite asbestos in the rat lung following inhalation. Toxicol Appl Pharmacol. 1998;151:262–75.

    CAS  PubMed  Google Scholar 

  121. Miller BG, Searl A, Davis JMG, et al. Influence of fibre length, dissolution and biopersistence on the production of mesothelioma in the rat peritoneal cavity. Ann Occup Hyg. 1999;43:155–66.

    CAS  PubMed  Google Scholar 

  122. Akiyama I, Ogami A, Oyabu T, Yamato H, Morimoto Y, Tanaka I. Pulmonary effects and biopersistence of deposited silicon carbide whisker after 1-year inhalation in rats. Inhal Toxicol. 2007;19:141–7.

    CAS  PubMed  Google Scholar 

  123. Johnson NF, Hahn FF. Induction of mesothelioma after intrapleural inoculation of F344 rats with silicon carbide whiskers or continuous ceramic filaments. Occup Environ Med. 1996;53:813–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Rodelsperger K, Bruckel B. The carcinogenicity of WHO fibers of silicon carbide: SiC whiskers compared to cleavage fragments of granular SiC. Inhal Toxicol. 2006;18:623–31.

    PubMed  Google Scholar 

  125. Mast RW, Yu CP, Oberdorster G, McConnell EE, Utell MJ. A retrospective review of the carcinogenicity of refractory ceramic fiber in two chronic fischer 344 rat inhalation studies: an assessment of the MTD and implications for risk assessment. Inhal Toxicol. 2000;12:1141–72.

    CAS  PubMed  Google Scholar 

  126. Wagner JC, Skidmore JW, Hill RJ, Griffiths DM. Erionite exposure and mesotheliomas in rats. Br J Cancer. 1985;51:727.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Johnson NF, Edwards RE, Munday DE, Rowe N, Wagner JC. Pluripotential nature of mesotheliomata induced by inhalation of erionite in rats. Br J Exp Pathol. 1984;65:377–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Kane AB. Animal models of malignant mesothelioma. Inhal Toxicol. 2006;18:1001–4.

    PubMed  Google Scholar 

  129. Pass H, Vogelzang N, Carbone M. Malignant Mesothelioma: Advances in Pathogenesis, Diagnosis, and Translational Therapies. Springer Verlag; New York, NY. 2005.

    Google Scholar 

  130. Liu X, Guo L, Morris D, Kane AB, Hurt RH. Targeted removal of bioavailable metal as a detoxification strategy for carbon nanotubes. Carbon N Y. 2008;46:489–500.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Allen BL, Kichambare PD, Gou P, et al. Biodegradation of single-walled carbon nanotubes through enzymatic catalysis. Nano Lett. 2008;8:3899–903.

    CAS  PubMed  Google Scholar 

  132. Liu X, Hurt RH, Kane AB. Biodurability of single-walled carbon nanotubes depends on surface functionalization. Carbon N Y. 2010;48:1961–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Nagai H, Toyokuni S. Biopersistent fiber-induced inflammation and carcinogenesis: lessons learned from asbestos toward safety of fibrous nanomaterials. Arch Biochem Biophys. 2010;502:1–7.

    CAS  PubMed  Google Scholar 

  134. Donaldson K, Aitken R, Tran L, et al. Carbon nanotubes: a review of their properties in relation to pulmonary toxicology and workplace safety. Toxicol Sci. 2006;92:5–22.

    CAS  PubMed  Google Scholar 

  135. Pacurari M, Castranova V, Vallyathan V. Single- and multi-wall carbon nanotubes versus asbestos: are the carbon nanotubes a new health risk to humans? J Toxicol Environ Health A. 2010;73:378–95.

    CAS  PubMed  Google Scholar 

  136. Wick P, Manser P, Limbach LK, et al. The degree and kind of agglomeration affect carbon nanotube cytotoxicity. Toxicol Lett. 2007;168:121–31.

    CAS  PubMed  Google Scholar 

  137. Jaurand MC, Renier A, Daubriac J. Mesothelioma: do asbestos and carbon nanotubes pose the same health risk? Part Fibre Toxicol. 2009;6:16–29.

    PubMed Central  PubMed  Google Scholar 

  138. Kane AB, Hurt RH. Nanotoxicology: the asbestos analogy revisited. Nat Nanotechnol. 2008;3:378–9.

    CAS  PubMed  Google Scholar 

  139. Aschberger K, Johnston HJ, Stone V, et al. Review of carbon nanotubes toxicity and exposure – appraisal of human health risk assessment based on open literature. Crit Rev Toxicol. 2010;40:759–90.

    CAS  PubMed  Google Scholar 

  140. Nymark P, Wikman H, Hienonen-Kempas T, Anttila S. Molecular and genetic changes in asbestos-related lung cancer. Cancer Lett. 2008;265:1–15.

    CAS  PubMed  Google Scholar 

  141. Broaddus VC, Everitt JI, Black B, Kane AB. Non-neoplastic and neoplastic pleural endpoints following fiber exposure. J Toxicol Environ Health B Crit Rev. 2011;14:153–78.

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Kinnula VL, Everitt JI, Mangum JB, Chang LY, Crapo JD. Antioxidant defense mechanisms in cultured pleural mesothelial cells. Am J Respir Cell Mol Biol. 1992;7:95–103.

    CAS  PubMed  Google Scholar 

  143. Hesterberg TW, Hart GA, Chevalier J, et al. The importance of fiber biopersistence and lung dose in determining the chronic inhalation effects of X607, RCF1, and chrysotile asbestos in rats. Toxicol Appl Pharmacol. 1998;153:68–82.

    CAS  PubMed  Google Scholar 

  144. Kodama Y, Boreiko CJ, Maness SC, Hesterberg TW. Cytotoxic and cytogenetic effects of asbestos on human bronchial epithelial cells in culture. Carcinogenesis. 1993;14:691–7.

    CAS  PubMed  Google Scholar 

  145. Kamp DW, Israbian VA, Yeldandi AV, Panos RJ, Graceffa P, Weitzman SA. Phytic acid, an iron chelator, attenuates pulmonary inflammation and fibrosis in rats after intratracheal instillation of asbestos. Toxicol Pathol. 1995;23:689–95.

    CAS  PubMed  Google Scholar 

  146. Shukla A, Jung M, Stern M, et al. Asbestos induces mitochondrial DNA damage and dysfunction linked to the development of apoptosis. Am J Physiol Lung Cell Mol Physiol. 2003;285:L1018–25.

    CAS  PubMed  Google Scholar 

  147. Srivastava RK, Lohani M, Pant AB, Rahman Q. Cyto-genotoxicity of amphibole asbestos fibers in cultured human lung epithelial cell line: role of surface iron. Toxicol Ind Health. 2010;26:575–82.

    CAS  PubMed  Google Scholar 

  148. Hei TK, He ZY, Suzuki K. Effects of antioxidants on fiber mutagenesis. Carcinogenesis. 1995;16:1573–8.

    CAS  PubMed  Google Scholar 

  149. Kamp DW, Weitzman SA. The molecular basis of asbestos induced lung injury. Thorax. 1999;54:638–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Heintz NH, Janssen-Heininger YM, Mossman BT. Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways. Am J Respir Cell Mol Biol. 2010;42:133–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Murthy SS, Testa JR. Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human malignant mesothelioma. J Cell Physiol. 1999;180:150–7.

    CAS  PubMed  Google Scholar 

  152. Christensen BC, Houseman EA, Godleski JJ, et al. Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome. Cancer Res. 2009;69:227–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  153. Valinluck V, Sowers LC. Inflammation-mediated cytosine damage: a mechanistic link between inflammation and the epigenetic alterations in human cancers. Cancer Res. 2007;67:5583–6.

    CAS  PubMed  Google Scholar 

  154. Kasai H, Kawai K. DNA methylation at the C-5 position of cytosine by methyl radicals: a possible role for epigenetic change during carcinogenesis by environmental agents. Chem Res Toxicol. 2009;22:984–9.

    CAS  PubMed  Google Scholar 

  155. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49:1603–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Mutsaers SE. The mesothelial cell. Int J Biochem Cell Biol. 2004;36:9–16.

    CAS  PubMed  Google Scholar 

  157. Michailova KN, Usunoff KG. Serosal membranes (pleura, pericardium, peritoneum). Normal structure, development and experimental pathology. Adv Anat Embryol Cell Biol. 2006;183:i–vii. 1–144, back cover.

    CAS  PubMed  Google Scholar 

  158. Mutsaers SE, Whitaker D, Papadimitriou JM. Mesothelial regeneration is not dependent on subserosal cells. J Pathol. 2000;190:86–92.

    CAS  PubMed  Google Scholar 

  159. Mutsaers SE. Mesothelial cells: their structure, function and role in serosal repair. Respirology. 2002;7:171–91.

    PubMed  Google Scholar 

  160. Foley-Comer AJ, Herrick SE, Al-Mishlab T, Prele CM, Laurent GJ, Mutsaers SE. Evidence for incorporation of free-floating mesothelial cells as a mechanism of serosal healing. J Cell Sci. 2002;115:1383–9.

    CAS  PubMed  Google Scholar 

  161. Mor O, Yaron P, Huszar M, et al. Absence of p53 mutations in malignant mesothelioma. Am J Respir Cell Mol Biol. 1997;16:9–13.

    CAS  PubMed  Google Scholar 

  162. Kitamura F, Araki S, Tanigawa T, Miura H, Akabane H, Iwasaki R. Assessment of mutations of Ha- and Ki-ras oncogenes and the p53 suppressor gene in seven malignant mesothelioma patients exposed to asbestos. PCR-SSCP and sequencing analyses of paraffin-embedded primary tumors. Ind Health. 1998;36:52–6.

    CAS  PubMed  Google Scholar 

  163. Sekido Y. Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells. Cancer Sci. 2010;101:1–6.

    CAS  PubMed  Google Scholar 

  164. Andujar P, Lecomte C, Renier A, et al. Clinico-pathological features and somatic gene alterations in refractory ceramic fibre-induced murine mesothelioma reveal mineral fibre-induced mesothelioma identities. Carcinogenesis. 2007;28:1599–605.

    CAS  PubMed  Google Scholar 

  165. Andujar P, Wang J, Descatha A, et al. p16INK4A inactivation mechanisms in non small-cell lung cancer patients occupationally exposed to asbestos. Lung Cancer. 2010;67:23–30.

    PubMed  Google Scholar 

  166. Christensen BC, Godleski JJ, Marsit CJ, et al. Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma. Carcinogenesis. 2008;29:1555–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Toyooka S, Toyooka KO, Maruyama R, et al. DNA methylation profiles of lung tumors. Mol Cancer Ther. 2001;1:61–7.

    CAS  PubMed  Google Scholar 

  168. Hirao T, Bueno R, Chen CJ, Gordon GJ, Heilig E, Kelsey KT. Alterations of the p16INK4 locus in human malignant mesothelial tumors. Carcinogenesis. 2002;23:1127–30.

    CAS  PubMed  Google Scholar 

  169. Wong L, Zhou J, Anderson D, Kratzke RA. Inactivation of p16INK4a expression in malignant mesothelioma by methylation. Lung Cancer. 2002;38:131–6.

    PubMed  Google Scholar 

  170. Marsit CJ, Houseman EA, Christensen BC, et al. Examination of a CpG island methylator phenotype and implications of methylation profiles in solid tumors. Cancer Res. 2006;66:10621–9.

    CAS  PubMed  Google Scholar 

  171. Destro A, Ceresoli GL, Baryshnikova E, et al. Gene methylation in pleural mesothelioma: correlations with clinico-pathological features and patient’s follow-up. Lung Cancer. 2008;59:369–76.

    PubMed  Google Scholar 

  172. Guled M, Lahti L, Lindholm PM, et al. CDKN2A, NF2, and JUN are dysregulated among other genes by miRNAs in malignant mesothelioma -A miRNA microarray analysis. Gene Chromosome Cancer. 2009;48:615–23.

    CAS  Google Scholar 

  173. Petitjean A, Mathe E, Kato S, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 2007;28:622–9.

    CAS  PubMed  Google Scholar 

  174. Le Calvez F, Mukeria A, Hunt JD, et al. TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. Cancer Res. 2005;65:5076–83.

    PubMed  Google Scholar 

  175. Husgafvel-Pursiainen K, Karjalainen A, Kannio A, et al. Lung cancer and past occupational exposure to asbestos. Role of p53 and K-ras mutations. Am J Respir Cell Mol Biol. 1999;20:667–74.

    CAS  PubMed  Google Scholar 

  176. Jean D, Thomas E, Renier A, et al. Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma. Am J Pathol. 2011;176:881–94.

    Google Scholar 

  177. Bianchi AB, Mitsunaga S, Cheng J, et al. High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesothelioma. Proc Natl Acad Sci U S A. 1995;92:10854–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  178. Sekido Y, Pass HI, Bader S, Mew DJ, Christmas MF, Gazdar AF. Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer. Cancer Res. 1995;55:1227–31.

    CAS  PubMed  Google Scholar 

  179. Lallemand D, Curto M, Saotome I, Giovannini M, McClatchey AI. NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev. 2003;17:1090–100.

    CAS  PubMed Central  PubMed  Google Scholar 

  180. Yi C, Troutman S, Fera D, et al. A tight Junction-associated merlin-angiomotin complex mediates Merlin’s regulation of mitogenic signaling and tumor suppressive functions. Cancer Cell. 2010;19:527–40.

    Google Scholar 

  181. Stamenkovic I, Yu Q. Merlin, a “magic” linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival. Curr Protein Pept Sci. 2010;11:471–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  182. Tiainen M, Tammilehto L, Mattson K, Knuutila S. Nonrandom chromosomal abnormalities in malignant pleural mesothelioma. Cancer Genet Cytogenet. 1988;33:251–74.

    CAS  PubMed  Google Scholar 

  183. Pyrhonen S, Tiainen M, Rautonen J, et al. Comparison of DNA and karyotype ploidy in malignant mesothelioma. Cancer Genet Cytogenet. 1992;60:8–13.

    CAS  PubMed  Google Scholar 

  184. Tiainen M, Hopman A, Moesker O, et al. Interphase cytogenetics on paraffin sections of malignant pleural mesothelioma. A comparison to conventional karyotyping and flow cytometric studies. Cancer Genet Cytogenet. 1992;62:171–9.

    CAS  PubMed  Google Scholar 

  185. Tiainen M, Kere J, Tammilehto L, Mattson K, Knuutila S. Abnormalities of chromosomes 7 and 22 in human malignant pleural mesothelioma: correlation between Southern blot and cytogenetic analyses. Gene Chromosome Cancer. 1992;4:176–82.

    CAS  Google Scholar 

  186. Tiainen M, Rautonen J, Pyrhonen S, Tammilehto L, Mattson K, Knuutila S. Chromosome number correlates with survival in patients with malignant pleural mesothelioma. Cancer Genet Cytogenet. 1992;62:21–4.

    CAS  PubMed  Google Scholar 

  187. Kivipensas P, Bjorkqvist AM, Karhu R, et al. Gains and losses of DNA sequences in malignant mesothelioma by comparative genomic hybridization. Cancer Genet Cytogenet. 1996;89:7–13.

    CAS  PubMed  Google Scholar 

  188. Lindholm PM, Salmenkivi K, Vauhkonen H, et al. Gene copy number analysis in malignant pleural mesothelioma using oligonucleotide array CGH. Cytogenet Genome Res. 2007;119:46–52.

    CAS  PubMed  Google Scholar 

  189. Ivanov SV, Miller J, Lucito R, et al. Genomic events associated with progression of pleural malignant mesothelioma. Int J Cancer. 2009;124:589–99.

    CAS  PubMed Central  PubMed  Google Scholar 

  190. Bueno R, De Rienzo A, Dong L, et al. Second generation sequencing of the mesothelioma tumor genome. PLoS One. 2010;5:e10612.

    PubMed Central  PubMed  Google Scholar 

  191. Cheung M, Pei J, Pei Y, Jhanwar SC, Pass HI, Testa JR. The promyelocytic leukemia zinc-finger gene, PLZF, is frequently downregulated in malignant mesothelioma cells and contributes to cell survival. Oncogene. 2010;29:1633–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  192. Christensen BC, Houseman EA, Poage GM, et al. Integrated profiling reveals a global correlation between epigenetic and genetic alterations in mesothelioma. Cancer Res. 2010;70:5686–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  193. Hagemeijer A, Versnel MA, Van Drunen E, et al. Cytogenetic analysis of malignant mesothelioma. Cancer Genet Cytogenet. 1990;47:1–28.

    CAS  PubMed  Google Scholar 

  194. Ribotta M, Roseo F, Salvio M, et al. Recurrent chromosome 6 abnormalities in malignant mesothelioma. Monaldi Arch Chest Dis. 1998;53:228–35.

    CAS  PubMed  Google Scholar 

  195. Mitelman F, Johansson B, Mertens F. Database of chromosome aberrations in cancer; 2008.

    Google Scholar 

  196. Gisselsson D, Pettersson L, Hoglund M, et al. Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc Natl Acad Sci U S A. 2000;97:5357–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  197. Tiainen M, Tammilehto L, Rautonen J, Tuomi T, Mattson K, Knuutila S. Chromosomal abnormalities and their correlations with asbestos exposure and survival in patients with mesothelioma. Br J Cancer. 1989;60:618–26.

    CAS  PubMed Central  PubMed  Google Scholar 

  198. Tammilehto L, Tuomi T, Tiainen M, et al. Malignant mesothelioma: clinical characteristics, asbestos mineralogy and chromosomal abnormalities of 41 patients. Eur J Cancer. 1992;28A:1373–9.

    CAS  PubMed  Google Scholar 

  199. Bjorkqvist AM, Tammilehto L, Nordling S, et al. Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung. Br J Cancer. 1998;77:260–9.

    CAS  PubMed  Google Scholar 

  200. Bjorkqvist AM, Wolf M, Nordling S, et al. Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis. Br J Cancer. 1999;81:1111–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  201. Assamaki R, Sarlomo-Rikala M, Lopez-Guerrero JA, et al. Array comparative genomic hybridization analysis of chromosomal imbalances and their target genes in gastrointestinal stromal tumors. Gene Chromosome Cancer. 2007;46:564–76.

    CAS  Google Scholar 

  202. Tsou JA, Shen LY, Siegmund KD, et al. Distinct DNA methylation profiles in malignant mesothelioma, lung adenocarcinoma, and non-tumor lung. Lung Cancer. 2005;47:193–204.

    PubMed  Google Scholar 

  203. Goto Y, Shinjo K, Kondo Y, et al. Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma. Cancer Res. 2009;69:9073–82.

    CAS  PubMed  Google Scholar 

  204. Tsou JA, Galler JS, Wali A, et al. DNA methylation profile of 28 potential marker loci in malignant mesothelioma. Lung Cancer. 2007;58:220–30.

    PubMed Central  PubMed  Google Scholar 

  205. Nymark P, Guled M, Borze I, Faisal A, Lahti L. Salmenkivi K. Integrative analysis of microRNA, mRNA and acGH data reveals asbestos- and histology-related changes in lung cancer. 2011;50(8):585–97.

    CAS  Google Scholar 

  206. Ivanov SV, Goparaju CM, Lopez P, et al. Pro-tumorigenic effects of miR-31 loss in mesothelioma. J Biol Chem. 2010;9:2124.

    Google Scholar 

  207. Pass HI, Goparaju C, Ivanov S, et al. hsa-miR-29c* is linked to the prognosis of malignant pleural mesothelioma. Cancer Res. 2010;70:1916–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  208. Murakami H, Mizuno T, Taniguchi T, et al. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res. 2011;71:873–83.

    CAS  PubMed  Google Scholar 

  209. Thurneysen C, Opitz I, Kurtz S, Weder W, Stahel RA, Felley-Bosco E. Functional inactivation of NF2/merlin in human mesothelioma. Lung Cancer. 2009;64:140–7.

    PubMed  Google Scholar 

  210. Romagnoli S, Fasoli E, Vaira V, et al. Identification of potential therapeutic targets in malignant mesothelioma using cell-cycle gene expression analysis. Am J Pathol. 2009;174:762–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  211. Crispi S, Fagliarone C, Biroccio A, et al. Antiproliferative effect of Aurora kinase targeting in mesothelioma. Lung Cancer. 2010;70:271–9.

    PubMed  Google Scholar 

  212. Roe OD, Anderssen E, Sandeck H, Christensen T, Larsson E, Lundgren S. Malignant pleural mesothelioma: genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets. Lung Cancer. 2010;67:57–68.

    PubMed  Google Scholar 

  213. Lopez-Rios F, Chuai S, Flores R, et al. Global gene expression profiling of pleural mesotheliomas: overexpression of aurora kinases and P16/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction. Cancer Res. 2006;66:2970–9.

    CAS  PubMed  Google Scholar 

  214. Rubin CI, Atweh GF. The role of stathmin in the regulation of the cell cycle. J Cell Biochem. 2004;93:242–50.

    CAS  PubMed  Google Scholar 

  215. Kim JY, Harvard C, You L, et al. Stathmin is overexpressed in malignant mesothelioma. Anticancer Res. 2007;27:39–44.

    CAS  PubMed  Google Scholar 

  216. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141:1117–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  217. Vintman L, Nielsen S, Berner A, Reich R, Davidson B. Mitogen-activated protein kinase expression and activation does not differentiate benign from malignant mesothelial cells. Cancer. 2005;103:2427–33.

    CAS  PubMed  Google Scholar 

  218. de Melo M, Gerbase MW, Curran J, Pache JC. Phosphorylated extracellular signal-regulated kinases are significantly increased in malignant mesothelioma. J Histochem Cytochem. 2006;54:855–61.

    PubMed  Google Scholar 

  219. Eguchi R, Fujimori Y, Takeda H, et al. Arsenic trioxide induces apoptosis through JNK and ERK in human mesothelioma cells. J Cell Physiol. 2011;226:762–8.

    CAS  PubMed  Google Scholar 

  220. Ou WB, Hubert C, Corson JM, et al. Targeted inhibition of multiple receptor tyrosine kinases in mesothelioma. Neoplasia. 2011;13:12–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  221. Ohta Y, Shridhar V, Bright RK, et al. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer. 1999;81:54–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  222. Konig J, Tolnay E, Wiethege T, Muller K. Co-expression of vascular endothelial growth factor and its receptor flt-1 in malignant pleural mesothelioma. Respiration. 2000;67:36–40.

    CAS  PubMed  Google Scholar 

  223. Strizzi L, Catalano A, Vianale G, et al. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol. 2001;193:468–75.

    CAS  PubMed  Google Scholar 

  224. Filho AL, Baltazar F, Bedrossian C, Michael C, Schmitt FC. Immunohistochemical expression and distribution of VEGFR-3 in malignant mesothelioma. Diagn Cytopathol. 2007;35:786–91.

    PubMed  Google Scholar 

  225. Lee AY, Raz DJ, He B, Jablons DM. Update on the molecular biology of malignant mesothelioma. Cancer. 2007;109:1454–61.

    CAS  PubMed  Google Scholar 

  226. Masood R, Kundra A, Zhu S, et al. Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops. Int J Cancer. 2003;104:603–10.

    CAS  PubMed  Google Scholar 

  227. Jacobson A, Brinck J, Briskin MJ, Spicer AP, Heldin P. Expression of human hyaluronan synthases in response to external stimuli. Biochem J. 2000;348:29–35.

    CAS  PubMed Central  PubMed  Google Scholar 

  228. Heldin P, Asplund T, Ytterberg D, Thelin S, Laurent TC. Characterization of the molecular mechanism involved in the activation of hyaluronan synthase by platelet-derived growth factor in human mesothelial cells. Biochem J. 1992;283(Pt 1):165–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  229. Gerwin BI, Lechner JF, Reddel RR, et al. Comparison of production of transforming growth factor-beta and platelet-derived growth factor by normal human mesothelial cells and mesothelioma cell lines. Cancer Res. 1987;47:6180–4.

    CAS  PubMed  Google Scholar 

  230. Versnel MA, Claessonwelsh L, Hammacher A, et al. Human malignant mesothelioma cell lines express PDGF beta-receptors whereas cultured normal mesothelial cells express predominantly PDGF alpha-receptors. Oncogene. 1991;6:2005–11.

    CAS  PubMed  Google Scholar 

  231. Metheny-Barlow LJ, Flynn B, van Gijssel HE, Marrogi A, Gerwin BI. Paradoxical effects of platelet-derived growth factor-A overexpression in malignant mesothelioma. Antiproliferative effects in vitro and tumorigenic stimulation in vivo. Am J Respir Cell Mol Biol. 2001;24:694–702.

    CAS  PubMed  Google Scholar 

  232. Van der Meeren A, Seddon MB, Betsholtz CA, Lechner JF, Gerwin BI. Tumorigenic conversion of human mesothelial cells as a consequence of platelet-derived growth factor-A chain overexpression. Am J Respir Cell Mol Biol. 1993;8:214–21.

    PubMed  Google Scholar 

  233. Agarwal V, Lind MJ, Cawkwell L. Targeted epidermal growth factor receptor therapy in malignant pleural mesothelioma: where do we stand. Cancer Treat Rev. 2010;37:533–542.

    PubMed  Google Scholar 

  234. Hoang CD, Zhang X, Scott PD, et al. Selective activation of insulin receptor substrate-1 and -2 in pleural mesothelioma cells: association with distinct malignant phenotypes. Cancer Res. 2004;64:7479–85.

    CAS  PubMed  Google Scholar 

  235. Whitson BA, Kratzke RA. Molecular pathways in malignant pleural mesothelioma. Cancer Lett. 2006;239:183–9.

    CAS  PubMed  Google Scholar 

  236. Jaurand MC, Fleury-Feith J. Mesothelial cells. In: Light RW, Lee YCG, editors. Textbook of pleural diseases. 2nd ed. London: Hodder Arnold; 2008. p. 27–37.

    Google Scholar 

  237. Lee TC, Zhang Y, Aston C, et al. Normal human mesothelial cells and mesothelioma cell lines express insulin-like growth factor I and associated molecules. Cancer Res. 1993;53:2858–64.

    CAS  PubMed  Google Scholar 

  238. Liu Z, Klominek J. Regulation of matrix metalloprotease activity in malignant mesothelioma cell lines by growth factors. Thorax. 2003;58:198–203.

    CAS  PubMed Central  PubMed  Google Scholar 

  239. Jagadeeswaran R, Ma PC, Seiwert TY, et al. Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma. Cancer Res. 2006;66:352–61.

    CAS  PubMed  Google Scholar 

  240. Kawaguchi K, Murakami H, Taniguchi T, et al. Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells. Carcinogenesis. 2009;30:1097–105.

    CAS  PubMed  Google Scholar 

  241. Tolnay E, Kuhnen C, Wiethege T, König JE, Voss B, Müller KM. Hepatocyte growth factor/scatter factor and its receptor c-Met are overexpressed and associated with an increased microvessel density in malignant pleural mesothelioma. J Cancer Res Clin Oncol. 1998;124:291–6.

    CAS  PubMed  Google Scholar 

  242. Thirkettle I, Harvey P, Hasleton PS, Ball RY, Warn RM. Immunoreactivity for cadherins, HGF/SF, met, and erbB-2 in pleural malignant mesotheliomas. Histopathology. 2000;36:522–8.

    CAS  PubMed  Google Scholar 

  243. Harvey P, Warn A, Dobbin S, et al. Expression of HGF/SF in mesothelioma cell lines and its effects on cell motility, proliferation and morphology. Br J Cancer. 1998;77:1052–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  244. Mukohara T, Civiello G, Davis IJ, et al. Inhibition of the met receptor in mesothelioma. Clin Cancer Res. 2005;11:8122–30.

    CAS  PubMed  Google Scholar 

  245. Besson A, Robbins SM, Yong VW. PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. Eur J Biochem. 1999;263:605–11.

    CAS  PubMed  Google Scholar 

  246. Daubriac J, Fleury-Feith J, Kheuang L, et al. Malignant pleural mesothelioma cells resist anoikis as quiescent pluricellular aggregates. Cell Death Differ. 2009;16:1146–55.

    CAS  PubMed  Google Scholar 

  247. Altomare DA, You H, Xiao GH, et al. Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth. Oncogene. 2005;24:6080–9.

    CAS  PubMed  Google Scholar 

  248. Suzuki Y, Murakami H, Kawaguchi K, et al. Activation of the PI3K-AKT pathway in human malignant mesothelioma cells. Mol Med Rep. 2009;2:181–8.

    CAS  PubMed  Google Scholar 

  249. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469–80.

    CAS  PubMed  Google Scholar 

  250. Lee AY, He B, You L, et al. Dickkopf-1 antagonizes Wnt signaling independent of beta-catenin in human mesothelioma. Biochem Biophys Res Commun. 2004;323:1246–50.

    CAS  PubMed  Google Scholar 

  251. He B, Lee AY, Dadfarmay S, et al. Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in beta-catenin-deficient human mesothelioma cells. Cancer Res. 2005;65:743–8.

    CAS  PubMed  Google Scholar 

  252. Batra S, Shi Y, Kuchenbecker KM, et al. Wnt inhibitory factor-1, a Wnt antagonist, is silenced by promoter hypermethylation in malignant pleural mesothelioma. Biochem Biophys Res Commun. 2006;342:1228–32.

    CAS  PubMed  Google Scholar 

  253. Kohno H, Amatya VJ, Takeshima Y, et al. Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma. Oncol Rep. 2010;24:423–31.

    CAS  PubMed  Google Scholar 

  254. Mazieres J, You L, He B, et al. Wnt2 as a new therapeutic target in malignant pleural mesothelioma. Int J Cancer. 2005;117:326–32.

    CAS  PubMed  Google Scholar 

  255. Soini Y, Kinnula V, Kaarteenaho-Wiik R, Kurttila E, Linnainmaa K, Paakko P. Apoptosis and expression of apoptosis regulating proteins bcl-2, mcl-1, bcl-X, and bax in malignant mesothelioma. Clin Cancer Res. 1999;5:3508–15.

    CAS  PubMed  Google Scholar 

  256. Rippo MR, Moretti S, Vescovi S, et al. FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells. Oncogene. 2004;23:7753–60.

    CAS  PubMed  Google Scholar 

  257. O’Kane SL, Pound RJ, Campbell A, Chaudhuri N, Lind MJ, Cawkwell L. Expression of bcl-2 family members in malignant pleural mesothelioma. Acta Oncol. 2006;45:449–53.

    PubMed  Google Scholar 

  258. Jin L, Amatya VJ, Takeshima Y, Shrestha L, Kushitani K, Inai K. Evaluation of apoptosis and immunohistochemical expression of the apoptosis-related proteins in mesothelioma. Hiroshima J Med Sci. 2010;59:27–33.

    CAS  PubMed  Google Scholar 

  259. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    CAS  PubMed  Google Scholar 

  260. Kafiri G, Thomas DM, Shepherd NA, Krausz T, Lane DP, Hall PA. p53 expression is common in malignant mesothelioma. Histopathology. 1992;21:331–4.

    CAS  PubMed  Google Scholar 

  261. Ramael M, Lemmens G, Eerdekens C, et al. Immunoreactivity for p53 protein in malignant mesothelioma and non-neoplastic mesothelium. J Pathol. 1992;168:371–5.

    CAS  PubMed  Google Scholar 

  262. Mayall FG, Goddard H, Gibbs AR. The frequency of p53 immunostaining in asbestos-associated mesotheliomas and non-asbestos-associated mesotheliomas. Histopathology. 1993;22:383–6.

    CAS  PubMed  Google Scholar 

  263. Attanoos RL, Griffin A, Gibbs AR. The use of immunohistochemistry in distinguishing reactive from neoplastic mesothelium. A novel use for desmin and comparative evaluation with epithelial membrane antigen, p53, platelet-derived growth factor-receptor, P-glycoprotein and Bcl-2. Histopathology. 2003;43:231–8.

    CAS  PubMed  Google Scholar 

  264. Feng Z, Levine AJ. The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol. 2010;20:427–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  265. Leard LE, Broaddus VC. Mesothelial cell proliferation and apoptosis. Respirology. 2004;9:292–9.

    PubMed  Google Scholar 

  266. Wilson SM, Barbone D, Yang TM, et al. mTOR mediates survival signals in malignant mesothelioma grown as tumor fragment spheroids. Am J Respir Cell Mol Biol. 2008;39:576–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  267. Singhal S, Wiewrodt R, Malden LD, et al. Gene expression profiling of malignant mesothelioma. Clin Cancer Res. 2003;9:3080–97.

    CAS  PubMed  Google Scholar 

  268. Lampson MA, Cheeseman IM. Sensing centromere tension: aurora B and the regulation of kinetochore function. Trends Cell Biol. 2011;21:133–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  269. Jensen CG, Jensen LCW, Rieder CL, Cole RW, Ault JG. Long crocidolite asbestos fibers cause polyploidy by sterically blocking cytokinesis. Carcinogenesis. 1996;17:2013–21.

    CAS  PubMed  Google Scholar 

  270. Cortez BA, Machadosantelli GM. Chrysotile effects on human lung cell carcinoma in culture: 3-D reconstruction and DNA quantification by image analysis. BMC Cancer. 2008;8:181.

    PubMed Central  PubMed  Google Scholar 

  271. Mijailovich SM, Kojic M, Tsuda A. Particle-induced indentation of the alveolar epithelium caused by surface tension forces. J Appl Physiol. 2010;109:1179–94.

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA

    Agnes B. Kane MD, PhD

  2. INSERM UMR-S 1162. Functional Genomics of Solid Tumors, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France

    Didier Jean PhD

  3. Department of Pathology and Genetics, HUSLAB, Helsinki University Central Hospital, Haartmaninkatu 3, 400, Helsinki, HUS, 00029, Finland

    Sakari Knuutila PhD

  4. UMR-S1162. Functional Genomics of Solid Tumors, Institut National de la Santé et de la Recherche Médicale (INSERM), 27, Rue Juliette Dodu, Paris, 75010, France

    Marie-Claude Jaurand DrSc, PhD

Authors
  1. Agnes B. Kane MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Didier Jean PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sakari Knuutila PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marie-Claude Jaurand DrSc, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marie-Claude Jaurand DrSc, PhD .

Editor information

Editors and Affiliations

  1. Helsinki University Central Hospital and Finnish Institute of Occupational Health, Helsinki, Finland

    Sisko Anttila

  2. Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Paolo Boffetta

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag London

About this chapter

Cite this chapter

Kane, A.B., Jean, D., Knuutila, S., Jaurand, MC. (2014). Malignant Mesothelioma: Mechanism of Carcinogenesis. In: Anttila, S., Boffetta, P. (eds) Occupational Cancers. Springer, London. https://doi.org/10.1007/978-1-4471-2825-0_17

Download citation

  • DOI: https://doi.org/10.1007/978-1-4471-2825-0_17

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-4471-2824-3

  • Online ISBN: 978-1-4471-2825-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation