Malignant Mesothelioma: Mechanism of Carcinogenesis

  • Agnes B. Kane
  • Didier Jean
  • Sakari Knuutila
  • Marie-Claude JaurandEmail author


Almost 60 years ago, malignant mesothelioma (MM) was acknowledged as a specific cancer related to the inhalation of asbestos fibers (Wagner et al., Br J Ind Med. 17:260–271, 1960). Its strong association with asbestos exposure triggered the development of researches. They consisted of epidemiological studies to know the risk factors that explain MM occurrence in the population and of experimental studies to understand MM biological development as a neoplastic disease. Since then, MM remains a rare and highly aggressive cancer that prompts researches to better manage patients with MM and to offer efficient therapies. To achieve this goal, a solid knowledge of the mechanisms of mesothelial carcinogenesis is needed and deserves basic researches to progress. So far, our knowledge is based on pathophysiological and toxicological researches and from biological and molecular studies using MM tissue tumor samples and cell lines from humans and experimental animals. Most experimental studies have been based on the cellular and/or animal responses to asbestos fibers and in genetically modified mice, demonstrating the genotoxic effect of asbestos and relationship with MM induction. The development of large-scale analyses allowing global integration of the molecular networks involved in mesothelial cell transformation should increase our understanding of mesothelial carcinogenesis. In human, MM tumors appeared as heterogeneous entities, based on morphological patterns and molecular specificities including gene mutations. The recent development of high-throughput methods allowed classification of MM according to their histological type, genomic and epigenomic characteristics, and deregulated pathways. The aim of the present review is to propose a potential mechanism of mesothelial carcinogenesis by integrating data, underlying the mechanisms that may be shared with other types of fibers that may pose current health issue.


Malignant mesothelioma Mesothelial carcinogenesis Asbestos Pleural carcinogenesis Genomic changes Epigenetic changes Signaling pathways 


  1. 1.
    Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med. 1960;17:260–71.PubMedPubMedCentralGoogle Scholar
  2. 2.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    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(4):435–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Goldberg M, Imbernon E, Rolland P, Gilg Soit Ilg A, Saves M, de Quillacq A, et al. The French National Mesothelioma Surveillance Program. Occup Environ Med. 2006;63(6):390–5.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    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(6):535–40.PubMedCrossRefGoogle Scholar
  6. 6.
    Attanoos RL, Churg A, Galateau-Salle F, Gibbs AR, Roggli VL. Malignant mesothelioma and its non-asbestos causes. Arch Pathol Lab Med. 2018;142(6):753–60.CrossRefGoogle Scholar
  7. 7.
    Grosse Y, Loomis D, Guyton KZ, Lauby-Secretan B, El Ghissassi F, Bouvard V, et al. Carcinogenicity of fluoro-edenite, silicon carbide fibres and whiskers, and carbon nanotubes. Lancet Oncol. 2014;15(13):1427–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Kane AB, Hurt RH, Gao H. The asbestos-carbon nanotube analogy: an update. Toxicol Appl Pharmacol. 2018;361:68–80.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Donaldson K, Poland CA, Murphy FA, Macfarlane M, Chernova T, Schinwald A. Pulmonary toxicity of carbon nanotubes and asbestos - similarities and differences. Adv Drug Deliv Rev. 2013;65(15):2078–86.PubMedCrossRefGoogle Scholar
  10. 10.
    Jaurand MC, Renier A, Daubriac J. Mesothelioma: do asbestos and carbon nanotubes pose the same health risk? Part Fibre Toxicol. 2009;6:16.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Kuempel ED, Jaurand MC, Moller P, Morimoto Y, Kobayashi N, Pinkerton KE, et al. Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans. Crit Rev Toxicol. 2017;47(1):1–58.PubMedCrossRefGoogle Scholar
  12. 12.
    Kane A, Jean D, Knuutila S, Jaurand MC. Malignant mesothelioma: mechanism of carcinogenesis. In: Anttila S, Boffetta P, editors. Occupational cancers. London: Springer-Verlag; 2014. p. 299319.Google Scholar
  13. 13.
    Lippmann M, Yeates DB, Albert RE. Deposition, retention and clearance of inhaled particles. Br J Ind Med. 1980;37:337–62.PubMedPubMedCentralGoogle Scholar
  14. 14.
    IARC. Man-made vitreous fibres. 2002.Google Scholar
  15. 15.
    Nielsen GD, Koponen IK. Insulation fiber deposition in the airways of men and rats. A review of experimental and computational studies. Regul Toxicol Pharmacol. 2018;94:252–70.PubMedCrossRefGoogle Scholar
  16. 16.
    Asgharian B, Owen TP, Kuempel ED, Jarabek AM. Dosimetry of inhaled elongate mineral particles in the respiratory tract: the impact of shape factor. Toxicol Appl Pharmacol. 2018;361:27–35.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Oberdorster G. Evaluation and use of animal models to assess mechanisms of fibre carcinogenicity. IARC Sci Publ. 1996;(140):107–25.Google Scholar
  18. 18.
    Miserocchi GA, Sancini GA, Mantegazza F, Chiappino G. Translocation pathways for inhaled asbestos fibers. Environ Health. 2008;7(1):4.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    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(1):5.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Wang NS. Anatomy of the pleura. Clin Chest Med. 1998;19(2):229–40.PubMedCrossRefGoogle Scholar
  21. 21.
    Wang NS. The preformed stomas connecting the pleural cavity and the lymphatics in the parietal pleura. Am Rev Respir Dis. 1975;111(1):12–20.PubMedGoogle Scholar
  22. 22.
    Hammar SP. The pathology of benign and malignant pleural disease. Chest Surg Clin N Am. 1994;4(3):405–30.PubMedGoogle Scholar
  23. 23.
    Fleury Feith J, Jaurand MC. [Pleural lymphatics and pleural diseases related to fibres]. Rev Pneumol Clin. 2013;69(6):358–362.Google Scholar
  24. 24.
    Mercer RR, Scabilloni JF, Hubbs AF, Wang L, Battelli LA, McKinney W, et al. Extrapulmonary transport of MWCNT following inhalation exposure. Part Fibre Toxicol. 2013;10(1):38.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Porter DW, Hubbs AF, Mercer RR, Wu N, Wolfarth MG, Sriram K, et al. Mouse pulmonary dose- and time course-responses induced by exposure to multi-walled carbon nanotubes. Toxicology. 2010;269(2–3):136–47.PubMedCrossRefGoogle Scholar
  26. 26.
    Oberdorster G, Graham U. Predicting EMP hazard: lessons from studies with inhaled fibrous and non-fibrous nano- and micro-particles. Toxicol Appl Pharmacol. 2018;361:50–61.CrossRefGoogle Scholar
  27. 27.
    Sinis SI, Hatzoglou C, Gourgoulianis KI, Zarogiannis SG. Carbon nanotubes and other engineered nanoparticles induced pathophysiology on mesothelial cells and mesothelial membranes. Front Physiol. 2018;9:295.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Shvedova AA, Yanamala N, Kisin ER, Tkach AV, Murray AR, Hubbs A, et al. Long-term effects of carbon containing engineered nanomaterials and asbestos in the lung: one year post exposure comparisons. Am J Physiol Lung Cell Mol Physiol. 2014;306(2):L170–82.PubMedCrossRefGoogle Scholar
  29. 29.
    Holt PF. Transport of inhaled dust to extrapulmonary sites. J Pathol. 1981;133(2):123–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Muller KM, Schmitz I, Konstantinidis K. Black spots of the parietal pleura: morphology and formal pathogenesis. Respiration. 2002;69(3):261–7.PubMedCrossRefGoogle Scholar
  31. 31.
    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(9):1198–206.PubMedCrossRefGoogle Scholar
  32. 32.
    Pooley FD. Proceedings: the recognition of various types of asbestos as minerals, and in tissues. Clin Sci Mol Med. 1974;47(3):11P–2P.PubMedGoogle Scholar
  33. 33.
    Dodson RF, O’Sullivan MF, Huang J, Holiday DB, Hammar SP. Asbestos in extrapulmonary sites: omentum and mesentery. Chest. 2000;117(2):486–93.PubMedCrossRefGoogle Scholar
  34. 34.
    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(1):444–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Pairon JC, Laurent F, Rinaldo M, Clin B, Andujar P, Ameille J, et al. Pleural plaques and the risk of pleural mesothelioma. J Natl Cancer Inst. 2013;105(4):293–301.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Boffetta P. Epidemiology of peritoneal mesothelioma: a review. Ann Oncol. 2007;18(6):985–90.PubMedCrossRefGoogle Scholar
  37. 37.
    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(7):576–88.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Straif K, Benbrahim-Tallaa L, Baan R, Grosse Y, Secretan B, El Ghissassi F, et al. A review of human carcinogens—part C: metals, arsenic, dusts, and fibres. Lancet Oncol. 2009;10(5):453–4.CrossRefGoogle Scholar
  39. 39.
    IARC. Arsenic, metals, fibres, and dusts. A review of human carcinogens 69372 Lyon Cedex 08, France: International Agency for Research on Cancer; 2012.Google Scholar
  40. 40.
    Paris C, Thaon I, Herin F, Clin B, Lacourt A, Luc A, et al. Occupational asbestos exposure and incidence of colon and rectal cancers in French men: the Asbestos-Related Diseases Cohort (ARDCo-Nut). Environ Health Perspect. 2017;125(3):409–15.CrossRefGoogle Scholar
  41. 41.
    Marant Micallef C, Shield KD, Vignat J, Baldi I, Charbotel B, Fervers B, et al. Cancers in France in 2015 attributable to occupational exposures. Int J Hyg Environ Health. 2019;222(1):22–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Clin B, Thaon I, Boulanger M, Brochard P, Chamming’s S, Gislard A, et al. Cancer of the esophagus and asbestos exposure. Am J Ind Med. 2017;60(11):968–75.PubMedCrossRefGoogle Scholar
  43. 43.
    Mutsaers SE. The mesothelial cell. Int J Biochem Cell Biol. 2004;36(1):9–16.PubMedCrossRefGoogle Scholar
  44. 44.
    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 coverGoogle Scholar
  45. 45.
    Batra H, Antony VB. Pleural mesothelial cells in pleural and lung diseases. J Thorac Dis. 2015;7(6):964–80.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Mutsaers SE, Whitaker D, Papadimitriou JM. Mesothelial regeneration is not dependent on subserosal cells. J Pathol. 2000;190:86–92.PubMedCrossRefGoogle Scholar
  47. 47.
    Mutsaers SE. Mesothelial cells: their structure, function and role in serosal repair. Respirology. 2002;7(3):171–91.PubMedCrossRefGoogle Scholar
  48. 48.
    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.(Pt 7:1383–9.PubMedGoogle Scholar
  49. 49.
    Kienzle A, Servais AB, Ysasi AB, Gibney BC, Valenzuela CD, Wagner WL, et al. Free-floating mesothelial cells in pleural fluid after lung surgery. Front Med (Lausanne). 2018;5:89.CrossRefGoogle Scholar
  50. 50.
    IARC. Some nanomaterials and some fibres. 69372 Lyon Cedex 08, France: International Agency for Research on Cancer; 2017.Google Scholar
  51. 51.
    Wagner JC, Berry G. Mesotheliomas in rats following inoculation with asbestos. Br J Cancer. 1969;23:567–81.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Davis JM. Structural variations between pleural and peritoneal mesotheliomas produced in rats by the injection of crocidolite asbestos. Ann Anat Pathol (Paris). 1976;21(2):199–210.Google Scholar
  53. 53.
    Davis JM. The histopathology and ultrastructure of pleural mesotheliomas produced in the rat by injections of crocidolite asbestos. Br J Exp Pathol. 1979;60(6):642–52.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Fleury-Feith J, Lecomte C, Renier A, Matrat M, Kheuang L, Abramowski V, et al. Hemizygosity of Nƒ2 is associated with increased susceptibility to asbestos-induced peritoneal tumours. Oncogene. 2003;22:3799–805.PubMedCrossRefGoogle Scholar
  55. 55.
    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.PubMedCrossRefGoogle Scholar
  56. 56.
    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. Fundam Appl Toxicol. 1996;30(1):39–46.PubMedCrossRefGoogle Scholar
  57. 57.
    Everitt JI, Gelzleichter TR, Bermudez E, Mangum JB, Wong BA, Janszen DB, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Xu J, Alexander DB, Futakuchi M, Numano T, Fukamachi K, Suzui M, et al. Size- and shape-dependent pleural translocation, deposition, fibrogenesis, and mesothelial proliferation by multiwalled carbon nanotubes. Cancer Sci. 2014;105(7):763–9.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Liao D, Wang Q, He J, Alexander DB, Abdelgied M, El-Gazzar AM, et al. Persistent pleural lesions and inflammation by pulmonary exposure of multiwalled carbon nanotubes. Chem Res Toxicol. 2018;31(10):1025–31.PubMedCrossRefGoogle Scholar
  60. 60.
    Libbus BL, Craighead JE. Chromosomal translocations with specific breakpoints in asbestos-induced rat mesotheliomas. Cancer Res. 1988;48:6455–61.PubMedGoogle Scholar
  61. 61.
    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.PubMedGoogle Scholar
  62. 62.
    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(1–2):59–65.PubMedCrossRefGoogle Scholar
  63. 63.
    Yamaguchi R, Hirano T, Ootsuyama Y, Asami S, Tsurudome Y, Fukada S, et al. Increased 8-hydroxyguanine in DNA and its repair activity in hamster and rat lung after intratracheal instillation of crocidolite asbestos. Jpn J Cancer Res. 1999;90(5):505–9.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    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.PubMedCrossRefGoogle Scholar
  65. 65.
    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(3–4):181–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Bueno R, Stawiski EW, Goldstein LD, Durinck S, De Rienzo A, Modrusan Z, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet. 2016;48(4):407–16.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Jarvis MC, Ebrahimi D, Temiz NA, Harris RS. Mutation signatures including APOBEC in cancer cell lines. JNCI Cancer Spectr. 2018;2(1):1–7.Google Scholar
  68. 68.
    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.PubMedCrossRefGoogle Scholar
  69. 69.
    Shukla A, Gulumian M, Hei TK, Kamp D, Rahman Q, Mossman BT. Multiple roles of oxidants in the pathogenesis of asbestos-induced diseases. Free Radic Biol Med. 2003;34(9):1117–29.CrossRefGoogle Scholar
  70. 70.
    Jiang L, Nagai H, Ohara H, Hara S, Tachibana M, Hirano S, et al. Characteristics and modifying factors of asbestos-induced oxidative DNA damage. Cancer Sci. 2008;99(11):2142–51.PubMedCrossRefGoogle Scholar
  71. 71.
    Huang SX, Jaurand MC, Kamp DW, Whysner J, Hei TK. Role of mutagenicity in asbestos fiber-induced carcinogenicity and other diseases. J Toxicol Environ Health B Crit Rev. 2011;14(1–4):179–245.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Moller P, Danielsen PH, Jantzen K, Roursgaard M, Loft S. Oxidatively damaged DNA in animals exposed to particles. Crit Rev Toxicol. 2013;43(2):96–118.PubMedCrossRefGoogle Scholar
  73. 73.
    Sayan M, Mossman BT. The NLRP3 inflammasome in pathogenic particle and fibre-associated lung inflammation and diseases. Part Fibre Toxicol. 2016;13(1):51.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Arnoldussen YJ, Skaug V, Aleksandersen M, Ropstad E, Anmarkrud KH, Einarsdottir E, et al. Inflammation in the pleural cavity following injection of multi-walled carbon nanotubes is dependent on their characteristics and the presence of IL-1 genes. Nanotoxicology. 2018;12(6):522–38.PubMedCrossRefGoogle Scholar
  75. 75.
    Yanamala N, Kisin ER, Gutkin DW, Shurin MR, Harper M, Shvedova AA. Characterization of pulmonary responses in mice to asbestos/asbestiform fibers using gene expression profiles. J Toxicol Environ Health A. 2018;81(4):60–79.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Teeguarden JG, Webb-Robertson BJ, Waters KM, Murray AR, Kisin ER, Varnum SM, et al. Comparative proteomics and pulmonary toxicity of instilled single-walled carbon nanotubes, crocidolite asbestos, and ultrafine carbon black in mice. Toxicol Sci. 2011;120(1):123–35.PubMedCrossRefGoogle Scholar
  77. 77.
    Chernova T, Murphy FA, Galavotti S, Sun XM, Powley IR, Grosso S, et al. Long-fiber carbon nanotubes replicate asbestos-induced mesothelioma with disruption of the tumor suppressor gene Cdkn2a (Ink4a/Arf). Curr Biol. 2017;27(21):3302–14.e6.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Sneddon S, Patch AM, Dick IM, Kazakoff S, Pearson JV, Waddell N, et al. Whole exome sequencing of an asbestos-induced wild-type murine model of malignant mesothelioma. BMC Cancer. 2017;17(1):396.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Port J, Murphy DJ. Mesothelioma: identical routes to malignancy from asbestos and carbon nanotubes. Curr Biol. 2017;27(21):R1173–R6.PubMedCrossRefGoogle Scholar
  80. 80.
    Huaux F, d’Ursel de Bousies V, Parent MA, Orsi M, Uwambayinema F, Devosse R, et al. Mesothelioma response to carbon nanotubes is associated with an early and selective accumulation of immunosuppressive monocytic cells. Part Fibre Toxicol. 2016;13(1):46.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Kumagai-Takei N, Maeda M, Chen Y, Matsuzaki H, Lee S, Nishimura Y, et al. Asbestos induces reduction of tumor immunity. Clin Dev Immunol. 2011;2011:481439.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Maeda M, Nishimura Y, Kumagai N, Hayashi H, Hatayama T, Katoh M, et al. Dysregulation of the immune system caused by silica and asbestos. J Immunotoxicol. 2010;7(4):268–78.PubMedCrossRefGoogle Scholar
  83. 83.
    Jean D, Jaurand MC. Mesotheliomas in genetically engineered mice unravel mechanism of mesothelial carcinogenesis. Int J Mol Sci. 2018;19(8):2–15.PubMedCentralCrossRefPubMedGoogle Scholar
  84. 84.
    Guo Y, Chirieac LR, Bueno R, Pass H, Wu W, Malinowska IA, et al. Tsc1-Tp53 loss induces mesothelioma in mice, and evidence for this mechanism in human mesothelioma. Oncogene. 2014;33(24):3151–60.PubMedCrossRefGoogle Scholar
  85. 85.
    Jongsma J, van Montfort E, Vooijs M, Zevenhoven J, Krimpenfort P, van der Valk M, et al. A conditional mouse model for malignant mesothelioma. Cancer Cell. 2008;13(3):261–71.PubMedCrossRefGoogle Scholar
  86. 86.
    Kadariya Y, Cheung M, Xu J, Pei J, Sementino E, Menges CW, et al. Bap1 is a Bona fide tumor suppressor: genetic evidence from mouse models carrying heterozygous germline Bap1 mutations. Cancer Res. 2016;76(9):2836–44.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Sementino E, Menges CW, Kadariya Y, Peri S, Xu J, Liu Z, et al. Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas. J Cell Physiol. 2018;233:8952–61.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Nasu M, Emi M, Pastorino S, Tanji M, Powers A, Luk H, et al. High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma. J Thorac Oncol. 2015;10(4):565–76.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Bott M, Brevet M, Taylor BS, Shimizu S, Ito T, Wang L, et al. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet. 2011;43(7):668–72.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Vaslet CA, Messier NJ, Kane AB. Accelerated progression of asbestos-induced mesotheliomas in heterozygous p53 (+/−) mice. Toxicol Sci. 2002;68:331–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Altomare DA, Vaslet CA, Skele KL, De Rienzo A, Devarajan K, Jhanwar SC, et al. A mouse model recapitulating molecular features of human mesothelioma. Cancer Res. 2005;65(18):8090–5.PubMedCrossRefGoogle Scholar
  92. 92.
    Lecomte C, Andujar P, Renier A, Kheuang L, Abramowski V, Mellottee L, et al. Similar tumor suppressor gene alteration profiles in asbestos-induced murine and human mesothelioma. Cell Cycle. 2005;4(12):1862–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Altomare DA, Menges CW, Pei J, Zhang L, Skele-Stump KL, Carbone M, 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(9):3420–5.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    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.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Robinson C, Dick IM, Wise MJ, Holloway A, Diyagama D, Robinson BW, et al. Consistent gene expression profiles in MexTAg transgenic mouse and wild type mouse asbestos-induced mesothelioma. BMC Cancer. 2015;15:983.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Kane A, Jean D, Jaurand MC. Mechanism of mesothelial carcinogenesis. In: Anttila S, Boffetta P, editors. Occupational cancers. London: Springer-Verlag; 2014.Google Scholar
  97. 97.
    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.PubMedCrossRefGoogle Scholar
  98. 98.
    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.PubMedPubMedCentralGoogle Scholar
  99. 99.
    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.PubMedPubMedCentralGoogle Scholar
  100. 100.
    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(2):186–91.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    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(11):2751–8.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Levresse V, Renier A, Fleury-Feith J, Levy F, Moritz S, Vivo C, 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.PubMedCrossRefGoogle Scholar
  103. 103.
    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(3):239–44.PubMedCrossRefGoogle Scholar
  104. 104.
    Pietruska JR, Kane AB. SV40 oncoproteins enhance asbestos-induced DNA double-strand breaks and abrogate senescence in murine mesothelial cells. Cancer Res. 2007;67(8):3637–45.PubMedCrossRefGoogle Scholar
  105. 105.
    Renier A, Levy F, Pilliere F, Jaurand MC. Unscheduled DNA synthesis in rat pleural mesothelial cells treated with mineral fibres or benzo[a]pyrene. Mutat Res. 1990;241:361–7.PubMedCrossRefGoogle Scholar
  106. 106.
    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(6):1251–5.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    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(4):825–32.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    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.PubMedPubMedCentralGoogle Scholar
  110. 110.
    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. 2000;12:2275–80.CrossRefGoogle Scholar
  111. 111.
    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(54):8834–40.PubMedCrossRefGoogle Scholar
  112. 112.
    Broaddus VC. Asbestos, the mesothelial cell and malignancy: a matter of life or death. Am J Respir Cell Mol Biol. 1997;17(6):657–9.PubMedCrossRefGoogle Scholar
  113. 113.
    Acencio MM, Soares B, Marchi E, Silva CS, Teixeira LR, Broaddus VC. Inflammatory cytokines contribute to Asbestos-induced injury of mesothelial cells. Lung. 2015;193(5):831–7.PubMedCrossRefGoogle Scholar
  114. 114.
    Bononi A, Giorgi C, Patergnani S, Larson D, Verbruggen K, Tanji M, et al. BAP1 regulates IP3R3-mediated Ca(2+) flux to mitochondria suppressing cell transformation. Nature. 2017;546(7659):549–53.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Thompson JK, MacPherson MB, Beuschel SL, Shukla A. Asbestos-induced mesothelial to fibroblastic transition is modulated by the inflammasome. Am J Pathol. 2017;187(3):665–78.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Casalone E, Allione A, Viberti C, Pardini B, Guarrera S, Betti M, et al. DNA methylation profiling of asbestos-treated MeT5A cell line reveals novel pathways implicated in asbestos response. Arch Toxicol. 2018;92(5):1785–95.PubMedCrossRefGoogle Scholar
  117. 117.
    Nymark P, Lindholm PM, Korpela MV, Lahti L, Ruosaari S, Kaski S, et al. Gene expression profiles in asbestos-exposed epithelial and mesothelial lung cell lines. BMC Genomics. 2007;8:62.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Shukla A, Macpherson MB, Hillegass J, Ramos-Nino ME, Alexeeva V, Vacek PM, et al. Alterations in gene expression in human mesothelial cells correlate with mineral pathogenicity. Am J Respir Cell Mol Biol. 2009;41:114–23.PubMedCrossRefGoogle Scholar
  119. 119.
    Wang H, Gillis A, Zhao C, Lee E, Wu J, Zhang F, et al. Crocidolite asbestos-induced signal pathway dysregulation in mesothelial cells. Mutat Res. 2011;723(2):171–6.PubMedCrossRefGoogle Scholar
  120. 120.
    Burmeister B, Schwerdtle T, Poser I, Hoffmann E, Hartwig A, Muller WU, 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(1–2):81–92.PubMedCrossRefGoogle Scholar
  121. 121.
    Lohcharoenkal W, Wang L, Stueckle TA, Dinu CZ, Castranova V, Liu Y, et al. Chronic exposure to carbon nanotubes induces invasion of human mesothelial cells through matrix metalloproteinase-2. ACS Nano. 2013;7(9):7711–23.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Boulanger G, Andujar P, Pairon JC, Billon-Galland MA, Dion C, Dumortier P, et al. Quantification of short and long asbestos fibers to assess asbestos exposure: a review of fiber size toxicity. Environ Health. 2014;13:59.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Greillier L, Astoul P. Mesothelioma and asbestos-related pleural diseases. Respiration. 2008;76(1):1–15.PubMedCrossRefGoogle Scholar
  125. 125.
    Fazzo L, Minelli G, De Santis M, Bruno C, Zona A, Conti S, et al. Epidemiological surveillance of mesothelioma mortality in Italy. Cancer Epidemiol. 2018;55:184–91.PubMedCrossRefGoogle Scholar
  126. 126.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Baris YI, Grandjean P. Prospective study of mesothelioma mortality in Turkish villages with exposure to fibrous zeolite. J Natl Cancer Inst. 2006;98(6):414–7.PubMedCrossRefGoogle Scholar
  128. 128.
    IOM. Asbestos: selected cancers. Washington, D.C.: The National Academies Press; 2006.Google Scholar
  129. 129.
    Fubini B. Surface reactivity in the pathogenic response to particulates. Environ Health Perspect. 1997;105(Suppl 5):1013–20.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    McDonald JC. Epidemiology of malignant mesothelioma—an outline. Ann Occup Hyg. 2010;54(8):851–7.PubMedGoogle Scholar
  131. 131.
    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(4):363–6.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    IARC. Silica and some silicates. IARC Monogr Eval Carcinog Risk Chem Hum. 1987;42:1–239.Google Scholar
  133. 133.
    Harik VM. Geometry of carbon nanotubes and mechanisms of phagocytosis and toxic effects. Toxicol Lett. 2017;273:69–85.PubMedCrossRefGoogle Scholar
  134. 134.
    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
  135. 135.
    Hei T, Louie D, Zhao YL. Genotoxicity versus carcinogenicity: implications from fiber toxicity studies. Inhal Toxicol. 2000;12(s3):141–7.PubMedCrossRefGoogle Scholar
  136. 136.
    MacCorkle RA, Slattery SD, Nash DR, Brinkley BR. Intracellular protein binding to asbestos induces aneuploidy in human lung fibroblasts. Cell Motil Cytoskeleton. 2006;63(10):646–57.CrossRefGoogle Scholar
  137. 137.
    Kisin ER, Murray AR, Sargent L, Lowry D, Chirila M, Siegrist KJ, et al. Genotoxicity of carbon nanofibers: are they potentially more or less dangerous than carbon nanotubes or asbestos? Toxicol Appl Pharmacol. 2011;252(1):1–10.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Muller J, Decordier I, Hoet PH, Lombaert N, Thomassen L, Huaux F, et al. Clastogenic and aneugenic effects of multi-wall carbon nanotubes in epithelial cells. Carcinogenesis. 2008;29(2):427–33.PubMedCrossRefGoogle Scholar
  139. 139.
    Lindberg HK, Falck GC, Suhonen S, Vippola M, Vanhala E, Catalan J, 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.PubMedCrossRefGoogle Scholar
  140. 140.
    Cammisuli F, Giordani S, Gianoncelli A, Rizzardi C, Radillo L, Zweyer M, et al. Iron-related toxicity of single-walled carbon nanotubes and crocidolite fibres in human mesothelial cells investigated by synchrotron XRF microscopy. Sci Rep. 2018;8(1):706.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Liu G, Beri R, Mueller A, Kamp DW. Molecular mechanisms of asbestos-induced lung epithelial cell apoptosis. Chem Biol Interact. 2010;188(2):309–18.PubMedCrossRefGoogle Scholar
  142. 142.
    Fubini B, Mollo L. Role of iron in the reactivity of mineral fibers. Toxicol Lett. 1995;82–83:951–60.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    van Berlo D, Clift MJ, Albrecht C, Schins RP. Carbon nanotubes: an insight into the mechanisms of their potential genotoxicity. Swiss Med Wkly. 2012;142:w13698.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Bernstein D, Castranova V, Donaldson K, Fubini B, Hadley J, Hesterberg T, et al.; ILSI Risk Science Institute Working Group. Testing of fibrous particles: short-term assays and strategies. Inhal Toxicol. 2005;17(10):497–537.Google Scholar
  145. 145.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Casali M, Carugno M, Cattaneo A, Consonni D, Mensi C, Genovese U, et al. Asbestos lung burden in necroscopic samples from the general population of Milan, Italy. Ann Occup Hyg. 2015;59(7):909–21.PubMedCrossRefGoogle Scholar
  147. 147.
    Merler E, Somigliana A, Girardi P, Barbieri PG. Residual fibre lung burden among patients with pleural mesothelioma who have been occupationally exposed to asbestos. Occup Environ Med. 2017;74(3):218–27.PubMedCrossRefGoogle Scholar
  148. 148.
    Pollastri S, Gualtieri AF, Vigliaturo R, Ignatyev K, Strafella E, Pugnaloni A, et al. Stability of mineral fibres in contact with human cell cultures. An in situ muXANES, muXRD and XRF iron mapping study. Chemosphere. 2016;164:547–57.CrossRefGoogle Scholar
  149. 149.
    Song Y, Thiagarajah J, Verkman AS. Sodium and chloride concentrations, pH, and depth of airway surface liquid in distal airways. J Gen Physiol. 2003;122(5):511–9.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    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(3):201–10.PubMedCrossRefGoogle Scholar
  151. 151.
    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(9):679–84.PubMedCrossRefGoogle Scholar
  152. 152.
    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):1–7.PubMedCrossRefGoogle Scholar
  153. 153.
    Shinohara N, Nakazato T, Ohkawa K, Tamura M, Kobayashi N, Morimoto Y, et al. Long-term retention of pristine multi-walled carbon nanotubes in rat lungs after intratracheal instillation. J Appl Toxicol. 2016;36(4):501–9.PubMedCrossRefGoogle Scholar
  154. 154.
    Lechner JF, Tokiwa T, LaVeck M, Benedict WF, Banks-Schlegel S, Yeager H Jr, et al. Asbestos-associated chromosomal changes in human mesothelial cells. Proc Natl Acad Sci U S A. 1985;82(11):3884–8.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Hesterberg TW, Hart GA, Chevalier J, Miiller WC, Hamilton RD, Bauer 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.PubMedCrossRefGoogle Scholar
  156. 156.
    Kodama Y, Boreiko CJ, Maness SC, Hesterberg TW. Cytotoxic and cytogenetic effects of asbestos on human bronchial epithelial cells in culture. Carcinogenesis. 1993;14(4):691–7.CrossRefGoogle Scholar
  157. 157.
    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(6):689–95.PubMedCrossRefGoogle Scholar
  158. 158.
    Shukla A, Jung M, Stern M, Fukagawa NK, Taatjes DJ, Sawyer D, et al. Asbestos induces mitochondrial DNA damage and dysfunction linked to the development of apoptosis. Am J Physiol Lung Cell Mol Physiol. 2003;285(5):L1018–25.PubMedCrossRefGoogle Scholar
  159. 159.
    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(9):575–82.PubMedCrossRefGoogle Scholar
  160. 160.
    Hei TK, He ZY, Suzuki K. Effects of antioxidants on fiber mutagenesis. Carcinogenesis. 1995;16(7):1573–8.PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Kamp DW, Weitzman SA. The molecular basis of asbestos induced lung injury. Thorax. 1999;54(7):638–52.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Valinluck V, Sowers LC. Inflammation-mediated cytosine damage: a mechanistic link between inflammation and the epigenetic alterations in human cancers. Cancer Res. 2007;67(12):5583–6.PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    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(6):984–9.PubMedCrossRefPubMedCentralGoogle Scholar
  164. 164.
    Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49(11):1603–16.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    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(2):133–9.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Kettunen E, Knuutila S, Sarhadi VK. Malignant mesothelioma: molecular markers. In: Anttila S, Boffetta P, editors. Occupational cancers. London: Springer-Verlag.Google Scholar
  167. 167.
    Yoshikawa Y, Emi M, Hashimoto-Tamaoki T, Ohmuraya M, Sato A, Tsujimura T, et al. High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. Proc Natl Acad Sci U S A. 2016;113(47):13432–7.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Sekido Y. Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells. Cancer Sci. 2010;101(1):1–6.CrossRefGoogle Scholar
  169. 169.
    de Reynies A, Jaurand MC, Renier A, Couchy G, Hysi I, Elarouci N, et al. Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition. Clin Cancer Res. 2014;20(5):1323–34.PubMedCrossRefGoogle Scholar
  170. 170.
    Hmeljak J, Sanchez-Vega F, Hoadley KA, Shih J, Stewart C, Heiman D, et al. Integrative molecular characterization of Malignant pleural Mesothelioma. Cancer Discov. 2018;8(12):1548–65.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Andujar P, Wang J, Descatha A, Galateau-Sallé F, Abd-Alsamad A, Billon-Galland MA, et al. p16INK4A inactivation mechanisms in non small-cell lung cancer patients occupationally exposed to asbestos. Lung Cancer. 2010;67(1):23–30.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Christensen BC, Godleski JJ, Marsit CJ, Houseman EA, Lopez-Fagundo CY, Longacker JL, et al. Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma. Carcinogenesis. 2008;29(8):1555–9.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Christensen BC, Houseman EA, Godleski JJ, Marsit CJ, Longacker JL, Roelofs CR, et al. Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome. Cancer Res. 2009;69(1):227–34.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Toyooka S, Toyooka KO, Maruyama R, Virmani AK, Girard L, Miyajima K, et al. DNA methylation profiles of lung tumors. Mol Cancer Ther. 2001;1(1):61–7.PubMedGoogle Scholar
  175. 175.
    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.PubMedCrossRefGoogle Scholar
  176. 176.
    Wong L, Zhou J, Anderson D, Kratzke RA. Inactivation of p16INK4a expression in malignant mesothelioma by methylation. Lung Cancer. 2002;38(2):131–6.CrossRefGoogle Scholar
  177. 177.
    Marsit CJ, Houseman EA, Christensen BC, Eddy K, Bueno R, Sugarbaker DJ, et al. Examination of a CpG island methylator phenotype and implications of methylation profiles in solid tumors. Cancer Res. 2006;66(21):10621–9.PubMedCrossRefGoogle Scholar
  178. 178.
    Destro A, Ceresoli GL, Baryshnikova E, Garassino I, Zucali PA, De Vincenzo F, et al. Gene methylation in pleural mesothelioma: correlations with clinico-pathological features and patient’s follow-up. Lung Cancer. 2008;59(3):369–76.PubMedCrossRefGoogle Scholar
  179. 179.
    Guled M, Lahti L, Lindholm PM, Salmenkivi K, Bagwan I, Nicholson AG, et al. CDKN2A, NF2, and JUN are dysregulated among other genes by miRNAs in malignant mesothelioma—a miRNA microarray analysis. Genes Chromosomes Cancer. 2009;48(7):615–23.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Andujar P, Lecomte C, Renier A, Fleury-Feith J, Kheuang L, Daubriac J, 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(7):1599–605.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Mor O, Yaron P, Huszar M, Yellin A, Jakobovitz O, Brok-imoni F, et al. Absence of p53 mutations in malignant mesothelioma. Am J Respir Cell Mol Biol. 1997;16:9–13.PubMedCrossRefGoogle Scholar
  182. 182.
    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.PubMedCrossRefGoogle Scholar
  183. 183.
    Andujar P, Pairon JC, Renier A, Descatha A, Hysi I, Abd-Alsamad I, et al. Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma. Mutagenesis. 2013;28(3):323–31.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Bianchi AB, Mitsunaga S, Cheng J, Klein W, Jhanwar SC, Seizinger B, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    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.PubMedGoogle Scholar
  186. 186.
    Miyanaga A, Masuda M, Tsuta K, Kawasaki K, Nakamura Y, Sakuma T, et al. Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing. J Thorac Oncol. 2015;10(5):844–51.PubMedCrossRefGoogle Scholar
  187. 187.
    Sekido Y. Molecular pathogenesis of malignant mesothelioma. Carcinogenesis. 2013;34(7):1413–9.PubMedCrossRefGoogle Scholar
  188. 188.
    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(6):471–84.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Murthy SS, Testa JR. Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human malignant mesothelioma. J Cell Physiol. 1999;180:150–7.CrossRefPubMedPubMedCentralGoogle Scholar
  190. 190.
    Jean D, Thomas E, Renier A, de Reynies A, Lecomte C, Andujar P, et al. Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma. Am J Pathol. 2011;176(2):881–94.CrossRefGoogle Scholar
  191. 191.
    Lallemand D, Curto M, Saotome I, Giovannini M, McClatchey AI. NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev. 2003;17(9):1090–100.PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Yi C, Troutman S, Fera D, Stemmer-Rachamimov A, Avila JL, Christian N, et al. A tight junction-associated Merlin-Angiomotin complex mediates Merlin’s regulation of mitogenic signaling and tumor suppressive functions. Cancer Cell. 2010;19(4):527–40.CrossRefGoogle Scholar
  193. 193.
    Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43(10):1022–5.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Sneddon S, Leon JS, Dick IM, Cadby G, Olsen N, Brims F, et al. Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma. Gene. 2015;563(1):103–5.PubMedCrossRefGoogle Scholar
  195. 195.
    Panou V, Vyberg M, Weinreich UM, Meristoudis C, Falkmer UG, Roe OD. The established and future biomarkers of malignant pleural mesothelioma. Cancer Treat Rev. 2015;41(6):486–95.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Tallet A, Nault JC, Renier A, Hysi I, Galateau-Salle F, Cazes A, et al. Overexpression and promoter mutation of the TERT gene in malignant pleural mesothelioma. Oncogene. 2014;33(28):3748–452.PubMedCrossRefGoogle Scholar
  197. 197.
    Jaurand MC, Jean D. Biomolecular pathways and malignant pleural mesothelioma. In: Mineo TC, editor. Malignant pleural mesothelioma: present status and future directions. Sharjah: Bentham Science Publishers; 2015. p. 173–96.Google Scholar
  198. 198.
    Hylebos M, Van Camp G, van Meerbeeck JP, Op de Beeck K. The genetic landscape of malignant pleural mesothelioma: results from massively parallel sequencing. J Thorac Oncol. 2016;11(10):1615–26.PubMedCrossRefGoogle Scholar
  199. 199.
    Liu XL, Zuo R, Ou WB. The hippo pathway provides novel insights into lung cancer and mesothelioma treatment. J Cancer Res Clin Oncol. 2018;144(11):2097–106.PubMedCrossRefGoogle Scholar
  200. 200.
    Sato T, Sekido Y. NF2/Merlin inactivation and potential therapeutic targets in mesothelioma. Int J Mol Sci. 2018;19(4):988.PubMedCentralCrossRefPubMedGoogle Scholar
  201. 201.
    Felley-Bosco E, Stahel R. Hippo/YAP pathway for targeted therapy. Transl Lung Cancer Res. 2014;3(2):75–83.PubMedPubMedCentralGoogle Scholar
  202. 202.
    Tranchant R, Quetel L, Tallet A, Meiller C, Renier A, de Koning L, et al. Co-occurring mutations of tumor suppressor genes, LATS2 and NF2, in malignant pleural mesothelioma. Clin Cancer Res. 2017;23(12):3191–202.PubMedCrossRefGoogle Scholar
  203. 203.
    Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, et al. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res. 2011;71(3):873–83.PubMedCrossRefGoogle Scholar
  204. 204.
    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(2):140–7.PubMedCrossRefGoogle Scholar
  205. 205.
    Romagnoli S, Fasoli E, Vaira V, Falleni M, Pellegrini C, Catania A, et al. Identification of potential therapeutic targets in malignant mesothelioma using cell-cycle gene expression analysis. Am J Pathol. 2009;174(3):762–70.PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Crispi S, Fagliarone C, Biroccio A, D’Angelo C, Galati R, Sacchi A, et al. Antiproliferative effect of Aurora kinase targeting in mesothelioma. Lung Cancer. 2010;70(3):271–9.PubMedCrossRefGoogle Scholar
  207. 207.
    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(1):57–68.CrossRefPubMedPubMedCentralGoogle Scholar
  208. 208.
    Lopez-Rios F, Chuai S, Flores R, Shimizu S, Ohno T, Wakahara K, 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(6):2970–9.CrossRefPubMedPubMedCentralGoogle Scholar
  209. 209.
    Rubin CI, Atweh GF. The role of stathmin in the regulation of the cell cycle. J Cell Biochem. 2004;93(2):242–50.PubMedCrossRefGoogle Scholar
  210. 210.
    Kim JY, Harvard C, You L, Xu Z, Kuchenbecker K, Baehner R, et al. Stathmin is overexpressed in malignant mesothelioma. Anticancer Res. 2007;27(1A):39–44.PubMedGoogle Scholar
  211. 211.
    Birnie KA, Yip YY, Ng DC, Kirschner MB, Reid G, Prele CM, et al. Loss of mir-223 and JNK signalling contribute to elevated stathmin in malignant pleural mesothelioma. Mol Cancer Res. 2015;13(7):1106–18.PubMedCrossRefGoogle Scholar
  212. 212.
    Aubrey BJ, Strasser A, Kelly GL. Tumor-suppressor functions of the TP53 pathway. Cold Spring Harb Perspect Med. 2016;6(5):1–16.PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. BAP1 and cancer. Nat Rev Cancer. 2013;13(3):153–9.PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Luchini C, Wood LD, Cheng L, Nottegar A, Stubbs B, Solmi M, et al. Extranodal extension of lymph node metastasis is a marker of poor prognosis in oesophageal cancer: a systematic review with meta-analysis. J Clin Pathol. 2016;69:956.CrossRefGoogle Scholar
  215. 215.
    Knijnenburg TA, Wang L, Zimmermann MT, Chambwe N, Gao GF, Cherniack AD, et al. Genomic and molecular landscape of DNA damage repair deficiency across the cancer genome atlas. Cell Rep. 2018;23(1):239–54.e6.PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Mairinger FD, Werner R, Flom E, Schmeller J, Borchert S, Wessolly M, et al. miRNA regulation is important for DNA damage repair and recognition in malignant pleural mesothelioma. Virchows Arch. 2017;470(6):627–37.PubMedCrossRefGoogle Scholar
  217. 217.
    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(11):3508–15.PubMedGoogle Scholar
  218. 218.
    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(4):449–53.PubMedCrossRefGoogle Scholar
  219. 219.
    Daubriac J, Fleury-Feith J, Kheuang L, Galipon J, Saint-Albin A, Renier A, et al. Malignant pleural mesothelioma cells resist anoikis as quiescent pluricellular aggregates. Cell Death Differ. 2009;16(8):1146–55.PubMedCrossRefGoogle Scholar
  220. 220.
    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(2):27–33.PubMedPubMedCentralGoogle Scholar
  221. 221.
    Leard LE, Broaddus VC. Mesothelial cell proliferation and apoptosis. Respirology. 2004;9(3):292–9.PubMedCrossRefPubMedCentralGoogle Scholar
  222. 222.
    Wilson SM, Barbone D, Yang TM, Jablons DM, Bueno R, Sugarbaker DJ, et al. mTOR mediates survival signals in malignant mesothelioma grown as tumor fragment spheroids. Am J Respir Cell Mol Biol. 2008;39(5):576–83.PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Kafiri G, Thomas DM, Shepherd NA, Krausz T, Lane DP, Hall PA. p53 expression is common in malignant mesothelioma. Histopathology. 1992;21(4):331–4.PubMedCrossRefGoogle Scholar
  224. 224.
    Ramael M, Lemmens G, Eerdekens C, Buysse C, Deblier I, Jacobs W, et al. Immunoreactivity for p53 protein in malignant mesothelioma and non-neoplastic mesothelium. J Pathol. 1992;168:371–5.PubMedCrossRefGoogle Scholar
  225. 225.
    Mayall FG, Goddard H, Gibbs AR. The frequency of p53 immunostaining in asbestos-associated mesotheliomas and non-asbestos-associated mesotheliomas. Histopathology. 1993;22(4):383–6.PubMedCrossRefGoogle Scholar
  226. 226.
    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(3):231–8.CrossRefPubMedPubMedCentralGoogle Scholar
  227. 227.
    Feng Z, Levine AJ. The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol. 2010;20(7):427–34.PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Singhal S, Wiewrodt R, Malden LD, Amin KM, Matzie K, Friedberg J, et al. Gene expression profiling of malignant mesothelioma. Clin Cancer Res. 2003;9(8):3080–97.PubMedGoogle Scholar
  229. 229.
    Lei YY, Wang WJ, Mei JH, Wang CL. Mitogen-activated protein kinase signal transduction in solid tumors. Asian Pac J Cancer Prev. 2014;15(20):8539–48.PubMedCrossRefPubMedCentralGoogle Scholar
  230. 230.
    Ohta Y, Shridhar V, Bright RK, Kalemkerian GP, Du W, Carbone M, 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(1):54–61.PubMedPubMedCentralCrossRefGoogle Scholar
  231. 231.
    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.PubMedCrossRefGoogle Scholar
  232. 232.
    Strizzi L, Catalano A, Vianale G, Orecchia S, Casalini A, Tassi G, et al. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol. 2001;193:468–75.PubMedCrossRefGoogle Scholar
  233. 233.
    Filho AL, Baltazar F, Bedrossian C, Michael C, Schmitt FC. Immunohistochemical expression and distribution of VEGFR-3 in malignant mesothelioma. Diagn Cytopathol. 2007;35(12):786–91.PubMedCrossRefGoogle Scholar
  234. 234.
    Lee AY, Raz DJ, He B, Jablons DM. Update on the molecular biology of malignant mesothelioma. Cancer. 2007;109(8):1454–61.PubMedCrossRefGoogle Scholar
  235. 235.
    Masood R, Kundra A, Zhu S, Xia G, Scalia P, Smith DL, et al. Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops. Int J Cancer. 2003;104(5):603–10.PubMedCrossRefGoogle Scholar
  236. 236.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Heldin P, Asplund T, Ytterberg D, Thelin S, Laurent TC. Characterization of the molecular mechanism involved in the activation of hyaluronan synthetase by platelet-derived growth factor in human mesothelial cells. Biochem J. 1992;283((Pt 1):165–70.PubMedPubMedCentralCrossRefGoogle Scholar
  238. 238.
    Gerwin BI, Lechner JF, Reddel RR, Roberts AB, Robbins KC, Gabrielson EW, 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(23):6180–4.PubMedGoogle Scholar
  239. 239.
    Versnel MA, Claessonwelsh L, Hammacher A, Bouts MJ, Vanderkwast TH, Eriksson 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(11):2005–11.PubMedGoogle Scholar
  240. 240.
    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(6):694–702.PubMedCrossRefPubMedCentralGoogle Scholar
  241. 241.
    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(2):214–21.PubMedCrossRefGoogle Scholar
  242. 242.
    Honda M, Kanno T, Fujita Y, Gotoh A, Nakano T, Nishizaki T. Mesothelioma cell proliferation through autocrine activation of PDGF-betabeta receptor. Cell Physiol Biochem. 2012;29(5–6):667–74.PubMedCrossRefGoogle Scholar
  243. 243.
    Agarwal V, Lind MJ, Cawkwell L. Targeted epidermal growth factor receptor therapy in malignant pleural mesothelioma: where do we stand? Cancer Treat Rev. 2011;37(7):533–42.PubMedCrossRefGoogle Scholar
  244. 244.
    Hoang CD, Zhang X, Scott PD, Guillaume TJ, Maddaus MA, Yee D, et al. Selective activation of insulin receptor substrate-1 and -2 in pleural mesothelioma cells: association with distinct malignant phenotypes. Cancer Res. 2004;64(20):7479–85.PubMedCrossRefGoogle Scholar
  245. 245.
    Whitson BA, Kratzke RA. Molecular pathways in malignant pleural mesothelioma. Cancer Lett. 2006;239(2):183–9.PubMedCrossRefGoogle Scholar
  246. 246.
    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.CrossRefGoogle Scholar
  247. 247.
    Lee TC, Zhang Y, Aston C, Hintz R, Jagirdar J, Perle MA, et al. Normal human mesothelial cells and mesothelioma cell lines express insulin-like growth factor I and associated molecules. Cancer Res. 1993;53(12):2858–64.PubMedGoogle Scholar
  248. 248.
    Liu Z, Klominek J. Regulation of matrix metalloprotease activity in malignant mesothelioma cell lines by growth factors. Thorax. 2003;58(3):198–203.PubMedPubMedCentralCrossRefGoogle Scholar
  249. 249.
    Thayaparan T, Spicer JF, Maher J. The role of the HGF/Met axis in mesothelioma. Biochem Soc Trans. 2016;44(2):363–70.PubMedCrossRefGoogle Scholar
  250. 250.
    Harvey P, Warn A, Dobbin S, Arakaki N, Daikuhara Y, Jaurand MC, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  251. 251.
    Mukohara T, Civiello G, Davis IJ, Taffaro ML, Christensen J, Fisher DE, et al. Inhibition of the met receptor in mesothelioma. Clin Cancer Res. 2005;11(22):8122–30.PubMedCrossRefGoogle Scholar
  252. 252.
    Jagadeeswaran R, Ma PC, Seiwert TY, Jagadeeswaran S, Zumba O, Nallasura V, et al. Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma. Cancer Res. 2006;66(1):352–61.PubMedCrossRefGoogle Scholar
  253. 253.
    Kawaguchi K, Murakami H, Taniguchi T, Fujii M, Kawata S, Fukui T, et al. Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells. Carcinogenesis. 2009;30(7):1097–105.PubMedCrossRefGoogle Scholar
  254. 254.
    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(11):2427–33.PubMedCrossRefGoogle Scholar
  255. 255.
    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(8):855–61.PubMedCrossRefGoogle Scholar
  256. 256.
    Eguchi R, Fujimori Y, Takeda H, Tabata C, Ohta T, Kuribayashi K, et al. Arsenic trioxide induces apoptosis through JNK and ERK in human mesothelioma cells. J Cell Physiol. 2011;226(3):762–8.PubMedCrossRefGoogle Scholar
  257. 257.
    Ou WB, Hubert C, Corson JM, Bueno R, Flynn DL, Sugarbaker DJ, et al. Targeted inhibition of multiple receptor tyrosine kinases in mesothelioma. Neoplasia. 2011;13(1):12–22.PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Zhou S, Liu L, Li H, Eilers G, Kuang Y, Shi S, et al. Multipoint targeting of the PI3K/mTOR pathway in mesothelioma. Br J Cancer. 2014;110(10):2479–88.PubMedPubMedCentralCrossRefGoogle Scholar
  259. 259.
    Besson A, Robbins SM, Yong VW. PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. Eur J Biochem. 1999;263(3):605–11.PubMedCrossRefGoogle Scholar
  260. 260.
    Altomare DA, You H, Xiao GH, Ramos-Nino ME, Skele KL, De Rienzo A, et al. Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth. Oncogene. 2005;24(40):6080–9.PubMedCrossRefGoogle Scholar
  261. 261.
    Suzuki Y, Murakami H, Kawaguchi K, Taniguchi T, Fujii M, Shinjo K, et al. Activation of the PI3K-AKT pathway in human malignant mesothelioma cells. Mol Med Rep. 2009;2(2):181–8.PubMedGoogle Scholar
  262. 262.
    Makena MR, Ranjan A, Thirumala V, Reddy AP. Cancer stem cells: road to therapeutic resistance and strategies to overcome resistance. Biochim Biophys Acta Mol Basis Dis. 2018; S0925–4439(18):30476–9.Google Scholar
  263. 263.
    Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, et al. Targeting notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015;12(8):445–64.PubMedPubMedCentralCrossRefGoogle Scholar
  264. 264.
    Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127(3):469–80.PubMedCrossRefPubMedCentralGoogle Scholar
  265. 265.
    Lee AY, He B, You L, Xu Z, Mazieres J, Reguart N, et al. Dickkopf-1 antagonizes Wnt signaling independent of beta-catenin in human mesothelioma. Biochem Biophys Res Commun. 2004;323(4):1246–50.PubMedCrossRefPubMedCentralGoogle Scholar
  266. 266.
    He B, Lee AY, Dadfarmay S, You L, Xu Z, Reguart N, 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(3):743–8.PubMedPubMedCentralGoogle Scholar
  267. 267.
    Batra S, Shi Y, Kuchenbecker KM, He B, Reguart N, Mikami I, et al. Wnt inhibitory factor-1, a Wnt antagonist, is silenced by promoter hypermethylation in malignant pleural mesothelioma. Biochem Biophys Res Commun. 2006;342(4):1228–32.PubMedCrossRefGoogle Scholar
  268. 268.
    Kohno H, Amatya VJ, Takeshima Y, Kushitani K, Hattori N, Kohno N, et al. Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma. Oncol Rep. 2010;24(2):423–31.PubMedGoogle Scholar
  269. 269.
    Mazieres J, You L, He B, Xu Z, Twogood S, Lee AY, et al. Wnt2 as a new therapeutic target in malignant pleural mesothelioma. Int J Cancer. 2005;117(2):326–32.PubMedCrossRefGoogle Scholar
  270. 270.
    Felley-Bosco E, Opitz I, Meerang M. Hedgehog signaling in malignant pleural mesothelioma. Genes. 2015;6(3):500–11.PubMedPubMedCentralCrossRefGoogle Scholar
  271. 271.
    Kim HA, Kim MC, Kim NY, Kim Y. Inhibition of hedgehog signaling reduces the side population in human malignant mesothelioma cell lines. Cancer Gene Ther. 2015;22(8):387–95.PubMedPubMedCentralCrossRefGoogle Scholar
  272. 272.
    Mutti L, Peikert T, Robinson BWS, Scherpereel A, Tsao AS, de Perrot M, et al. Scientific advances and new frontiers in mesothelioma therapeutics. J Thorac Oncol. 2018;13(9):1269–83.PubMedPubMedCentralCrossRefGoogle Scholar
  273. 273.
    Lim CB, Prele CM, Cheah HM, Cheng YY, Klebe S, Reid G, et al. Mutational analysis of hedgehog signaling pathway genes in human malignant mesothelioma. PLoS One. 2013;8(6):e66685.PubMedPubMedCentralCrossRefGoogle Scholar
  274. 274.
    Rossini M, Rizzo P, Bononi I, Clementz A, Ferrari R, Martini F, et al. New perspectives on diagnosis and therapy of malignant pleural mesothelioma. Front Oncol. 2018;8:91.PubMedPubMedCentralCrossRefGoogle Scholar
  275. 275.
    Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12–27.PubMedCrossRefGoogle Scholar
  276. 276.
    McLoughlin KC, Kaufman AS, Schrump DS. Targeting the epigenome in malignant pleural mesothelioma. Transl Lung Cancer Res. 2017;6(3):350–65.PubMedPubMedCentralCrossRefGoogle Scholar
  277. 277.
    Vandermeers F, Neelature Sriramareddy S, Costa C, Hubaux R, Cosse JP, Willems L. The role of epigenetics in malignant pleural mesothelioma. Lung Cancer. 2013;81(3):311–8.PubMedCrossRefGoogle Scholar
  278. 278.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.PubMedPubMedCentralCrossRefGoogle Scholar
  279. 279.
    Lievense LA, Sterman DH, Cornelissen R, Aerts JG. Checkpoint blockade in lung cancer and mesothelioma. Am J Respir Crit Care Med. 2017;196(3):274–82.PubMedCrossRefGoogle Scholar
  280. 280.
    Minnema-Luiting J, Vroman H, Aerts J, Cornelissen R. Heterogeneity in immune cell content in malignant pleural mesothelioma. Int J Mol Sci. 2018;19(4):2–12.PubMedCentralCrossRefPubMedGoogle Scholar
  281. 281.
    Guazzelli A, Bakker E, Krstic-Demonacos M, Lisanti MP, Sotgia F, Mutti L. Anti-CTLA-4 therapy for malignant mesothelioma. Immunotherapy. 2017;9(3):273–80.PubMedCrossRefPubMedCentralGoogle Scholar
  282. 282.
    Oehl K, Vrugt B, Opitz I, Meerang M. Heterogeneity in malignant pleural mesothelioma. Int J Mol Sci. 2018;19(6):1–12.PubMedCentralCrossRefGoogle Scholar
  283. 283.
    Galateau-Salle F, Churg A, Roggli V, Travis WD. The 2015 World Health Organization classification of tumors of the pleura: advances since the 2004 classification. J Thorac Oncol. 2016;11(2):142–54.CrossRefPubMedPubMedCentralGoogle Scholar
  284. 284.
    Husain AN, Colby TV, Ordonez NG, Allen TC, Attanoos RL, Beasley MB, et al. Guidelines for pathologic diagnosis of malignant mesothelioma 2017 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med. 2018;142(1):89–108.PubMedPubMedCentralCrossRefGoogle Scholar
  285. 285.
    Comertpay S, Pastorino S, Tanji M, Mezzapelle R, Strianese O, Napolitano A, et al. Evaluation of clonal origin of malignant mesothelioma. J Transl Med. 2014;12:301.PubMedPubMedCentralCrossRefGoogle Scholar
  286. 286.
    Gordon GJ, Rockwell GN, Jensen RV, Rheinwald JG, Glickman JN, Aronson JP, et al. Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling. Am J Pathol. 2005;166(6):1827–40.PubMedPubMedCentralCrossRefGoogle Scholar
  287. 287.
    Felley-Bosco E. Special issue on mechanisms of mesothelioma heterogeneity: highlights and open questions. Int J Mol Sci. 2018;19(11):1–5.PubMedCentralCrossRefPubMedGoogle Scholar
  288. 288.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.PubMedPubMedCentralCrossRefGoogle Scholar
  289. 289.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2012;144(5):646–74.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Agnes B. Kane
    • 1
  • Didier Jean
    • 2
  • Sakari Knuutila
    • 3
  • Marie-Claude Jaurand
    • 2
    Email author
  1. 1.Department of Pathology and Laboratory MedicineBrown UniversityProvidenceUSA
  2. 2.Centre de Recherche des Cordeliers, Sorbonne Université, Université de ParisParisFrance
  3. 3.Department of Pathology and Genetics, HUSLABHelsinki University Central HospitalHelsinkiFinland

Personalised recommendations