Environmental Agents in Lung and Pleural Neoplasms

  • Steven R. Blumen
  • Brooke T. Mossman
Part of the Molecular Pathology Library book series (MPLB, volume 1)


A number of chemical and other environmental pollutants, including noxious gases and metals, infectious agents, insoluble agents such as asbestos and wood dusts, and dietary factors, induce or promote lung cancers. Many of these agents are classified as “known” or “reasonably anticipated” carcinogens, including polycyclic aromatic hydrocarbons, metals such as cadmium, hexavalent chromium, and nickel compounds, and mineral fibers such as asbestos and erionite.1 Others are “suspect” carcinogens based on inconclusive data from epidemiologic, animal, and mechanistic studies. The use of mechanistic studies to predict carcinogenicity of environmental and occupational agents in humans has been advocated recently as a critical component of risk analysis.2 With the evolution and vast potential of new technologies such as microarray analysis and proteomics, our knowledge of the mechanisms of lung carcinogenesis has increased.


Polycyclic Aromatic Hydrocarbon Mesothelial Cell Malignant Mesothelioma Mesothelioma Cell Chrysotile Asbestos 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    National Institute for Environmental Health Sciences (NTP). Tenth Report on Carcinogens. Washington, DC: National Institute for Environmental Health Sciences; 2002.Google Scholar
  2. 2.
    Mossman BT, Klein G, Zur Hausen H. Modern criteria to determine the etiology of human carcinogens. Semin Cancer Biol 2004;14(6):449–452.CrossRefPubMedGoogle Scholar
  3. 3.
    Mossman BT, Gee JB. Asbestos-related diseases. N Engl J Med 1989;320(26):1721–1730.PubMedCrossRefGoogle Scholar
  4. 4.
    Mossman BT, Bignon J, Corn M, et al. Asbestos: scientific developments and implications for public policy. Science 1990;247(4940):294–301.CrossRefPubMedGoogle Scholar
  5. 5.
    Robinson BW, Lake RA. Advances in malignant mesothelioma. N Engl J Med 2005;353(15):1591–1603.CrossRefPubMedGoogle Scholar
  6. 6.
    Vogelzang NJ. Emerging insights into the biology and therapy of malignant mesothelioma. Semin Oncol 2002;29(6 Suppl 18):35–42.PubMedGoogle Scholar
  7. 7.
    Powers A, Carbone M. The role of environmental carcinogens, viruses and genetic predisposition in the pathogenesis of mesothelioma. Cancer Biol Ther 2002;1(4):348–353.PubMedGoogle Scholar
  8. 8.
    Coleman W, Tsongalis G, eds. Molecular Basis of Human Cancer. Totowa, NJ: Humana Press; 2001.Google Scholar
  9. 9.
    Choy H, Pass HI, Rosell R, et al. Lung cancer. In Chang AE, Ganz PA, Hayes DF, et al., eds. Oncology: A Evidence-Based Approach. New York: Springer; 2006:545–621.Google Scholar
  10. 10.
    Murthy SS, Testa JR. Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human malignant mesothelioma. J Cell Physiol 1999;180(2):150–157.CrossRefPubMedGoogle Scholar
  11. 11.
    Guthrie GD, Mossman BT, eds. Health Effects of Mineral Dusts. Washington, DC: Mineralogic Society of America; 1993.Google Scholar
  12. 12.
    Shukla A, Gulumian M, Hei TK, et al. Multiple roles of oxidants in the pathogenesis of asbestos-induced diseases. Free Radic Biol Med 2003;34(9):1117–1129.CrossRefPubMedGoogle Scholar
  13. 13.
    McDonald AD, McDonald JC. Epidemiology of malignant mesothelioma. In Antman K, Aisner J, eds. Asbestos-Related Malignancy. Orlando, FL: Grune & Stratton; 1987:31–55.Google Scholar
  14. 14.
    Churg A. Chrysotile, tremolite, and malignant mesothelioma in man. Chest 1988;93(3):621–628.CrossRefPubMedGoogle Scholar
  15. 15.
    Saracci R. The interactions of tobacco smoking and other agents in cancer etiology. Epidemiol Rev 1987;9:175–193.PubMedGoogle Scholar
  16. 16.
    McDonald JC, McDonald JC. Epidemiology of asbestosrelated lung cancer. In: Antman K, Aisner J, eds. Asbestos-Related Malignancy. Orlando, FL: Grune & Stratton; 1987:57–79.Google Scholar
  17. 17.
    Soutar CA, Simon G, Turner-Warwick M. The radiology of asbestos-induced disease of the lungs. Br J Dis Chest 1974;68:235–252.CrossRefPubMedGoogle Scholar
  18. 18.
    Weiss W. Asbestosis and lobar site of lung cancer. Occup Environ Med 2000;57(5):358–360.CrossRefPubMedGoogle Scholar
  19. 19.
    Mossman BT, Churg A. Mechanisms in the pathogenesis of asbestosis and silicosis. Am J Respir Crit Care Med 1998;157(5 Pt 1):1666–1680.PubMedGoogle Scholar
  20. 20.
    Haus BM, Razavi H, Kuschner WG. Occupational and environmental causes of bronchogenic carcinoma. Curr Opin Pulm Med 2001;7(4):220–225.CrossRefPubMedGoogle Scholar
  21. 21.
    Rom WN. Assessment of activation, differentiation, and carcinogenesis of lung cells by quantitative competitive RTPCR. Am J Respir Cell Mol Biol 1998;19(1):3–5.PubMedGoogle Scholar
  22. 22.
    Kannerstein M, Churg J. Pathology of carcinoma of the lung associated with asbestos exposure. Cancer 1972;30(1):14–21.CrossRefPubMedGoogle Scholar
  23. 23.
    Weiss W. Cigarette smoke, asbestos, and small irregular opacities. Am Rev Respir Dis 1984;130(2):293–301.PubMedGoogle Scholar
  24. 24.
    Hofmann J, Mintzer D, Warhol MJ. Malignant mesothelioma following radiation therapy. Am J Med 1994;97(4):379–382.CrossRefPubMedGoogle Scholar
  25. 25.
    Hubbard R. The aetiology of mesothelioma: are risk factors other than asbestos exposure important? Thorax 1997;52(6):496–497.CrossRefPubMedGoogle Scholar
  26. 26.
    Hillerdal G, Berg J. Malignant mesothelioma secondary to chronic inflammation and old scars. Two new cases and review of the literature. Cancer 1985;55(9):1968–1972.CrossRefPubMedGoogle Scholar
  27. 27.
    Carbone M, Kratzke RA, Testa JR. The pathogenesis of mesothelioma. Semin Oncol 2002;29(1):2–17.CrossRefPubMedGoogle Scholar
  28. 28.
    Hughes JM, Weill H. Asbestos exposure—quantitative assessment of risk. Am Rev Respir Dis 1986;133(1):5–13.PubMedGoogle Scholar
  29. 29.
    Health Effects Institute. Asbestos Research. Asbestos in Public and Commercial Buildings: A Literature Review and Synthesis of Current Knowledge. Cambridge, MA: Health Effects Institute; 1991.Google Scholar
  30. 30.
    Jaurand MC, Gaudichet A, Halpern S, et al. In vitro biodegradation of chrysotile fibres by alveolar macrophages and mesothelial cells in culture: comparison with a pH effect. Br J Ind Med 1984;41(3):389–395.PubMedGoogle Scholar
  31. 31.
    Ault JG, Cole RW, Jensen CG, et al. Behavior of crocidolite asbestos during mitosis in living vertebrate lung epithelial cells. Cancer Res 1995;55(4):792–798.PubMedGoogle Scholar
  32. 32.
    Fung H, Kow YW, Van Houten B, et al. 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):825–832.CrossRefPubMedGoogle Scholar
  33. 33.
    Nygren J, Suhonen S, Norppa H, et al. DNA damage in bronchial epithelial and mesothelial cells with and without associated crocidolite asbestos fibers. Environ Mol Mutagen 2004;44(5):477–482.CrossRefPubMedGoogle Scholar
  34. 34.
    Heintz NH, Janssen YM, Mossman BT. Persistent induction of c-fos and c-jun expression by asbestos. Proc Natl Acad Sci USA 1993;90(8):3299–3303.CrossRefPubMedGoogle Scholar
  35. 35.
    Gerwin BI, Lechner JF, Reddel RR, et al. Comparison of production of transforming growth factor-beta and plateletderived growth factor by normal human mesothelial cells and mesothelioma cell lines. Cancer Res 1987;47(23):6180–6184.PubMedGoogle Scholar
  36. 36.
    Janssen YM, Barchowsky A, Treadwell M, et al. Asbestos induces nuclear factor kappa B (NF-kappa B) DNA-binding activity and NF-kappa B-dependent gene expression in tracheal epithelial cells. Proc Natl Acad Sci USA 1995;92(18):8458–8462.CrossRefPubMedGoogle Scholar
  37. 37.
    Broaddus VC, Dansen TB, Abayasiriwardana KS, et al. Bid mediates apoptotic synergy between tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL) and DNA damage. J Biol Chem 2005;280(13):12486–12493.CrossRefPubMedGoogle Scholar
  38. 38.
    Cacciotti P, Libener R, Betta P, et al. SV40 replication in human mesothelial cells induces HGF/Met receptor activation: a model for viral-related carcinogenesis of human malignant mesothelioma. Proc Natl Acad Sci USA 2001;98(21):12032–12037.CrossRefPubMedGoogle Scholar
  39. 39.
    Zanella CL, Posada J, Tritton TR, et al. 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(23):5334–5338.PubMedGoogle Scholar
  40. 40.
    Zanella CL, Timblin CR, Cummins A, et al. Asbestosinduced phosphorylation of epidermal growth factor receptor is linked to c-fos and apoptosis. Am J Physiol 1999;277(4 Pt 1):L684–L693.PubMedGoogle Scholar
  41. 41.
    Janssen YM, Driscoll KE, Howard B, et al. Asbestos causes translocation of p65 protein and increases NFkappa B DNA binding activity in rat lung epithelial and pleural mesothelial cells. Am J Pathol 1997;151(2):389–401.PubMedGoogle Scholar
  42. 42.
    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(40):6080–6089.CrossRefPubMedGoogle Scholar
  43. 43.
    Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002;298(5600):1911–1912.CrossRefPubMedGoogle Scholar
  44. 44.
    Pache JC, Janssen YM, Walsh ES, et al. Increased epidermal growth factor-receptor protein in a human mesothelial cell line in response to long asbestos fibers. Am J Pathol 1998;152(2):333–340.PubMedGoogle Scholar
  45. 45.
    Jimenez LA, Zanella C, Fung H, et al. Role of extracellular signal-regulated protein kinases in apoptosis by asbestos and H2O2. Am J Physiol 1997;273(5 Pt 1):L1029–L1035.PubMedGoogle Scholar
  46. 46.
    Scapoli L, Ramos-Nino ME, Martinelli M, et al. Srcdependent ERK5 and Src/EGFR-dependent ERK1/2 activation is required for cell proliferation by asbestos. Oncogene 2004;23(3):805–813.CrossRefPubMedGoogle Scholar
  47. 47.
    Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005;5(10):749–759.CrossRefPubMedGoogle Scholar
  48. 48.
    Cacciotti P, Barbone D, Porta C, et al. SV40-dependent AKT activity drives mesothelial cell transformation after asbestos exposure. Cancer Res 2005;65(12):5256–5262.CrossRefPubMedGoogle Scholar
  49. 49.
    Kim D, Chung J. Akt: versatile mediator of cell survival and beyond. J Biochem Mol Biol 2002;35(1):106–115.PubMedGoogle Scholar
  50. 50.
    Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006;441(7092):424–430.CrossRefPubMedGoogle Scholar
  51. 51.
    Karin M. Nuclear factor-kappaB in cancer development and progression. Nature 2006;441(7092):431–436.CrossRefPubMedGoogle Scholar
  52. 52.
    Altomare DA, Vaslet CA, Skele KL, et al. A mouse model recapitulating molecular features of human mesothelioma. Cancer Res 2005;65(18):8090–8095.CrossRefPubMedGoogle Scholar
  53. 53.
    Ramos-Nino ME, Vianale G, Sabo-Attwood T, et al. Human mesothelioma cells exhibit tumor cell-specific differences in phosphatidylinositol 3-kinase/AKT activity that predict the efficacy of Onconase. Mol Cancer Ther 2005;4(5):835–842.CrossRefPubMedGoogle Scholar
  54. 54.
    Sabo-Attwood T, Ramos-Nino M, Mossman BT. Environmental carcinogens. In Chang AE, ed. Oncology: An Evidence-Based Approach. New York: Springer; 2006:233–243.Google Scholar
  55. 55.
    Mossman BT, Cameron GS, Yotti LP. Cocarcinogenic and tumor promoting properties of asbestos and other minerals in tracheobronchial epithelium. Carcinog Compr Surv 1985;8:217–238.PubMedGoogle Scholar
  56. 56.
    Mossman BT, Lounsbury KM, Reddy SP. Oxidants and signaling by mitogen-activated protein kinases in lung epithelium. Am J Respir Cell Mol Biol 2006;34(6):666–669.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Steven R. Blumen
    • 1
  • Brooke T. Mossman
    • 1
  1. 1.Department of PathologyUniversity of VermontBurlingtonUSA

Personalised recommendations