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Mechanisms of smoking-related lung and pancreatic adenocarcinoma development

Key Points

  • Adenocarcinomas of the lung and pancreas are among the most common and most deadly cancers. They share two risk factors — smoking and high-fat diet — with cardiovascular disease.

  • The arachidonic acid (AA) cascade is important in cardiovascular disease, and the overexpression of the gene that encodes cyclooxygenase-2 (COX2) in pulmonary and pancreatic adenocarcinoma indicates that the AA-cascade is also involved in the development of these cancers.

  • A nicotine-derived nitrosamine, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), causes adenocarcinomas of the lung and pancreas in laboratory animals, and is thought to be largely responsible for the development of these cancers in smokers.

  • NNK has genotoxic effects on cells, such as the formation of DNA adducts and mutations in the RAS gene. These effects of NNK probably cause the development of cancers that express such gene mutations (30% of pulmonary and 50–90% of pancreatic adenocarcinomas).

  • NNK also has epigenetic effects on pulmonary and pancreatic cells by functioning as an agonist for β-adrenergic receptors. This reaction activates various signal-transduction pathways, and causes the release of AA followed by the formation of mitogenic AA metabolites. These β-adrenergic-receptor-mediated events activate transcription and cell proliferation, and are thought to cause pulmonary and pancreatic adenocarcinomas that do not express RAS mutations, as well as synergizing with the cancer-causing effects of mutated RAS.

  • β-Blockers, inhibitors of AA-metabolizing enzymes and a low-fat diet are already widely used for the treatment and prevention of cardiovascular disease. The data compiled in this review indicate that they will also be effective for the treatment and prevention of pulmonary and pancreatic adenocarcinomas.

  • Overexpression of COX2 in adenocarcinomas of the colon, prostate and breast, as well as recent reports that β-adrenergic signalling regulates growth of these cancers, indicate that adenocarcinomas at these organ sites might also be treated or prevented with β-blockers. They might also be treated with pharmacological or dietary inhibitors of the AA cascade.

Abstract

Adenocarcinoma of the lungs and pancreas are among the most common and most deadly smoking-associated cancers. Cigarette smoke contains various toxic chemicals, including a carcinogenic nitrosamine, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). One of the most well-known features of NNK is the ability of its metabolites to bind to DNA and induce activating point mutations in the RAS gene. But NNK is also a β-adrenergic-receptor agonist that stimulates arachidonic acid release, leading to the formation of mitogenic metabolites that stimulate DNA synthesis and cell proliferation. NNK therefore contributes to tobacco-induced carcinogenesis by several mechanisms.

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Figure 1: Structures of nicotine, NNK and β-adrenergic-receptor agonists.
Figure 2: Potential mitogenic signal transduction pathways activated by binding of NNK to β-adrenergic receptors expressed in pulmonary and pancreatic adenocarcinomas.
Figure 3: Indirect growth stimulation of pulmonary and pancreatic adenocarcinomas in smokers by nicotine.

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References

  1. American Cancer Society. Cancer facts and figures. (American Cancer Society, Atlanta, Georgia, 2002).

  2. Zheng, T. et al. Time trend and the age-period-cohort effect on the incidence of histologic types of lung cancer in Connecticut, 1960–1989. Cancer 74, 1556–1567 (1994).

    CAS  PubMed  Google Scholar 

  3. Kelly, A., Blair, N. & Pechacek, T. F. Women and smoking: issues and opportunities. J. Womens Health Gender-Based Med. 10, 515–518 (2001).This reference summarizes the 2001 report of the Surgeon General on women and smoking. It documents that smoking-related lung cancer mortality in women in the United States has increased by about 600% since 1950.

    CAS  Google Scholar 

  4. Bunn, P. A. Jr, Vokes, E. E., Langer, C. J. & Schiller, J. H. An update on North American randomized studies in non-small cell lung cancer. Semin. Oncol. 25, 2–10 (1998).

    CAS  PubMed  Google Scholar 

  5. Wynder, E. L. & Muscat, J. E. The changing epidemiology of smoking and lung cancer histology. Environ. Health Perspect. 103 (Suppl. 8), 143–148 (1995).

    PubMed  PubMed Central  Google Scholar 

  6. Levi, F., Franceschi, S., La Vecchia, C., Randimbison, L. & Te, V. C. Lung carcinoma trends by histologic type in Vaud and Neuchatel, Switzerland, 1974–1994. Cancer 79, 906–914 (1997).

    CAS  PubMed  Google Scholar 

  7. Osann, K. E. Lung cancer in women: the importance of smoking, family history of cancer, and medical history of respiratory disease. Cancer Res. 51, 4893–4897 (1991).

    CAS  PubMed  Google Scholar 

  8. Risch, H. A. et al. Are female smokers at higher risk for lung cancer than male smokers? A case–control analysis by histologic type. Am. J. Epidemiol. 138, 281–293 (1993).

    CAS  PubMed  Google Scholar 

  9. Harris, R. E., Zang, E. A., Anderson, J. I. & Wynder, E. L. Race and sex differences in lung cancer risk associated with cigarette smoking. Int. J. Epidemiol. 22, 592–599 (1993).

    CAS  PubMed  Google Scholar 

  10. Haugen, A. Women who smoke: are women more susceptible to tobacco-induced lung cancer? Carcinogenesis 23, 227–229 (2002).

    CAS  PubMed  Google Scholar 

  11. Radzikowska, E., Roszkowski, K. & Glaz, P. Lung cancer in patients under 50 years old. Lung Cancer 33, 203–211 (2001).

    CAS  PubMed  Google Scholar 

  12. Stellman, S. D. et al. Smoking and lung cancer risk in American and Japanese men: an international case–control study. Cancer Epidemiol. Biomarkers Prev. 10, 1193–1199 (2001).

    CAS  PubMed  Google Scholar 

  13. Lee, P. N. Lung cancer and type of cigarette smoked. Inhal. Toxicol. 13, 951–976 (2001).

    CAS  PubMed  Google Scholar 

  14. Chowdhury, P. & Rayford, P. L. Smoking and pancreatic disorders. Eur. J. Gastroenterol. Hepatol. 12, 869–877 (2000).

    CAS  PubMed  Google Scholar 

  15. Gold, E. B. & Goldin, S. B. Epidemiology of and risk factors for pancreatic cancer. Surg. Oncol. Clin. N. Am. 7, 67–91 (1998).This epidemiological study identifies smoking and diets that are high in meat as risk factors for pancreatic cancer (see also reference 29).

    CAS  PubMed  Google Scholar 

  16. Silverman, D. T. Risk factors for pancreatic cancer: a case–control study based on direct interviews. Teratog. Carcinog. Mutagen. 21, 7–25 (2001).

    CAS  PubMed  Google Scholar 

  17. Duell, E. J. et al. A population-based, case–control study of polymorphisms in carcinogen-metabolizing genes, smoking, and pancreatic adenocarcinoma risk. J. Natl Cancer Inst. 94, 297–306 (2002).

    CAS  PubMed  Google Scholar 

  18. Boyle, P. et al. Cigarette smoking and pancreas cancer: a case–control study of the search programme of the IARC. Int. J. Cancer 67, 63–71 (1996).

    CAS  PubMed  Google Scholar 

  19. Hoffmann, D. et al. A study of tobacco carcinogenesis. LI. Relative potencies of tobacco-specific N-nitrosamines as inducers of lung tumours in A/J mice. Cancer Lett. 71, 25–30 (1993).

    CAS  PubMed  Google Scholar 

  20. Schuller, H. M. et al. Pathobiology of lung tumors induced in hamsters by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and the modulating effect of hyperoxia. Cancer Res. 50, 1960–1965 (1990).

    CAS  PubMed  Google Scholar 

  21. Schuller, H. M., Jorquera, R., Reichert, A. & Castonguay, A. Transplacental induction of pancreas tumors in hamsters by ethanol and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cancer Res. 53, 2498–2501 (1993).

    CAS  PubMed  Google Scholar 

  22. Hoffmann, D., Rivenson, A. & Hecht, S. S. The biological significance of tobacco-specific N-nitrosamines: smoking and adenocarcinoma of the lung. Crit. Rev. Toxicol. 26, 199–211 (1996).

    CAS  PubMed  Google Scholar 

  23. Hecht, S. S. Recent studies on mechanisms of bioactivation and detoxification of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific lung carcinogen. Crit. Rev. Toxicol. 26, 163–181 (1996).

    CAS  PubMed  Google Scholar 

  24. Hecht, S. S. Carcinogen-derived biomarkers and lung cancer. Prev. Med. 25, 7–9 (1996).

    CAS  PubMed  Google Scholar 

  25. Rivenson, A., Hoffmann, D., Prokopczyk, B., Amin, S. & Hecht, S. S. Induction of lung and exocrine pancreas tumors in F344 rats by tobacco-specific and Areca-derived N-nitrosamines. Cancer Res. 48, 6912–6917 (1988).

    CAS  PubMed  Google Scholar 

  26. Hecht, S. S., Trushin, N., Castonguay, A. & Rivenson, A. Comparative tumorigenicity and DNA methylation in F344 rats by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N-nitrosodimethylamine. Cancer Res. 46, 498–502 (1986).

    CAS  PubMed  Google Scholar 

  27. Hoffmann, D., Castonguay, A., Rivenson, A. & Hecht, S. S. Comparative carcinogenicity and metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N′-nitrosonornicotine in Syrian golden hamsters. Cancer Res. 41, 2386–2393 (1981).

    CAS  PubMed  Google Scholar 

  28. Hecht, S. S. Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem. Res. Toxicol. 11, 559–603 (1998).

    CAS  PubMed  Google Scholar 

  29. Hoffmann, D., Rivenson, A., Chung, F. L. & Hecht, S. S. Nicotine-derived N-nitrosamines (TSNA) and their relevance in tobacco carcinogenesis. Crit. Rev. Toxicol. 21, 305–311 (1991).

    CAS  PubMed  Google Scholar 

  30. Hecht, S. S. & Hoffmann, D. N-nitroso compounds and tobacco-induced cancers in man. IARC Sci. Publ. 105, 54–61 (1991).

    Google Scholar 

  31. Brunnemann, K. D., Prokopczyk, B., Djordjevic, M. V. & Hoffmann, D. Formation and analysis of tobacco-specific N-nitrosamines. Crit. Rev. Toxicol. 26, 121–137 (1996).

    CAS  PubMed  Google Scholar 

  32. Carmella, S. G., Borukhova, A., Desai, D. & Hecht, S. S. Evidence for endogenous formation of tobacco-specific nitrosamines in rats treated with tobacco alkaloids and sodium nitrite. Carcinogenesis 18, 587–592 (1997).

    CAS  PubMed  Google Scholar 

  33. Correa, E., Joshi, P. A., Castonguay, A. & Schuller, H. M. The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is an active transplacental carcinogen in Syrian golden hamsters. Cancer Res. 50, 3435–3438 (1990).

    CAS  PubMed  Google Scholar 

  34. Lackmann, G. M. et al. Metabolites of a tobacco-specific carcinogen in urine from newborns. J. Natl Cancer Inst. 91, 459–465 (1999).

    CAS  PubMed  Google Scholar 

  35. Alavanja, M. C. et al. Lung cancer risk and red meat consumption among Iowa women. Lung Cancer 34, 37–46 (2001).

    CAS  PubMed  Google Scholar 

  36. Alavanja, M. C., Brown, C. C., Swanson, C. & Brownson, R. C. Saturated fat intake and lung cancer risk among nonsmoking women in Missouri. J. Natl Cancer Inst. 85, 1906–1916 (1993).

    CAS  PubMed  Google Scholar 

  37. Truninger, K. [Risk groups for pancreatic and bile duct carcinomas]. Schweiz Rundsch. Med. Prax. 89, 1299–1304 (2000).Describes, for the first time, the tumour-promoting effects of dietary fat on NNK-induced lung cancer in an animal model.

    CAS  Google Scholar 

  38. Howe, G. R. et al. A collaborative case–control study of nutrient intake and pancreatic cancer within the search programme. Int. J. Cancer 51, 365–372 (1992).

    CAS  PubMed  Google Scholar 

  39. Hoffmann, D., Rivenson, A., Abbi, R. & Wynder, E. L. A study of tobacco carcinogenesis: effect of the fat content of the diet on the carcinogenic activity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in F344 rats. Cancer Res. 53, 2758–2761 (1993).

    CAS  PubMed  Google Scholar 

  40. Veierod, M. B., Laake, P. & Thelle, D. S. Dietary fat intake and risk of lung cancer: a prospective study of 51,452 Norwegian men and women. Eur. J. Cancer Prev. 6, 540–549 (1997).This epidemiological study reports that dietary fat increases the risk of lung cancer in smokers.

    CAS  PubMed  Google Scholar 

  41. Tucker, O. N. et al. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res. 59, 987–990 (1999).Reports that cyclooxygenase is upregulated in human pancreatic cancer.

    CAS  PubMed  Google Scholar 

  42. Molina, M. A., Sitja-Arnau, M., Lemoine, M. G., Frazier, M. L. & Sinicrope, F. A. Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res. 59, 4356–4362 (1999).

    CAS  PubMed  Google Scholar 

  43. Hida, T. et al. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res. 58, 3761–3764 (1998).Reports that, of the various types of lung cancer, adenocarcinoma are most likely to overexpress cyclooxygenase-2.

    CAS  PubMed  Google Scholar 

  44. Rioux, N. & Castonguay, A. Recovery from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced immunosuppression in A/J mice by treatment with nonsteroidal anti-inflammatory drugs. J. Natl Cancer Inst. 89, 874–880 (1997).

    CAS  PubMed  Google Scholar 

  45. Duperron, C. & Castonguay, A. Chemopreventive efficacies of aspirin and sulindac against lung tumorigenesis in A/J mice. Carcinogenesis 18, 1001–1006 (1997).The first report that documents a chemopreventive effect of a non-steroidal anti-inflammatory drug on NNK-induced lung cancer in an animal model.

    CAS  PubMed  Google Scholar 

  46. Castonguay, A. & Rioux, N. Inhibition of lung tumourigenesis by sulindac: comparison of two experimental protocols. Carcinogenesis 18, 491–496 (1997).

    CAS  PubMed  Google Scholar 

  47. Rioux, N. & Castonguay, A. Prevention of NNK-induced lung tumorigenesis in A/J mice by acetylsalicylic acid and NS-398. Cancer Res. 58, 5354–5360 (1998).Shows, for the first time, a cancer-preventive effect of a lipoxygenase inhibitor on NNK-induced lung cancer in an animal model.

    CAS  PubMed  Google Scholar 

  48. Rioux, N. & Castonguay, A. Inhibitors of lipoxygenase: a new class of cancer chemopreventive agents. Carcinogenesis 19, 1393–1400 (1998).

    CAS  PubMed  Google Scholar 

  49. Malkinson, A. M. et al. Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mouse lung tumor formation by FGN-1 (sulindac sulfone). Carcinogenesis 19, 1353–1356 (1998).

    CAS  PubMed  Google Scholar 

  50. Castonguay, A., Rioux, N., Duperron, C. & Jalbert, G. Inhibition of lung tumorigenesis by NSAIDS: a working hypothesis. Exp. Lung Res. 24, 605–615 (1998).

    CAS  PubMed  Google Scholar 

  51. El-Bayoumy, K., Iatropoulos, M., Amin, S., Hoffmann, D. & Wynder, E. L. Increased expression of cyclooxygenase-2 in rat lung tumors induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone: the impact of a high-fat diet. Cancer Res. 59, 1400–1403 (1999).

    CAS  PubMed  Google Scholar 

  52. Harris, R. E., Schuller, H. M., Bell, J. L., Lu, P. Y. & Alshafie, G. A. Association of nonsteroidal anti-inflammatory drugs (NSAIDs) and anti-hypertensive medications (AHMs) with lung cancer among smokers and in a hamster model of NNK–induced lung cancer. Proc. Am. Assoc. Cancer Res. 42, 1424 (2001).

    Google Scholar 

  53. Schuller, H. M., Tithof, P. K., Williams, M. & Plummer, H. The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a β-adrenergic agonist and stimulates DNA synthesis in lung adenocarcinoma via β-adrenergic receptor-mediated release of arachidonic acid. Cancer Res. 59, 4510–4515 (1999).In vitro experiments that identify, for the first time, the tobacco nitrosamine NNK as an agonist for β-adrenergic receptors. This study also shows that binding of NNK to β-adrenergic receptors in human lung cancer cells causes the release of arachidonic acid, resulting in stimulation of DNA synthesis.

    CAS  PubMed  Google Scholar 

  54. Schuller, H. M., Porter, B. & Riechert, A. β-Adrenergic modulation of NNK-induced lung carcinogenesis in hamsters. J. Cancer Res. Clin. Oncol. 126, 624–630 (2000).Reports that a β-blocker acts as a potent chemopreventive agent on NNK-induced lung cancer in an animal model. This study also showed that adrenaline and theophylline promoted the development of lung cancer.

    CAS  PubMed  Google Scholar 

  55. Schuller, H. M. et al. Co-expression of β-adrenergic receptors and cyclooxygenase-2 in pulmonary adenocarcinoma. Int. J. Oncol. 19, 445–449 (2001).

    CAS  PubMed  Google Scholar 

  56. Baek, S. J., Kim, K. S., Nixon, J. B., Wilson, L. C. & Eling, T. E. Cyclooxygenase inhibitors regulate the expression of a TGF-β superfamily member that has proapoptotic and antitumorigenic activities. Mol. Pharmacol. 59, 901–908 (2001).

    CAS  PubMed  Google Scholar 

  57. Kim, K. S. et al. Expression and regulation of nonsteroidal anti-inflammatory drug-activated gene (NAG-1) in human and mouse tissue. Gastroenterology 122, 1388–1398 (2002).

    CAS  PubMed  Google Scholar 

  58. Weddle, D. L., Tithoff, P., Williams, M. & Schuller, H. M. β-Adrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas. Carcinogenesis 22, 473–479 (2001).In vitro studies describe, for the first time, that the growth of human pancreatic cancer cells is regulated by β-adrenergic receptors by the release of arachidonic acid and that NNK activates this pathway.

    CAS  PubMed  Google Scholar 

  59. Schuller, H. M. et al. Inhibition of pancreatic carcinogenesis in hamsters by inhibitors of the AA-cascade or a β–blocker. Proc. Am. Assoc. Cancer Res. 43, 3201 (2002).

    Google Scholar 

  60. Hecht, S. S. et al. Quantitation of metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone after cessation of smokeless tobacco use. Cancer Res. 62, 129–134 (2002).Supports the hypothesis that β-adrenergic-receptor pathways are involved in NNK-induced lung carcinogenesis. The authors conclude that retention of NNAL in lungs of smokers and smokeless-tobacco users is best explained by the presence of β-adrenergic receptors.

    CAS  PubMed  Google Scholar 

  61. Ruffolo, R. R. Jr, Bondinell, W. & Hieble, J. P. α- and β-adrenoceptors: from the gene to the clinic. 2. Structure–activity relationships and therapeutic applications. J. Med. Chem. 38, 3681–3716 (1995).

    CAS  PubMed  Google Scholar 

  62. Hieble, J. P., Bondinell, W. E. & Ruffolo, R. R., Jr. α- and β-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification. J. Med. Chem. 38, 3415–3444 (1995).

    CAS  PubMed  Google Scholar 

  63. Pavoine, C., Magne, S., Sauvadet, A. & Pecker, F. Evidence for a β2-adrenergic/arachidonic acid pathway in ventricular cardiomyocytes. Regulation by the β1-adrenergic/cAMP pathway. J. Biol. Chem. 274, 628–637 (1999).

    CAS  PubMed  Google Scholar 

  64. Borda, E. S., Tenenbaum, A., Sales, M. E., Rumi, L. & Sterin-Borda, L. Role of arachidonic acid metabolites in the action of a β-adrenergic agonist on human monocyte phagocytosis. Prostaglandins Leukot. Essent. Fatty Acids 58, 85–90 (1998).

    CAS  PubMed  Google Scholar 

  65. Kan, H., Ruan, Y. & Malik, K. U. Signal transduction mechanism(s) involved in prostacyclin production elicited by acetylcholine in coronary endothelial cells of rabbit heart. J. Pharmacol. Exp. Ther. 282, 113–122 (1997).

    CAS  PubMed  Google Scholar 

  66. Ruan, Y., Kan, H. & Malik, K. U. β-Adrenergic receptor stimulated prostacyclin synthesis in rabbit coronary endothelial cells is mediated by selective activation of phospholipase D: inhibition by adenosine 3′5′-cyclic monophosphate. J. Pharmacol. Exp. Ther. 281, 1038–1046 (1997).

    CAS  PubMed  Google Scholar 

  67. Luttrell, L. M. et al. β-arrestin-dependent formation of β2 adrenergic receptor–Src protein kinase complexes. Science 283, 655–661 (1999).

    CAS  PubMed  Google Scholar 

  68. Luttrell, L. M., Daaka, Y. & Lefkowitz, R. J. Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Curr. Opin. Cell Biol. 11, 177–183 (1999).

    CAS  PubMed  Google Scholar 

  69. Muyderman, H., Sinclair, J., Jardemark, K., Hansson, E. & Nilsson, M. Activation of β-adrenoceptors opens calcium-activated potassium channels in astroglial cells. Neurochem. Int. 38, 269–276 (2001).

    CAS  PubMed  Google Scholar 

  70. Vossler, M. R. et al. cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 89, 73–82 (1997).

    CAS  PubMed  Google Scholar 

  71. Daniel, P. B., Walker, W. H. & Habener, J. F. Cyclic AMP signaling and gene regulation. Annu. Rev. Nutr. 18, 353–383 (1998).

    CAS  PubMed  Google Scholar 

  72. Walker, W. H., Daniel, P. B. & Habener, J. F. Inducible cAMP early repressor ICER down-regulation of CREB gene expression in Sertoli cells. Mol. Cell Endocrinol. 143, 167–178 (1998).

    CAS  PubMed  Google Scholar 

  73. Maudsley, S. et al. The β2-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor. J. Biol. Chem. 275, 9572–9580 (2000).

    CAS  PubMed  Google Scholar 

  74. Ahn, S., Maudsley, S., Luttrell, L. M., Lefkowitz, R. J. & Daaka, Y. Src-mediated tyrosine phosphorylation of dynamin is required for β2-adrenergic receptor internalization and mitogen-activated protein kinase signaling. J. Biol. Chem. 274, 1185–1188 (1999).

    CAS  PubMed  Google Scholar 

  75. Biscardi, J. S., Belsches, A. P. & Parsons, S. J. Characterization of human epidermal growth factor receptor and c-Src interactions in human breast tumor cells. Mol. Carcinog. 21, 261–272 (1998).

    CAS  PubMed  Google Scholar 

  76. Maa, M. C., Leu, T. H., McCarley, D. J., Schatzman, R. C. & Parsons, S. J. Potentiation of epidermal growth factor receptor-mediated oncogenesis by c-Src: implications for the etiology of multiple human cancers. Proc. Natl Acad. Sci. USA 92, 6981–6985 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Blake, R. A. et al. SU6656, a selective src family kinase inhibitor, used to probe growth factor signaling. Mol. Cell. Biol. 20, 9018–9027 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Chaturvedi, P., Reddy, M. V. & Reddy, E. P. Src kinases and not JAKs activate STATs during IL-3 induced myeloid cell proliferation. Oncogene 16, 1749–1758 (1998).

    CAS  PubMed  Google Scholar 

  79. Garcia, R. et al. Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ. 8, 1267–1276 (1997).

    CAS  PubMed  Google Scholar 

  80. Smith, P. D. & Crompton, M. R. Expression of v-src in mammary epithelial cells induces transcription via STAT3. Biochem. J. 331, 381–385 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Darnell, J. E. Jr. STATs and gene regulation. Science 277, 1630–1635 (1997).

    CAS  PubMed  Google Scholar 

  82. Mousavi, M., Hellstrom-Lindahl, E., Guan, Z. Z., Bednar, I. & Nordberg, A. Expression of nicotinic acetylcholine receptors in human and rat adrenal medulla. Life Sci. 70, 577–590 (2001).

    CAS  PubMed  Google Scholar 

  83. Tachikawa, E. et al. Characterization of the functional subunit combination of nicotinic acetylcholine receptors in bovine adrenal chromaffin cells. Neurosci. Lett. 312, 161–164 (2001).

    CAS  PubMed  Google Scholar 

  84. Ohta, S. et al. A comparative study of characteristics of current-type and conventional-type cationic bactericides. Biol. Pharm. Bull. 24, 1093–1096 (2001).

    CAS  PubMed  Google Scholar 

  85. Utsunomiya, K. et al. Stimulation of catecholamine synthesis in cultured bovine adrenal medullary cells by leptin. J. Neurochem. 76, 926–934 (2001).

    CAS  PubMed  Google Scholar 

  86. Li, Q. & Forsberg, E. J. Catecholamine secretion induced by nicotine is due to Ca2+ channel but not Na+ channel activation in porcine adrenal chromaffin cells. J. Pharmacol. Exp. Ther. 277, 1209–1214 (1996).

    CAS  PubMed  Google Scholar 

  87. Masur, K., Niggemann, B., Zanker, K. S. & Entschladen, F. Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by β-blockers. Cancer Res. 61, 2866–2869 (2001).Evidence that noradrenaline binds to β-adrenergic receptors to induce the migration of colon cancer cells. These findings provide strong support for our theory that, in addition to adenocarcinomas in the lungs and pancreas, adenocarcinomas in the colon might benefit from therapy and prevention with β-blockers or inhibitors of AA-metabolizing enzymes.

    CAS  PubMed  Google Scholar 

  88. Langenfeld, J. et al. Inhibited transformation of immortalized human bronchial epithelial cells by retinoic acid is linked to cyclin E down-regulation. Oncogene 13, 1983–1990 (1996).

    CAS  PubMed  Google Scholar 

  89. Lonardo, F. et al. Evidence for the epidermal growth factor receptor as a target for lung cancer prevention. Clin. Cancer Res. 8, 54–60 (2002).

    CAS  PubMed  Google Scholar 

  90. Hsieh, E. T., Shepherd, F. A. & Tsao, M. S. Co-expression of epidermal growth factor receptor and transforming growth factor-α is independent of RAS mutations in lung adenocarcinoma. Lung Cancer 29, 151–157 (2000).

    CAS  PubMed  Google Scholar 

  91. Poch, B. et al. Epidermal growth factor induces cyclin D1 in human pancreatic carcinoma: evidence for a cyclin D1-dependent cell cycle progression. Pancreas 23, 280–287 (2001).

    CAS  PubMed  Google Scholar 

  92. Murphy, L. O. et al. Pancreatic cancer cells require an EGF receptor-mediated autocrine pathway for proliferation in serum-free conditions. Br. J. Cancer 84, 926–935 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Tungekar, M. F. et al. Interleukin 4 receptor expression on human lung tumors and normal lung. Cancer Res. 51, 261–264 (1991).

    CAS  PubMed  Google Scholar 

  94. Pai, R. et al. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nature Med. 8, 289–293 (2002).

    CAS  PubMed  Google Scholar 

  95. Hecht, S. S. DNA adduct formation from tobacco-specific N-nitrosamines. Mutat. Res. 424, 127–142 (1999).

    CAS  PubMed  Google Scholar 

  96. Hecht, S. S. Tobacco smoke carcinogens and lung cancer. J. Natl Cancer Inst. 91, 1194–1210 (1999).

    CAS  PubMed  Google Scholar 

  97. Belinsky, S. A., Devereux, T. R., Maronpot, R. R., Stoner, G. D. & Anderson, M. W. Relationship between the formation of promutagenic adducts and the activation of the K-ras protooncogene in lung tumors from A/J mice treated with nitrosamines. Cancer Res. 49, 5305–5311 (1989).

    CAS  PubMed  Google Scholar 

  98. Belinsky, S. A., Devereux, T. R. & Anderson, M. W. Role of DNA methylation in the activation of proto-oncogenes and the induction of pulmonary neoplasia by nitrosamines. Mutat. Res. 233, 105–116 (1990).

    CAS  PubMed  Google Scholar 

  99. Belinsky, S. A., Foley, J. F., White, C. M., Anderson, M. W. & Maronpot, R. R. Dose-response relationship between O6-methylguanine formation in Clara cells and induction of pulmonary neoplasia in the rat by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cancer Res. 50, 3772–3780 (1990).

    CAS  PubMed  Google Scholar 

  100. Peterson, L. A. & Hecht, S. S. O6-methylguanine is a critical determinant of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone tumorigenesis in A/J mouse lung. Cancer Res. 51, 5557–5564 (1991).

    CAS  PubMed  Google Scholar 

  101. Staretz, M. E., Foiles, P. G., Miglietta, L. M. & Hecht, S. S. Evidence for an important role of DNA pyridyloxobutylation in rat lung carcinogenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: effects of dose and phenethyl isothiocyanate. Cancer Res. 57, 259–266 (1997).

    CAS  PubMed  Google Scholar 

  102. Chyczewski, L. et al. Morphological and molecular aspects of cancerogenesis in the lung. Folia Histochem. Cytobiol. 39, 149–152 (2001).

    CAS  PubMed  Google Scholar 

  103. Kovalchuk, O. et al. K-ras codon 12 mutations detected with enriched PCR method in operable non-small cell lung cancer. Folia Histochem. Cytobiol. 39 (Suppl. 2), 68–69 (2001).

    PubMed  Google Scholar 

  104. Vahakangas, K. H. et al. p53 and K-ras mutations in lung cancers from former and never-smoking women. Cancer Res. 61, 4350–4356 (2001).

    CAS  PubMed  Google Scholar 

  105. van Laethem, J. L. Ki-ras oncogene mutations in chronic pancreatitis: which discriminating ability for malignant potential? Ann. NY Acad. Sci. 880, 210–218 (1999).

    CAS  PubMed  Google Scholar 

  106. Oreffo, V. I., Lin, H. W., Padmanabhan, R. & Witschi, H. K-ras and p53 point mutations in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced hamster lung tumors. Carcinogenesis 14, 451–455 (1993).

    CAS  PubMed  Google Scholar 

  107. Berger, D. H. et al. Mutational activation of K-ras in nonneoplastic exocrine pancreatic lesions in relation to cigarette smoking status. Cancer 85, 326–332 (1999).

    CAS  PubMed  Google Scholar 

  108. Malats, N. et al. Ki-ras mutations in exocrine pancreatic cancer: association with clinico-pathological characteristics and with tobacco and alcohol consumption. PANK-ras I Project Investigators. Int. J. Cancer 70, 661–667 (1997).

    CAS  PubMed  Google Scholar 

  109. Pabst, B. et al. Analysis of K-ras mutations in pancreatic tissue after fine needle aspirates. Anticancer Res. 19, 2481–2483 (1999).

    CAS  PubMed  Google Scholar 

  110. Luttges, J. et al. The K-ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium. Cancer 85, 1703–1710 (1999).

    CAS  PubMed  Google Scholar 

  111. Wang, L., Spratt, T. E., Pegg, A. E. & Peterson, L. A. Synthesis of DNA oligonucleotides containing site-specifically incorporated O6-[4-oxo-4-(3-pyridyl)butyl]guanine and their reaction with O6-alkylguanine-DNA alkyltransferase. Chem. Res. Toxicol. 12, 127–131 (1999).

    CAS  PubMed  Google Scholar 

  112. Wang, L. et al. Pyridyloxobutyl adduct O6-[4-oxo-4-(3-pyridyl)butyl]guanine is present in 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone-treated DNA and is a substrate for O6-alkylguanine-DNA alkyltransferase. Chem. Res. Toxicol. 10, 562–567 (1997).

    CAS  PubMed  Google Scholar 

  113. Kuller, L. H. Dietary fat and chronic diseases: epidemiologic overview. J. Am. Diet Assoc. 97, S9–S15 (1997).

    CAS  PubMed  Google Scholar 

  114. Halimi, J. M. et al. The risk of hypertension in men: direct and indirect effects of chronic smoking. J. Hypertens. 20, 187–193 (2002).

    CAS  PubMed  Google Scholar 

  115. Schaefer, E. J. Lipoproteins, nutrition, and heart disease. Am. J. Clin. Nutr. 75, 191–212 (2002).

    CAS  PubMed  Google Scholar 

  116. Fitzpatrick, A. L., Daling, J. R., Furberg, C. D., Kronmal, R. A. & Weissfeld, J. L. Hypertension, heart rate, use of antihypertensives, and incident prostate cancer. Ann. Epidemiol. 11, 534–542 (2001).Epidemiolgical study reporting a protective effect of anti-hypertensive medication against prostate cancer and providing strong support for the hypothesis that, in addition to adenocarcinomas in the lungs and pancreas, adenocarcinomas of the prostate might benefit from treatment and prevention by β-blockers or inhibitors of AA-metabolizing enzymes.

    CAS  PubMed  Google Scholar 

  117. Cakir, Y., Plummer, H. K. & Schuller, H. M. β-Adrenergic-arachidonic acid–GIRK channel associated regulation of human breast cancer cell lines. Proc. 7th Int. Eicosanoid Conf. 355 (2001).

  118. Whelan, J. Antagonistic effects of dietary arachidonic acid and n-3 polyunsaturated fatty acids. J. Nutr. 126, S1086–S1091 (1996).

    Google Scholar 

  119. Whelan, J., Broughton, K. S., Surette, M. E. & Kinsella, J. E. Dietary arachidonic and linoleic acids: comparative effects on tissue lipids. Lipids 27, 85–88 (1992).

    CAS  PubMed  Google Scholar 

  120. Whelan, J., Broughton, K. S. & Kinsella, J. E. The comparative effects of dietary α-linoleic acid and fish oil on 4- and 5-series leukotriene formation in vivo. Lipids 26, 119–126 (1991).

    CAS  PubMed  Google Scholar 

  121. Petrik, M. B., McEntee, M. F., Chiu, C. H. & Whelan, J. Antagonism of arachidonic acid is linked to the antitumorigenic effect of dietary eicosapentaenoic acid in ApcMin/+ mice. J. Nutr. 130, 1153–1158 (2000).

    CAS  PubMed  Google Scholar 

  122. Harris, R. E., Namboodiri, K., Stellman, S. D. & Wynder, E. L. Breast cancer and NSAID use: heterogeneity of effect in a case–control study. Prev. Med. 24, 119–120 (1995).

    CAS  PubMed  Google Scholar 

  123. Rose, D. P. & Connolly, J. M. Dietary fat and breast cancer metastasis by human tumor xenografts. Breast Cancer Res. Treat. 46, 225–237 (1997).

    CAS  PubMed  Google Scholar 

  124. Connolly, J. M., Liu, X. H. & Rose, D. P. Effects of dietary menhaden oil, soy, and a cyclooxygenase inhibitor on human breast cancer cell growth and metastasis in nude mice. Nutr. Cancer 29, 48–54 (1997).

    CAS  PubMed  Google Scholar 

  125. Connolly, J. M., Coleman, M. & Rose, D. P. Effects of dietary fatty acids on DU145 human prostate cancer cell growth in athymic nude mice. Nutr. Cancer 29, 114–119 (1997).

    CAS  PubMed  Google Scholar 

  126. Rose, D. P., Connolly, J. M. & Liu, X. H. Fatty acid regulation of breast cancer cell growth and invasion. Adv. Exp. Med. Biol. 422, 47–55 (1997).

    CAS  PubMed  Google Scholar 

  127. Wu, A. H. et al. Previous lung disease and risk of lung cancer among lifetime nonsmoking women in the United States. Am. J. Epidemiol. 141, 1023–1032 (1995).

    CAS  PubMed  Google Scholar 

  128. Mayne, S. T., Buenconsejo, J. & Janerich, D. T. Previous lung disease and risk of lung cancer among men and women nonsmokers. Am. J. Epidemiol. 149, 13–20 (1999).

    CAS  PubMed  Google Scholar 

  129. Brenner, A. V. et al. Previous pulmonary diseases and risk of lung cancer in Gansu Province, China. Int. J. Epidemiol. 30, 118–124 (2001).

    CAS  PubMed  Google Scholar 

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DATABASES

Cancer.gov

breast cancer

colon cancer

lung cancer

pancreatic cancer

prostate cancer

LocusLink

ATF-1

B-RAF

COX2

Cox2

CREB

CREM

cyclin D1

cytochrome P450

EGF

EGFR

ERK1

ERK2

interleukin-3

K-ras

K-RAS

5-LOX

12-LOX

15-LOX

MAPK

MEKs

MYC

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phospholipase-A2

PKA

RAF-1

RAP1

RAS

RSKs

c-SRC

STAT3

Medscape DrugInfo

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atenolol

celecoxib

docetaxel

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OMIM

asthma

FURTHER INFORMATION

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Glossary

PANCREATIC DUCTAL/DUCTULAR EPITHELIUM

The pancreas contains a network of ducts that branch into smaller ductules, the inner lining of which are called ductal and ductular epithelium, respectively.

DNA ADDUCT

DNA bound to a chemical compound.

NITROSATION

Nitrosation is a chemical reaction that adds two nitrogen atoms and one oxygen atom — which comprise the 'nitroso group' — to another chemical.

INTRATRACHEAL INSTILLATION

'Trachea' is the Latin word for windpipe. When agents such as chemicals or drugs are given by a tube inserted into the mouth through the larynx into the windpipe, this is called an intratracheal instillation. This form of drug administration is used to make sure that the drug goes directly into the lungs.

N3 POLYUNSATURATED FATTY ACIDS

Fatty acids consist of a chain of carbon and hydrogen atoms with the acidic carboxyl group 'COOH' at the end. The term 'polyunsaturated' means that the carbon chain includes double bonds. The term 'N3' means that the first double bond starts at the third carbon atom on the side of the molecule that is opposite to the carboxyl group.

CATECHOLAMINES

Adrenaline and noradrenaline (also known S-adrenaline) are produced by cells in the adrenal gland. They are called catecholamines because their chemical structure is characterized by the presence of a catechol ring.

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Schuller, H. Mechanisms of smoking-related lung and pancreatic adenocarcinoma development. Nat Rev Cancer 2, 455–463 (2002). https://doi.org/10.1038/nrc824

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