Inflammation and human cancer

  • S. P. Hussain
  • X. W. Wang
  • C. C. Harris
Conference paper
Part of the Falk Symposium book series (FASS, volume 160)


Chronic inflammation and infection is frequently associated with increased cancer risk, although exceptions can be eited including rheumatoid arthritis and human papillomavirus infection (Table 1) 1. Infection with hepatitis B and C viruses (HBV and HCV) causes inflammation with the release of free radicals, chemokines and cytokines resulting in DNA damage, cell proliferation, fibrosis, and angiogenesis. The p53 pathway is a key responder to inflammatory stress 2. Free radicals, e.g. reactive nitrogen or oxygen species, can directly damage DNA and proteins and indirectly damage these macromolecules via lipid peroxidation (Figure 1). The p53 pathway responds to lower levels of DNA damage by cell cycle checkpoint arrest, facilitating DNA repair as an adapter in the formation of DNA repair protein complexes and transcriptional transactivation of DNA repair genes 3. By mediating cell death due to extensive DNA damage, p53 also contributes to these processes by switching from increased expression of anti- to pro-oxidant genes. p53 can both transcriptionally transrepress pro-oxidant/nitrosative genes, e.g. NOS2, and transactivate anti-oxidant genes expressing glutathione peroxidase, aldehyde dehydrogenase, and Mn-superoxide dismutase, sestrins, and TIGAR (TP53-induced glycolysis and apoptosis regulator) (Table 2). An animal model of the Li-Fraumeni syndrome has provided new insights into the protective anti-oxidative and nitrosative function of p53.


Cell Cycle Checkpoint Increase Cancer Risk Mediate Cell Death Checkpoint Arrest Transcriptional Transactivation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer. 2003;3:276–85.PubMedCrossRefGoogle Scholar
  2. 2.
    Staib F, Robles AI, Varticovski L et al. The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. Cancer Res. 2005;65:10255–64.PubMedCrossRefGoogle Scholar
  3. 3.
    Sengupta S, Harris CC. p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Cell Mol Biol. 2005;6:44–55.CrossRefGoogle Scholar
  4. 4.
    Donehower LA, Harvey M, Slagle BL et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992;356:215–21.PubMedCrossRefGoogle Scholar
  5. 5.
    Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM. The antioxidant function of the p53 tumor suppressor. Nat Med. 2005;11:1306–13.PubMedCrossRefGoogle Scholar
  6. 6.
    Ambs S, Hussain SP, Harris CC. Interactive effects of nitric oxide and the p53 tumor suppressor gene in carcinogenesis and tumor progression. FASEB J. 1997;11:443–8.PubMedGoogle Scholar
  7. 7.
    Bredt DS, Snyder SH. Nitric oxide: a physiologic messenger molecule. Annu Rev Biochem. 1994;63:175–95.PubMedCrossRefGoogle Scholar
  8. 8.
    Hentze MW, Kuhn LC. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci USA. 1996;93:8175–82.PubMedCrossRefGoogle Scholar
  9. 9.
    Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43:109–42.PubMedGoogle Scholar
  10. 10.
    Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell. 1994;78:915–18.PubMedCrossRefGoogle Scholar
  11. 11.
    Tamir S, Tannenbaum SR. The role of nitric oxide (NO) in the carcinogenic process. Biochim Biophys Acta. 1996;1288:F31–6.PubMedGoogle Scholar
  12. 12.
    Forstermann U, Kleinert H. Nitric oxide synthase: expression and expressional control of the three isoforms. Naunyn Schmiedebergs Arch Pharmacol. 1995;352:351–64.PubMedCrossRefGoogle Scholar
  13. 13.
    Marletta MA. Nitric oxide synthase structure and mechanism. J Biol Chem. 1993;268:12231–4.PubMedGoogle Scholar
  14. 14.
    Lombard DB, Guarente L. Nijmegen breakage syndrome disease protein and MRE11 at PML nuclear bodies and meiotic telomeres. Cancer Res. 2000;60:2331–4.PubMedGoogle Scholar
  15. 15.
    Nussler AK, Di Silvio M, Billiar TR et al. Stimulation of the nitric oxide synthase pathway in human hepatocytes by cytokines and endotoxin. J Exp Med. 1992;176:261–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Wild CP, Umbenhauer D, Chapot B, Montesano R. Monitoring of individual human exposure to aflatoxins (AF) and N-nitrosamines (NNO) by immunoassays. J Cell Biochem. 1986;30:171–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Xie QW, Cho HJ, Calaycay J et al. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science. 1992;256:225–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Mowat M, Sauder M, Pereira D. The activated form of p53 is not a transactivator of the intracisternal A particle long terminal repeat promoter. Oncogene. 1990;5:241–4.PubMedGoogle Scholar
  19. 19.
    Vodovotz Y, Kim PK, Bagci EZ et al. Inflammatory modulation of hepatocyte apoptosis by nitric oxide: in vivo, in vitro, and in silico studies. Curr Mol Med. 2004;4:753–62.PubMedCrossRefGoogle Scholar
  20. 20.
    Gonzalez-Amaro R, Garcia-Monzon C, Garcia-Buey L et al. Induction of tumor necrosis factor alpha production by human hepatocytes in chronic viral hepatitis. J Exp Med. 1994;179:841–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Mihm S, Hutschenreiter A, Fayyazi A, Pingel S, Ramadori G. High inflammatory activity is associated with an increased amount of IFN-gamma transcripts in peripheral blood cells of patients with chronic hepatitis C virus infection. Med Microbiol Immunol (Berl). 1996;185:95–102.CrossRefGoogle Scholar
  22. 22.
    de Vera ME, Shapiro RA, Nussler AK et al. Transcriptional regulation of human inducible nitric oxide synthase (NOS2) gene by cytokines: initial analysis of the human NOS2 promoter. Proc Natl Acad Sci USA 1996;93:1054–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Laskin DL, Heck DE, Laskin JD. Role of inflammatory cytokines and nitric oxide in hepatic and pulmonary toxicity. Toxicol Lett. 1998;102–3:289–93.CrossRefGoogle Scholar
  24. 24.
    Elmore LW, Hancock AR, Chang SF et al. Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proc Natl Acad Sci USA. 1997;94:14707–12.PubMedCrossRefGoogle Scholar
  25. 25.
    Amaro MJ, Bartolome J, Carreno V. Hepatitis B virus X protein transactivates the inducible nitric oxide synthase promoter. Hepatology. 1999;29:915–23.PubMedCrossRefGoogle Scholar
  26. 26.
    Majano PL, Garcia-Monzon C, Lopez-Cabrera M et al. Inducible nitric oxide synthase expression in chronic viral hepatitis. Evidence for a virus-induced gene upregulation. J Clin Invest. 1998;101:1343–52.PubMedCrossRefGoogle Scholar
  27. 27.
    Liu RH, Jacob JR, Hotchkiss JH, Cote PJ, Gerin JL, Tennant BC. Woodchuck hepatitis virus surface antigen induces nitric oxide synthesis in hepatocytes: possible role in hepatocarcinogenesis. Carcinogenesis. 1994;15:2875–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Kane JM, III, Shears LL, Hierholzer C, Ambs S, Billiar TR, Posner MC. Chronic hepatitis C virus infection in humans: induction of hepatic nitric oxide synthase and proposed mechanisms for carcinogenesis. J Surg Res. 1997;69:321–4.PubMedCrossRefGoogle Scholar
  29. 29.
    Forrester K, Ambs S, Lupold SE et al. Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase (NOS2) expression by wild-type p53. Proc Natl Acad Sci USA. 1996;93:2442–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Messmer UK, Brune B. Nitric oxide-induced apoptosis: p53-dependent and p53-independent signalling pathways. Biochem J. 1996;319:299–305.PubMedGoogle Scholar
  31. 31.
    Ambs S, Ogunfusika MO, Merriam WG, Bennett WP, Billiar TR, Harris CC. Upregulation of NOS2 expression in cancer-prone p53 knockout mice. Proc Natl Acad Sci USA. 1998;95:8823–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Hussain SP, Hofseth LJ, Harris CC. Tumor suppressor genes: at the crossroads of molecular carcinogenesis, molecular epidemiology and human risk assessment. Lung Cancer. 2001;34(Suppl. 2):S7–15.CrossRefGoogle Scholar
  33. 33.
    Kim SF, Huri DA, Snyder SH. Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science. 2005;310:1966–70.PubMedCrossRefGoogle Scholar
  34. 34.
    Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science. 2005;310:1504–10.PubMedCrossRefGoogle Scholar
  35. 35.
    Buchanan FG, DuBois RN. Connecting COX-2 and Wnt in cancer. Cancer Cell. 2006;9:6–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31:339–46.PubMedCrossRefGoogle Scholar
  37. 37.
    Kondo M, Yamamoto H, Nagano H et al. Increased expression of COX-2 in nontumor liver tissue is associated with shorter disease-free survival in patients with hepatocellular carcinoma. Clin Cancer Res. 1999;5:4005–12.PubMedGoogle Scholar
  38. 38.
    Du Q, Park KS, Guo Z et al. Regulation of human nitric oxide synthase 2 expression by Wnt beta-catenin signaling. Cancer Res. 2006;66:7024–31.PubMedCrossRefGoogle Scholar
  39. 39.
    Araki Y, Okamura S, Hussain SP et al. Regulation of cyclooxygenase-2 expression by the wnt and ras pathways. Cancer Res. 2003;63:728–34.PubMedGoogle Scholar
  40. 40.
    Devereux TR, Stern MC, Flake GP et al. CTNNB1 mutations and beta-catenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1. Mol Carcinogen. 2001;31:68–73.CrossRefGoogle Scholar
  41. 41.
    Gupta RA, DuBois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer. 2001;1:11–21.PubMedCrossRefGoogle Scholar
  42. 42.
    Ambs S, Bennett WP, Merriam WG et al. Relationship between p53 mutations and inducible nitric oxide synthase expression in human colorectal cancer. J Natl Cancer Inst. 1999;91:86–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Ambs S, Bennett WP, Merriam WG et al. Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53. Br J Cancer. 1998;78:233–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Fujimoto H, Sasaki J, Matsumoto M et al. Significant correlation of nitric oxide synthase activity and p53 gene mutation in stage I lung adenocarcinoma. Jpn J Cancer Res. 1998;89:696–702.PubMedGoogle Scholar
  45. 45.
    Honda M, Kaneko S, Kawai H, Shirota Y, Kobayashi K. Differential gene expression between chronic hepatitis b and c hepatic lesion. Gastroenterology. 2001;120:955–66.PubMedCrossRefGoogle Scholar
  46. 46.
    Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW. Insights into the pathobiology of hepatitis C virus-associated cirrhosis: analysis of intrahepatic differential gene expression. Am J Pathol. 2002;160:641–54.PubMedGoogle Scholar
  47. 47.
    Dou J, Liu P, Zhang X. Cellular response to gene expression profiles of different hepatitis C virus core proteins in the Huh-7 cell line with microarray analysis. J Nanosci Nanotechnol. 2005;5:1230–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Fukutomi T, Zhou Y, Kawai S, Eguchi H, Wands JR, Li J. Hepatitis C virus core protein stimulates hepatocyte growth: correlation with upregulation of wnt-1 expression. Hepatology. 2005;41:1096–105.PubMedCrossRefGoogle Scholar
  49. 49.
    Okada T, Iizuka N, Yamada-Okabe H et al. Gene expression profile linked to p53 status in hepatitis C virus-related hepatocellular carcinoma. FEBS Lett. 2003;555:583–90.PubMedCrossRefGoogle Scholar
  50. 50.
    Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene. 2006;25:3834–47.PubMedCrossRefGoogle Scholar
  51. 51.
    Kremsdorf D, Soussan P, Paterlini-Brechot P, Brechot C. Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis. Oncogene. 2006;25:3823–33.PubMedCrossRefGoogle Scholar
  52. 52.
    Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol. 2007;8:275–83.PubMedCrossRefGoogle Scholar
  53. 53.
    Bartsch H, Nair J. Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation. DNA damage, and repair. Langenbecks Arch Surg. 2006;391:499–510.PubMedCrossRefGoogle Scholar
  54. 54.
    Hussain SP, Raja K, Amstad PA et al. Increased p53 mutation load in nontumorous human liver of Wilson disease and hemochromatosis: oxyradical overload diseases. Proc Natl Acad Sci USA. 2000;97:12770–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Marrogi AJ, Khan MA, van Gijssel HE et al. Oxidative stress and p53 mutations in the carcinogenesis of iron overload-associated hepatocellular carcinoma. J Natl Cancer Inst. 2001;93:1652–5.PubMedCrossRefGoogle Scholar
  56. 56.
    Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855–78.PubMedGoogle Scholar
  57. 57.
    Hussain SP, Schwank J, Staib F, Wang XW, Harris CC. TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene. 2007;26:2166–76.PubMedCrossRefGoogle Scholar
  58. 58.
    Budhu A, Wang XW. The role of cytokines in hepatocellular carcinoma. J Leukocyte Biol. 2006;80:1197–213.PubMedCrossRefGoogle Scholar
  59. 59.
    Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007;117:1175–83.PubMedCrossRefGoogle Scholar
  60. 60.
    Budhu A, Forgues M, Ye QH et al. Prediction of venous metastases, recurrence and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. 2006;10:99–111.PubMedCrossRefGoogle Scholar
  61. 61.
    Stewart B, Kleihues P. World Cancer Report. IARC Press. 2003:57.Google Scholar
  62. 62.
    Tan M, Li S, Swaroop M, Guan K, Oberley LW, Sun Y. Transcriptional activation of the human glutathione peroxidase promoter by p53. J Biol Chem. 1999;274:12061–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Yoon KA, Nakamura Y, Arakawa H. Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. J Hum Genet. 2004;49:134–40.PubMedCrossRefGoogle Scholar
  64. 64.
    Hussain SP, Amstad P, He P et al. p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis. Cancer Res. 2004;64:2350–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Bensaad K, Tsuruta A, Selak MA et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006;126:107–20.PubMedCrossRefGoogle Scholar
  66. 66.
    Budhu AS, Zipser B, Forgues M, Ye QH, Sun Z, Wang XW. The molecular signature of metastases of human hepatocellular carcinoma. Oncology. 2005;69(Suppl. 1):23–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer and Falk Foundation e.V. 2008

Authors and Affiliations

  • S. P. Hussain
  • X. W. Wang
  • C. C. Harris
    • 1
  1. 1.Laboratory of Human Carcinogenesis National Cancer InstituteNational Institutes of HealthBethesdaUSA

Personalised recommendations