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Role of nitric oxide in tumour progression: Lessons from human tumours

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Abstract

Varied cellular expression and localisation of nitric oxide synthase (NOS) isoforms has been shown in human cancers, including tumours of the breast, ovary, stomach, cervix and central nervous system. Mapping of NOS expression within tumour tissue from breast and gastric cancers shows inducible NOS (iNOS) is expressed predominantly in stromal (macrophage and endothelial) cells, although the level of NOS activity is at least 1–2 orders of magnitude lower than the enzyme activity associated with cytotoxicity and apoptosis. There is evidence that the intratumoural environment may provide chemoattractant signals for monocyte-macrophage recruitment and their subsequent activation via expression of interleukin-4, IgE, and CD23. Such signals lead to induction of iNOS in human macrophages in vitro. The correlation between NOS activity and grade for breast cancer suggests that NO may provide a positive growth signal within the tumour microenvironment. In vivo studies showing increased growth rate, vascular density and invasiveness of a human tumour cell line transfected to constitutively express iNOS support this. Furthermore, in vivo administration of a highly selective inhibitor of iNOS limited invasion and growth rate of iNOS transfected tumours and other murine tumours expressing this isoform. Inhibition of NO generation in the intratumoural microenvironment may prove a useful cancer therapy by preventing angiogenesis, invasion and metastasis.

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References

  1. Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109-142, 1991

    PubMed  Google Scholar 

  2. De Belder AJ, Radomski MW: Nitric oxide in the clinical arena. J Hypertension 12: 617-624, 1994

    Google Scholar 

  3. Knowles RG, Moncada S: Nitric oxide synthase in mammals. Biochem J 298: 249-258, 1994

    PubMed  Google Scholar 

  4. Folkman J: What is the evidence that tumours are angiogenesis-dependent? J Natl Cancer Inst 82: 4-6, 1990

    PubMed  Google Scholar 

  5. Rilke F, Colnaghi MI, Cascinelli N, Andreola S, Baldini MT, Bufalino R, Della Porta G, Menard S, Pierotti M, Testori A: Prognostic significance of HER-2/neuexpression in breast cancer and its relationship to other prognostic factors. Int J Cancer 49: 44-49, 1991

    PubMed  Google Scholar 

  6. Rosen PP, Groshen S, Saigo PE, Kinne DW, Hellman S: Pathological prognostic features in stage I (T1N0M0) and II (T1N1M0) breast carcinoma: a study of 644 patients with median follow-up of 18 years. J Clin Oncol 7: 1239-1257, 1989

    PubMed  Google Scholar 

  7. Miles DW, Happerfield LC, Naylor MS, Bobrow LG, Rubens RD, Balkwill FR: Expression of tumour necrosis factor (TNFa) and its receptor in benign and malignant breast tissue. Int J Cancer 56: 777-782, 1994

    PubMed  Google Scholar 

  8. Radomski MW, Jenkins DC, Holmes L, Moncada S: Human colorectal adenocarcinoma cells: Differential nitric oxyde synthesis determines their ability to aggregate platelets. Cancer Res 51: 6073-6078, 1991

    PubMed  Google Scholar 

  9. Werner-Felmayer G, Werner ER, Fuchs D, Hausen D, Mayer B, Reibnegger G, Weiss G, Wachter H: Ca2?/calmodulin-dependent nitric oxide synthase activity in the human cervix carcinoma cell line ME-180. Biochem J 289: 357-361, 1993

    PubMed  Google Scholar 

  10. Sherman PA, Laubach VE, Reep BR, Wood ER: Purification and cDNA sequence of an inducible nitric oxide synthase from a human tumor cell line. Biochemistry 32: 11600-11605, 1993

    PubMed  Google Scholar 

  11. Fujisawa H, Ogura T, Hokari A, Weisz A, Yamashita J, Esumi H: Inducible nitric oxide synthase in a human glioblastoma cell line. J Neurochemistry 64: 85-91, 1995

    Google Scholar 

  12. Monti E, Gariboldi M: Antiproliferative effects of interleukin-1??and nitric oxide release in a human ovarian carcinoma cell line. Proc Am Assoc Cancer Res 35: 484, 1994

    Google Scholar 

  13. Thomsen LL, Miles DW, Jenkins DC, Affleck K, Holmes L, Moncada S: Nitric oxide synthase in human breast cancer is expressed in stromal cells and not in tumour cells or in human breast tumour cell lines. Br J Cancer 71: 18, 1995

    PubMed  Google Scholar 

  14. Jenkins DC, Charles IG, Baylis SA, Lelchuk R, Radomski MW, Moncada S: Human colon cancer cell lines show a diverse pattern of nitric oxide synthase gene expression and nitric oxide generation. Br J Cancer 70: 847-849, 1994

    PubMed  Google Scholar 

  15. Thomsen LL, Lawton FG, Knowles RG, Beesley JE, Riveros-Moreno V, Moncada S: Nitric oxide synthase activity in human gynecological cancer. Cancer Res 54: 1352-1354, 1994

    PubMed  Google Scholar 

  16. Thomsen LL, Miles DW, Happerfield L, Bobrow LG, Knowles RG, Moncada S: Nitric oxide synthase activity in human breast cancer. Br J Cancer 72: 41-44, 1995

    PubMed  Google Scholar 

  17. Cobbs CS, Brenman JE, Aldape KD, Bredt DS, Israel MA: Expression of nitric oxide synthase in human central nervous system tumors. Cancer Res 55: 727-730, 1995

    PubMed  Google Scholar 

  18. Thomsen LL, Farais-Eisner R, Chaudhuri G: Nitric oxide: Role in human cervical cancer. In: Moncada S, Stamler J, Gross S, Higgs EA (eds) The Biology of Nitric Oxide Part 5. Proceedings of the 4th International Meeting on the Biology of Nitric Oxide. Portland Press, London, 1996, p289

    Google Scholar 

  19. Miles DW, Happerfield LC, Thomsen LL, Filipe I: Nitric oxide synthase and localisation in gastric carcinoma. Proc Am Assoc Cancer Res 37: 154, 1996

    Google Scholar 

  20. Hibbs JB, Taintor RR, Vavrin Z, Rachlin EM: Nitric oxide: A cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 157: 87-94, 1988

    PubMed  Google Scholar 

  21. Drapier J-C, Wietzerbin J, Hibbs JB: Interferon-??and tumour necrosis factor induce the L-arginine-dependent cytotoxic effector mechanism in murine macrophages. Eur J Immunol 18: 1587-1592, 1988

    PubMed  Google Scholar 

  22. Keller R, Geiges M, Keist R: L-arginine-dependent reactive nitrogen intermediates as mediators of tumor cell killing by activated macrophages. Cancer Res 50: 1421-1425, 1990

    PubMed  Google Scholar 

  23. Xie K, Huang S, Dong Z, Juang S-H, Gutman M, Xie Q-W, Nathan C, Fidler IJ: Transfection with the inducible nitric oxide synthase gene suppresses tumorigenicity and abrogates metastasis by K-1735 murine melanoma cells. J Exp Med 181: 1333-1343, 1995

    Article  PubMed  Google Scholar 

  24. Thomsen LL, Baguley BC, Wilson WR: Nitric order: Its production in host-cell-infiltrated EMT6 spheroids and its role in tumour cell killing by flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid. Cancer Chemother Pharmacol 31: 151-155, 1992

    PubMed  Google Scholar 

  25. Liew FY, Millott S, Parkinson C, Palmer RMJ, Moncada S: Macrophage killing of Leishmaniaparasite in vivois mediated by nitric oxide from L-arginine. J Immunol 144: 4794-4797, 1990

    PubMed  Google Scholar 

  26. Garth LL, Nicholson GL, Fidler IJ: Direct in vitrolysis of metastatic tumor cells by cytokine-activated murine vascular endothelial cells. Cancer Res 51: 245-254, 1991

    PubMed  Google Scholar 

  27. Li L, Kilbourn RG, Adams J, Fidler IJ: Role of nitric oxide in lysis of tumor cells by cytokine-activated endothelial cells. Cancer Res 51: 2531-2535, 1991

    PubMed  Google Scholar 

  28. Denis M: Tumor necrosis factor and granulocyte macrophage-colony stimulating factor stimulate human macrophages to restrict growth of virulent Mycobacterium aviumand to kill avirulent M. avium.J Leukocyte Biol 49: 380-387, 1991

    PubMed  Google Scholar 

  29. Cameron ML, Granger DL, Weinberg JB, Kozumbo WJ, Koren HS: Human alveolar and peritoneal macrophages mediate fungistasis independently of L-arginine oxidation to nitrite or nitrate. Am Rev Respir Dis 142: 1313-1319, 1990

    PubMed  Google Scholar 

  30. Murray HW, Teitelbaum RF: L-arginine-dependent reactive nitrogen intermediates and the antimicrobial effect of activated mononuclear phagocytes. J Infect Dis 165: 513-518, 1992

    PubMed  Google Scholar 

  31. Schneemann M, Schoedon G, Hofer S, Blau N, Guerrero L, Schaffner A: Nitric oxide synthase is not a constituent of the antimicrobial armature of human mononuclear phagocytes. J Infect Dis 167: 1358-1364, 1993

    PubMed  Google Scholar 

  32. Dugas B, Mossalayi D, Damais C, Kolb J-P: Nitric oxide production by human monocytes: Evidence for a role of CD23. Immunol Today 16: 574-580, 1995

    Article  PubMed  Google Scholar 

  33. Mossalayi MD, Paul-Eugene N, Ouaaz F, Arock M, Koln JP, Kilchherr E, Debre P, Dugas B: Involvement of FcεRII/ CD23 and L-arginine-dependent pathway in IgE-mediated stimulation of human monocyte functions. Internat Immunol 6: 931-934, 1994

    Google Scholar 

  34. Miles DW, Happerfield LC, Rubens RD: Localisation of nitric oxide synthase (NOS) isoforms and co-expression of the low affinity IgE receptor (CD23) in primary breast cancer. Proc Am Assoc Cancer Res 37: 238, 1996

    Google Scholar 

  35. Lorenzen J, Lewis CE, McCracken D, Horak E, Greenall M, McGee JO: Human tumor-associated NK cells secrete increased amounts of interferon-gamma and interleukin-4. Br J Cancer 64: 457-462, 1991

    PubMed  Google Scholar 

  36. Scholl SM, Pallud C, Beuvon F, Hacene K, Stanley ER, Rohrschneider L, Tang R, Pouillard P, Lidereau R: Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis. J Natl Cancer Inst 86: 120-126, 1994

    PubMed  Google Scholar 

  37. Jenkins DC, Charles IG, Thomsen LL, Moss DW, Holmes LS, Baylis SA, Rhodes P, Westmore K, Emson PC, Moncada S: Roles of nitric oxide in tumor growth. Proc Natl Acad Sci USA 92: 4392-4396, 1995

    PubMed  Google Scholar 

  38. Leibovich SJ, Polverini PJ, Fong TW, Harlow LA, Koch AE: Production of angiogenic activity by human monocytes requires an L-arginine/nitric oxide-synthase-dependent affector mechanism. Proc Natl Acad Sci USA 91: 4190-4194, 1994

    PubMed  Google Scholar 

  39. Konturek S, Brzozowski T, Majka J, Pytko-Polonczyk J, Stachura J: Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers. Eur J Pharmacol 239: 215-217, 1993

    Article  PubMed  Google Scholar 

  40. Macchiarini P, Fontanini G, Hardin MJ, Squartini F, Angeletti CA: Relation of neovascularisation to metastasis of non-small cell lung cancer. Lancet 340: 145-146, 1992

    Article  PubMed  Google Scholar 

  41. Weidner N, Semple JP, Welch WR, Folkman J: Tumor angiogenesis and metastasis-correlation in invasive breast cancer. N Engl J Med 324: 1-8, 1991

    PubMed  Google Scholar 

  42. Fidler IJ, Ellis LM: The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79: 185-188, 1994

    Article  PubMed  Google Scholar 

  43. Kohn EC, Liotta LA: Molecular insights into cancer invasion: Strategies for prevention and intervention. Cancer Res 55: 1856-1862, 1995

    PubMed  Google Scholar 

  44. Davies B, Miles DW, Happerfield LC, Naylor MS, Bobrow LG, Rubens RD, Balkwill FR: Activity of type IV collagenases in benign and malignant breast disease. Br J Cancer 67: 1126-1131, 1993

    PubMed  Google Scholar 

  45. Murrell GAC, Jang D, Williams RJ: Nitric oxide activates metalloprotease enzymes in articular cartilage. Biochem Biophys Res Commun 206: 15-21, 1995

    Article  PubMed  Google Scholar 

  46. Tamura T, Nakanishi T, Kimura Y, Sasaki K, Norimatsu H, Takahashi K, Takigawa M: Nitric oxide mediates interleukin-1 induced matrix degradation and basic fibroblast growth factor release in cultured rabbit articular chondrocytes: A possible mechanism of pathological neovascularization in arthritis. Endocrinology 137: 3729-3737, 1996

    Article  PubMed  Google Scholar 

  47. Hibbs JB, Westenfelder C, Taintor R, Vavrin Z, Kabbitz C, Bararowski RL: Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy. J Clin Invest 89: 867-877, 1992

    PubMed  Google Scholar 

  48. Ochoa JB, Curti B, Peitzman AB, Simmons RL, Billiar TR, Hoffman R, Rault R, Longo DL, Urba WJ, Ochoa AC: Increased circulating nitrogen oxides after human tumor immunotherapy: Correlation with toxic hemodynamic changes. J Natl Cancer Inst 84: 864-867, 1992

    PubMed  Google Scholar 

  49. Miles DW, Thomsen LL, Balkwill F, Thavasu P, Moncada S: Association between biosynthesis of nitric oxide and changes in immunological and vascular parameters in patients treated with interleukin-2. Eur J Cin Invest 24: 287-290, 1994

    Google Scholar 

  50. Citterio G, Pellegatta F, Dilucca G, Fragasso G, Scagleitti U, Pini D, Fortis C, Tresoldi M, Rugarli C: Plasma nitrate plus nitrite changes during continuous intravenous infusion of interleukin-2. Br J Cancer 74: 1297-1301, 1996

    PubMed  Google Scholar 

  51. Ogilvie AC, Hack CE, Wagstaff J, Van Mierlo GJ, Erenberg AJ, Thomsen LL, Hoekman K, Rankin EM: IL-1 beta does not cause neutrophil degranulation, but does lead to IL-6, IL-8 and nitrite/nitrate release when used in patients with cancer. J Immunol 156: 389-394, 1996

    PubMed  Google Scholar 

  52. Thomsen LL, Baguley BC, Rustin GJS, O'Reilly SM: Flavone acetic acid (FAA) with recombinant interleukin-2 (TIL-2) in advanced malignant melanoma II: Induction of nitric oxide production. Br J Cancer 66: 723-727, 1992

    PubMed  Google Scholar 

  53. Moilanen E, Thomsen LL, Miles DW, Happerfield L, Knowles RG, Moncada S: Persistent induction of nitric oxide synthase in tumors from mice following treatment with the antitumor agent 5,6-dimethylxanthenone-4-acetic acid. Br J Cancer (in press)

  54. Andrade SP, Hart IR, Piper PJ: Inhibitors of nitric oxide synthase selectively reduce flow in tumour-associated neovas-culature. Br J Pharmacol 107: 1092-1095, 1992

    PubMed  Google Scholar 

  55. Wood PJ, Stratford IJ, Adams GE, Szabo C, Thiemermann C, Vane JR: Modification of energy metabolism and radiation response of a murine tumour by changes in nitric oxide availability. Biochem Biophys Res Commun 192: 505-510, 1993

    Article  PubMed  Google Scholar 

  56. Peterson HI: Modification of tumour blood flow - a review. Int J Radiat Biol 60: 201-210, 1991

    PubMed  Google Scholar 

  57. Rees DD, Palmer RMJ, Schulz R, Hodson HF, Moncada S: Characterization of three inhibitors of endothelial nitric oxide synthase in vitroand in vivo.Br J Pharmacol 101: 746-752, 1990

    PubMed  Google Scholar 

  58. Garvey EP, Oplinger JA, Furfine ES, Kiff RJ, Laszlo F, Whittle BJR, Knowles RG: 1400W is a slow tight binding, and highly selective inhibitor of inducible nitric oxide synthase in vitroand in vivo.J Biol Chem 272: 4959-4963, 1997

    Article  PubMed  Google Scholar 

  59. Omerovic I, Thomsen LL: Differential expression of nitric oxide synthase in five murine tumors. Proc Am Assoc Cancer Res 37: 493, 1996

    Google Scholar 

  60. Thomsen LL, Scott JMJ, Topley P, Knowles RG, Keerie A-J, Frend AJ: Selective inhibition of inducible nitric oxide synthase inhibits tumor growth in vivo.Studies with 1400W, a novel inhibitor. Cancer Res 57: 3300-3304, 1997

    PubMed  Google Scholar 

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  1. Glaxo Wellcome Research and Development, Gunnels Wood Road, Stevenage, Herts, UK

    Lindy L. Thomsen

  2. ICRF Clinical Onology Unit, Guy's Hospital, London, UK

    David W. Miles

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  1. Lindy L. Thomsen
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Thomsen, L.L., Miles, D.W. Role of nitric oxide in tumour progression: Lessons from human tumours. Cancer Metastasis Rev 17, 107–118 (1998). https://doi.org/10.1023/A:1005912906436

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