International Journal of Radiation Oncology * Biology * Physics
Volume 76, Issue 5 , Pages 1520-1527 , April 2010

Activated Macrophages as a Novel Determinant of Tumor Cell Radioresponse: The Role of Nitric Oxide–Mediated Inhibition of Cellular Respiration and Oxygen Sparing

  • Heng Jiang, M.S.

      Affiliations

    • Vrije Universiteit Brussel, Cancer Research Unit, Brussels, Belgium
    • ,
  • Mark De Ridder, M.D., Ph.D.

      Affiliations

    • Vrije Universiteit Brussel, Cancer Research Unit, Brussels, Belgium
    • UZ Brussel, Oncologisch Centrum, Radiotherapie, Université catholique de Louvain, Brussels, Belgium
    • Corresponding Author InformationReprint requests to: Mark De Ridder, UZ Brussel, Oncologisch Centrum, Radiotherapie, Laarbeeklaan 101, B-1090 Brussels, Belgium. Tel: (+32) 2-477-6147; Fax: (+32) 2-477-6212
    • ,
  • Valeri N. Verovski, Ph.D.

      Affiliations

    • UZ Brussel, Oncologisch Centrum, Radiotherapie, Université catholique de Louvain, Brussels, Belgium
    • ,
  • Pierre Sonveaux, Ph.D.

      Affiliations

    • Unit of Pharmacology and Therapeutics, Université catholique de Louvain, Brussels, Belgium
    • ,
  • Bénédicte F. Jordan, Ph.D.

      Affiliations

    • Unit of Biomedical Magnetic Resonance, Université catholique de Louvain, Brussels, Belgium
    • ,
  • Kalun Law, B.S.

      Affiliations

    • Vrije Universiteit Brussel, Cancer Research Unit, Brussels, Belgium
    • ,
  • Christinne Monsaert, B.S.

      Affiliations

    • Vrije Universiteit Brussel, Cancer Research Unit, Brussels, Belgium
    • ,
  • Dirk L. Van den Berge, M.D.

      Affiliations

    • UZ Brussel, Oncologisch Centrum, Radiotherapie, Université catholique de Louvain, Brussels, Belgium
    • ,
  • Dirk Verellen, Ph.D.

      Affiliations

    • UZ Brussel, Oncologisch Centrum, Radiotherapie, Université catholique de Louvain, Brussels, Belgium
    • ,
  • Olivier Feron, Ph.D.

      Affiliations

    • Unit of Pharmacology and Therapeutics, Université catholique de Louvain, Brussels, Belgium
    • ,
  • Bernard Gallez, Ph.D.

      Affiliations

    • Unit of Biomedical Magnetic Resonance, Université catholique de Louvain, Brussels, Belgium
    • ,
  • Guy A. Storme, M.D., Ph.D.

      Affiliations

    • Vrije Universiteit Brussel, Cancer Research Unit, Brussels, Belgium
    • UZ Brussel, Oncologisch Centrum, Radiotherapie, Université catholique de Louvain, Brussels, Belgium

Received 17 July 2009 ,Revised 9 October 2009 ,Accepted 14 October 2009.

References 

  1. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4:437–447
  2. Dewhirst MW, Navia IC, Brizel DM, et al. Multiple etiologies of tumor hypoxia require multifaceted solutions. Clin Cancer Res. 2007;13:375–377
  3. Crokart N, Jordan BF, Baudelet C, et al. Glucocorticoids modulate tumor radiation response through a decrease in tumor oxygen consumption. Clin Cancer Res. 2007;13:630–635
  4. Wink DA, Vodovotz Y, Laval J, et al. The multifaceted roles of nitric oxide in cancer. Carcinogenesis. 1998;19:711–721
  5. Brown GC. Nitric oxide and mitochondrial respiration. Biochim Biophys Acta. 1999;1411:351–369
  6. Jordan BF, Gregoire V, Demeure RJ, et al. Insulin increases the sensitivity of tumors to irradiation: Involvement of an increase in tumor oxygenation mediated by a nitric oxide-dependent decrease of the tumor cells oxygen consumption. Cancer Res. 2002;62:3555–3561
  7. Jordan BF, Sonveaux P, Feron O, et al. Nitric oxide as a radiosensitizer: Evidence for an intrinsic role in addition to its effect on oxygen delivery and consumption. Int J Cancer. 2004;109:768–773
  8. Janssens MY, Van den Berge DL, Verovski VN, et al. Activation of inducible nitric oxide synthase results in nitric oxide-mediated radiosensitization of hypoxic EMT-6 tumor cells. Cancer Res. 1998;58:5646–5648
  9. De Ridder M, Verellen D, Verovski VN, et al. Hypoxia tumor cell radiosensitization through nitric oxide. Nitric Oxide. 2008;19:164–169
  10. Sonveaux P, Jordan BF, Gallez B, et al. Nitric oxide delivery to cancer: Why and how?. Eur J Cancer. 2009;45:1352–1369
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  12. De Ridder M, Van den Berge DL, Verovski VN, et al. NF-kappaB inhibition impairs the radioresponse of hypoxic EMT-6 tumour cells through downregulation of inducible nitric oxide synthase. Br J Cancer. 2003;88:120–124
  13. De Ridder M, Verovski VN, Van den Berge DL, et al. Lipid a radiosensitizes hypoxic EMT-6 tumor cells: role of the NF-kappaB signaling pathway. Int J Radiat Oncol Biol Phys. 2003;57:779–786
  14. De Ridder M, Verovski VN, Chiavaroli C, et al. The radiosensitizing effect of immunoadjuvant OM-174 requires cooperation between immune and tumor cells through interferon-gamma and inducible nitric oxide synthase. Int J Radiat Oncol Biol Phys. 2006;66:1473–1480
  15. De Ridder M, Jiang H, Van Esch G, et al. IFN-gamma+ CD8 + T lymphocytes: possible link between immune and radiation responses in tumor-relevant hypoxia. Int J Radiat Oncol Biol Phys. 2008;71:647–651
  16. Mitchell JB, Wink DA, DeGraff W, et al. Hypoxic mammalian cell radiosensitization by nitric oxide. Cancer Res. 1993;53:5845–5848
  17. Verovski VN, Van den Berge DL, Soete GA, et al. Intrinsic radiosensitivity of human pancreatic tumour cells and the radiosensitising potency of the nitric oxide donor sodium nitroprusside. Br J Cancer. 1996;74:1734–1742
  18. Sica A, Larghi P, Mancino A, et al. Macrophage polarization in tumour progression. Semin Cancer Biol. 2008;18:349–355
  19. Weigert A, Brune B. Nitric oxide, apoptosis and macrophage polarization during tumor progression. Nitric Oxide. 2008;19:95–102
  20. Srisook K, Cha YN. Biphasic induction of heme oxygenase-1 expression in macrophages stimulated with lipopolysaccharide. Biochem Pharmacol. 2004;68:1709–1720
  21. D'Amico G, Lam F, Hagen T, et al. Inhibition of cellular respiration by endogenously produced carbon monoxide. J Cell Sci. 2006;119:2291–2298
  22. Frerart F, Sonveaux P, Rath G, et al. The acidic tumor microenvironment promotes the reconversion of nitrite into nitric oxide: Towards a new and safe radiosensitizing strategy. Clin Cancer Res. 2008;14:2768–2774
  23. Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66:605–612

 Supported by The Foundation Against Cancer, Foundation of Public Interest (Grant (219.2008), Fonds voor Wetenschappelijk Onderzoek–Vlaanderen (Grant 0386-07), Onderzoeksraad van de Vrije Universiteit Brussel, and Scientific Fund W. Gepts UZ-Brussel.

 Conflict of interest: none.

PII: S0360-3016(09)03518-4

doi: 10.1016/j.ijrobp.2009.10.047

International Journal of Radiation Oncology * Biology * Physics
Volume 76, Issue 5 , Pages 1520-1527 , April 2010

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