Cytokines, Iron Homeostasis, and Cancer

  • Frank M. Torti
  • Suzy V. Torti
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 375)


Iron is of central importance to all, from bacteria to higher eukaryotes.1–3 It is critical for such important cellular processes as DNA synthesis, cellular respiration, and oxygen transport. However, iron also is a catalytic participant in the generation of damaging oxygen free radicals. Given this balance of iron availability and cellular survival and iron availability and cell injury, the level and redox state of iron is very tightly regulated within cells by a number of important proteins. These proteins—transferrin, transferrin receptor, and ferritin—are highly conserved. In bacteria and lower eukaryotes, well-defined systems for uptake and regulation of iron show a high degree of similarity to those in mammals.4


Serum Ferritin Serum Iron Transferrin Receptor Serum Ferritin Level Transferrin Saturation 
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.
    J.V. Selby, G.D. Friedman, Epidemiologic evidence of an association between body iron stores and risk of cancer, Int J Cancer 41:677–682 (1988).PubMedCrossRefGoogle Scholar
  2. 2.
    R.G. Stevens, R.P. Beasley, B.S. Blumberg, Iron-binding proteins and risk of cancer in Taiwan, JNCI 76:605–610 (1989).Google Scholar
  3. 3.
    R.G. Stevens, D.Y. Jones, M.S. Micozzi, P.R. Taylor, Body iron stores and the risk of cancer, N Engl J Med 319:1047–1052 (1988).PubMedCrossRefGoogle Scholar
  4. 4.
    J.B. Neilands, Parallels in the mode of regulation of iron assimilation in all living species, in: Iron Transport and Storage, P. Ponka, H.M. Schulman, and R.C. Woodworm, eds., CRC Press, Boca Raton (1990).Google Scholar
  5. 5.
    J.D. Cook, Evaluation of the iron status of a population, Blood 48:449–455 (1976).PubMedGoogle Scholar
  6. 6.
    R.B. Lauffer, Iron, aging and human disease: Historical background and new hypotheses, in: Iron and Human Disease, R.B. Lauffer, ed., CRC Press, Boca Raton (1992).Google Scholar
  7. 7.
    V.R. Fairbanks, E. Beutler, Iron metabolism, in: Hematology, 2nd ed, W.J. Williams, E. Beutler, A.J. Erslev, and R.W. Rundles, eds., McGraw-Hill, New York (1977).Google Scholar
  8. 8.
    R.G. Stevens, S. Kuvibidila, M. Kapps, J. Friedlaender, B.S. Blumberg, Iron-binding proteins, hepatitis B virus, and mortality in the Solomon Islands, Am J Epidemiol 118:550–561 (1983).PubMedGoogle Scholar
  9. 9.
    RJ. Bergeron, R.R. Streiff, G.T. Elliot, Influence of iron on in vivo proliferation and lethality of L1210 cells, J Nutr 115:369–374 (1985).PubMedGoogle Scholar
  10. 10.
    H.W.L. Hann, M.W. Stahlhut, B.S. Blumberg, Iron, nutrition and tumor growth: Decreased tumor growth in iron-deficient mice, Cancer Res 48:4168–4170 (1988).PubMedGoogle Scholar
  11. 11.
    H.W.L. Hann, M.W. Stahlhut, H. Menduke, Iron enhances tumor growth, Cancer 68:2407–2410 (1991).PubMedCrossRefGoogle Scholar
  12. 12.
    H.J. Thompson, K. Kennedy, M. Witt, J. Juzefyk, Effect of dietary iron deficiency or excess on the induction of carcinogenesis by 1-methyl-1-nitrosourea, Carcinogenesis 12:111–114 (1991).PubMedCrossRefGoogle Scholar
  13. 13.
    C.P. Siegers, D. Bumann, G. Baretton, M. Younes, Dietary iron enhances the tumor rate in dimethylhydrazine-induced carcinogenesis in mice, Cancer Lett 41:251–256 (1988).PubMedCrossRefGoogle Scholar
  14. 14.
    A.G. Smith, J.R.P. Cabrai, P. Carthew, J.E. Francis, M.M. Manson, Carcinogenicity of iron in conjunction with a chlorinated environmental chemical, hexachlorobenzene, in C57BL/10ScSn mice, Int J Cancer 43:492 (1989).PubMedCrossRefGoogle Scholar
  15. 15.
    E.D. Weinberg, Iron in neoplastic disease, Nutr Canc 4:223–233 (1983).CrossRefGoogle Scholar
  16. 16.
    A. Donfrancesco, G. Deb, C. Dominici, D. Pileggi, M.A. Castello, L. Helson, Effects of a single course of deferoxamine in neuroblastoma patients, Cancer Res 50:4929–4930 (1990).PubMedGoogle Scholar
  17. 17.
    Z. Estrov, A. Tawa, X. Wang, I. Dube, H. Sulh, A. Cohen, E.W. Gelfand, M.H. Freedman, In vitro and in vivo effects of deferoxamine in neonatal leukemia, Blood 69:757 (1987).PubMedGoogle Scholar
  18. 18.
    H.M. Vriesendorp, J.M. Herpst, M.A. Germack, J.L. Klein, P.K. Leichner, D.M. Loudenslager, S.E. Order, Phase I-II studies of Yttrium-labeled antiferritin treatment for end-stage Hodgkin’s disease, including radiation therapy oncology group 87-01, J Clin Oncol 9:918 (1991).PubMedGoogle Scholar
  19. 19.
    S.E. Order, J.L. Klein, P.K. Leichner, J. Frincke, C. Lollo, DJ. Carlo, 90Yttrium antiferritin—a new therapeutic radiolabeled antibody, Int J Radiat Oncol Biol Phys 12:277 (1986).PubMedCrossRefGoogle Scholar
  20. 20.
    B.J. Foster, K. Clagett-Carr, D. Hoth, B. Leyland-Jones, Gallium nitrate: the second metal with clinical activity, Cancer Treat Rep 70:1311 (1986).PubMedGoogle Scholar
  21. 21.
    W.R. Bezwada, D.P. Derman, T.H. Bothwell, R. Baynes, C. Hesdorffer, A.P. MacPhail, Serum ferritin and Hodgkin’s disease, Scand J Haematol 35:505–10 (1985).CrossRefGoogle Scholar
  22. 22.
    A. Jacobs, A. Slater, J.A. Whittaker, G. Canellos, P.H. Wiernak, Serum ferritin concentration in untreated Hodgkin’s disease, Br J Cancer 34:162–166 (1976).PubMedCrossRefGoogle Scholar
  23. 23.
    H.W.L. Hann, B. Lange, M.W. Stahlhut, K.A. McGlynn, Prognostic importance of serum transferrin and ferritin in childhood Hodgkin’s disease, Cancer 66:313–316 (1990).PubMedCrossRefGoogle Scholar
  24. 24.
    Y. Matzner, A.M. Konijn, C. Hershko, Serum ferritin in hematologic malignancies, Am J Hematol 9:13–22 (1980).PubMedCrossRefGoogle Scholar
  25. 25.
    D.H. Parry, M. Worwood, A. Jacobs, Serum ferritin in acute leukaemia at presentation and during remission, Br Med J 1:245–247 (1975).PubMedCrossRefGoogle Scholar
  26. 26.
    P.A.E. Jones, F.M. Miller, M. Worwood, A. Jacobs, Ferritinaemia in leukaemia and Hodgkin’s disease, Br J Cancer 27:212–217 (1973).PubMedCrossRefGoogle Scholar
  27. 27.
    S. Gupta, A. Imam, K. Licorish, Serum ferritin in acquired immune deficiency syndrome, Clin Lab Immunol 20:11 (1986).Google Scholar
  28. 28.
    C. Moroz, S.L. Misrock, F.P. Siegal, Isoferritins in HIV infection: Relation to clinical stage, CD8 lymphocyte binding and the pathogenesis of AIDS, AIDS 3:11–16 (1989).PubMedGoogle Scholar
  29. 29.
    M.A. Sumes, W.C. Wang, P.R. Dallman, Elevated serum ferritin in children with malignancies, Scand J Haematol 19:153–158 (1977).CrossRefGoogle Scholar
  30. 30.
    D. Potaznik, S. Groshen, D. Miller, R. Bagin, R. Bhalla, M. Schwartz, M. de Sousa, Association of serum iron, serum transferrin saturation, and serum ferritin with survival in acute lymphocytic leukemia, Amer J Pediatr HematollOncol 9:350–355 (1987).CrossRefGoogle Scholar
  31. 31.
    H.W. Hann, C.Y. Kim, T. London, B.S. Blumberg, Increased serum ferritin in chronic liver disease: A risk factor for primary hepatocellular carcinoma, Int J Can 43:376–379 (1989).CrossRefGoogle Scholar
  32. 32.
    M. Tatsuta, H. Yamamura, H. Iishi, H. Kasugai, S. Okuda, Value of serum alpha-fetoprotein and ferritin in the diagnosis of hepatocellular carcinoma, Oncology 43:306–310 (1986).PubMedCrossRefGoogle Scholar
  33. 33.
    N. Nagasue, H. Yukaya, Y.-C. Chang, Y. Ogawa, Serum ferritin level after resection of hepatocellular carcinoma, Cancer 57:1820–1823 (1986).PubMedCrossRefGoogle Scholar
  34. 34.
    D. Basso, C. Fabris, G. Del Favero, T. Meggiato, M. Panozzo, D. Vianello, M. Plebani, R. Naccarato, Hepatic changes and serum ferritin in pancreatic cancer and other gastrointestinal diseases: The role of cholestasis, Ann Clin Biochem 28:34–38 (1991).PubMedGoogle Scholar
  35. 35.
    D. Nitti, C. Fabris, G. Del Favero, Serum ferritin in pancreatic disease. An accurate test of malignancy? Digestion 25:258–262 (1982).PubMedCrossRefGoogle Scholar
  36. 36.
    C. Fabris, R. Farini, G. Del Favero, Combined evaluation of serum ribonuclease and ferritin: Any advantages in pancreatic cancer diagnosis? Oncology 41:393–395 (1984).PubMedCrossRefGoogle Scholar
  37. 37.
    C. Fabris, R. Farini, A. Piccoli, CEA and ferritin in chronic pancreatic disease: A comparative evaluation, Hepatogastroenterology 32:146–148 (1985).PubMedGoogle Scholar
  38. 38.
    A. Esen, H. Ozen, A. Ayhan, A. Ergen, C. Tasar, F. Remzi, Serum ferritin: A tumor marker for renal cell carcinoma, J Urol 145:1134–1137 (1991).Google Scholar
  39. 39.
    P. Gaglia, B. Caldarola, R. Bussone, F. Potente, D. Lauro, A. Jayme, L. Caldarola, Prognostic value of CEA and ferritin assay in breast cancer; a multivariate analysis, Eur J Cancer Clin Oncol 24:1151–1155 (1988).PubMedCrossRefGoogle Scholar
  40. 40.
    M.R. Williams, A. Turkes, D. Pearson, K. Griffiths, R.W. Blarney, Serum ferritin as a marker of therapeutic response in stage III and IV breast cancer, Eur J Surg Oncol 16:22–27 (1990).PubMedGoogle Scholar
  41. 41.
    R. Cox, O.H. Gyde, M.J. Leyland, Serum ferritin levels in small cell lung cancer, Eur J Cancer Clin Oncol 22:831 (1986).PubMedCrossRefGoogle Scholar
  42. 42.
    S. Saji, Y. Yokoyama, H. Niwa, H. Takao, H. Kida, R. Kawata, H. Tanemura, K. Sakata, Clinical studies on serum immunosuppressive acidic protein (IAP) and ferritin in gastric cancer patients: With special reference to preoperative value and influence of surgical stress, J Surg Oncol 33:215–222 (1986).PubMedCrossRefGoogle Scholar
  43. 43.
    M. Akiba, K. Neriishi, W.J. Blot, H. Kabuto, R.G. Stevens, H. Kato, C.E. Land, Serum ferritin and stomach cancer risk among a Japanese population, Cancer 67:1707 (1991).PubMedCrossRefGoogle Scholar
  44. 44.
    F.M. Torti, B. Dieckmann, B. Beutler, A. Cerami, G.M. Ringold, A macrophage factor inhibits adipocyte gene expression: An in vitro model of cachexia, Science 229:867–869 (1985).PubMedCrossRefGoogle Scholar
  45. 45.
    S.V. Torti, E. Kwak, S.C. Miller, G. Ringold, K. Myambo, RM. Torti, The molecular cloning and characterization of murine ferritin heavy chain, a tumor necrosis factor-inducible gene, J Biol Chem 263:12638–12644 (1988).PubMedGoogle Scholar
  46. 46.
    S.C. Miller, H. Ito, H.M. Blau, F.M. Torti, Tumor necrosis factor inhibits human myogenesis in vitro, Molec Cell Biol 8:2295–2301 (1988).PubMedGoogle Scholar
  47. 47.
    Y. Wei, S.C. Miller, Y. Tsuji, S.V. Torti, RM. Torti, Interleukin 1 induces ferritin heavy chain in human muscle cells, Biochem Biophys Res Commun 169:289–296 (1990).PubMedCrossRefGoogle Scholar
  48. 48.
    J. Zahringer, B.S. Baliga, H.N. Munro, Novel mechanism for translational control in regulation of ferritin synthesis by iron, Proc Natl Acad Sci USA 73:857–861 (1976).PubMedCrossRefGoogle Scholar
  49. 49.
    L.L. Miller, S.C. Miller, S.V. Torti, Y. Tsuji, RM. Torti, Iron-independent induction of ferritin-H chain by tumor necrosis factor, Proc Natl Acad Sci USA 88:4946–4950 (1991).PubMedCrossRefGoogle Scholar
  50. 50.
    J.T. Rogers, K.R. Bridges, G.P. Durmowicz, J. Glass, P.E. Auron, H.N. Munro, Translational control during the acute phase response, J Biol Chem 265:14572–14578 (1990).PubMedGoogle Scholar
  51. 51.
    Y. Tsuji, L.L. Miller, S.C. Miller, S.V. Torti, RM. Torti, Tumor necrosis factor-α and interleukin-1-α regulate transferrin receptor in human diploid fibroblasts. Relationship to the induction of ferritin heavy chain, J Biol Chem 266:7257–7261 (1991).PubMedGoogle Scholar
  52. 52.
    S. Warren, S.C. Miller, S.V. Torti, Y. Tsuji, RM. Torti, The role of iron in the cytotoxicity of tumor necrosis factor, Lymphokine Cytokine Res 12:75 (1993).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Frank M. Torti
    • 1
  • Suzy V. Torti
    • 1
  1. 1.Department of MedicineStanford University and Palo Alto Veterans Affairs Medical CenterPalo AltoUSA

Personalised recommendations