Abstract
Research and clinical observations during the past six decades have shown that:
-
1.
Iron promotes cancer cell growth;
-
2.
Hosts attempt to withhold or withdraw iron from cancer cells; and
-
3.
Iron is a factor in prevention and in therapy of neoplastic disease.
Although normal and neoplastic cells have similar qualitative requirements for iron, the neoplastic cells have more flexibility in acquisition of the metal. Excessive iron levels in animals and humans are associated with enhanced neoplastic cell growth. In invaded hosts, cytokine-activated macrophages increase intracellular ferritin retention of the metal, scavenge iron in areas of tumor growth, and secrete reactive nitrogen intermediates to effect efflux of nonheme iron from tumor cells. Procedures associated with lowering host intake of excess iron can assist in prevention and in management of neoplastic disease. Chemical methods for prevention of iron assimilation by neoplastic cells are being, developed in experimental and clinical protocols. The antineoplastic activity of a considerable variety of chemicals, as well as of radiation, is modulated by iron. The present article focuses on recent findings and suggests directions for further canceriron research.
Similar content being viewed by others
References
J. B. Neilands,Annu. Rev. Nutr. 1, 27–45 (1981).
L. P. Wackett, W. H. Orme-Johnson, and C. T. Walsh, inMetal Ions and Bacteria, T. J. Beveridge and R. J. Doyle, eds., J. Wiley & Sons, New York, 1989, pp. 165–206.
E. D. Weinberg,Drug Metab. Revs. 22, 531–579 (1990).
E. D. Weinberg,Quart, Rev. Biol. 64, 261–290 (1989).
S. Bailey, R. W. Evans, R. C. Garratt, B. Gorinsky, S. Hasnain, C. Horsburgh H. Shoti, P. F. Lindley, A. Mydin, R. Sarra, and J. L. Watson,Biochemistry,27, 5804–5812 (1988).
W. S. May, Jr. and P. Cuatrecasas,J. Memb. Biol. 88, 205–215 (1985).
E. H. Morgan and E. Baker,Ann. NY Acad. Sci 526, 65–82 (1987).
U. Testa, A. Camagna, G. Gianella, E. Pelosi-Testa, M. Petrini, P. Samoggia, E. Montesoro, L. Bottero, N. M. Sposi, G. Salvo, F. Mavilio, G. Isacchi, G. Mastrobera-Dino, and C. Peschle,Ann. NY Acad. Sci. 511, 131–137 (1987).
L. M. Neckers,Curr. Top. Micro. Immunol. 113, 62–68 (1984).
M. Cazzola, G. Bergamaschi, L. Dezza, and P. Arosio,Blood 75, 1903–1919 (1990).
M. Vostrejs, P. L. Moran, and P. A. Seligman,J. Clin. Invest. 82, 331–339. (1988).
J. P. Brown, R. W. Hewick, I. Hellstrom, K. E. Hellstrom, R. F. Doolittle, and W. J. Dreyer,Nature 296, 171–173 (1982).
P. Basset, Y. Quesneau, and J. Zwiller,Canc. Res. 46, 1644–1647 (1986).
K. C. Gatter, G. Brown, I. S. Trowbridge, R. E. Woolston, and D. Y. Mason,J. Clin. Pathol. 36, 539–545 (1983).
W. P. Faulk, B. L. Hsi, and P. L. Stevens,The Lancet 2, 390–392 (1980).
J. E. Shindelman, A. E. Ortmeyer, and H. Sussman,Internat. J. Canc. 27, 329–334 (1981).
L. Esserman, S. Takahashi, V. Rojas, R. Warnke, and R. Levy,Blood,74 2718–2729 (1989).
E. Baker, K. Jones, D. Lloyd, E. H. Morgan, D. Trinder, and G. Yeoh,Abstr. 8th Internat. Conf. Iron Prot. Trans. Stor. 1987, p. 66.
Y. Niitsu, S. Ohtsuka, Y. Kohgo, N. Watanabe, J. Koseki, and I. Urushizaki,Tum. Res. 10, 31–42 (1975).
X-D. Zhou, L. Detolla, R. P. Custer, and W. T. London,Cancer 59, 1430–1437 (1987).
R. W. Holley,Proc. Natl. Acad. Sci. USA 69, 2840–2841 (1972).
E. D. Weinberg,Biol. Trace Elem. Res. 3, 55–80 (1981).
J. Benbassat, C. Hershko, R. Laskov, and M. Eliakim,Nutr. Canc. 3, 20–26 (1981).
R. J. Bergeron, R. R. Streiff, and G. T. Elliott,J. Nutr. 11, 369–374 (1985).
H-W. L. Hann, M. W. Stahut, and B. S. Blumberg,Canc. Res. 48, 4168–4170 (1988).
C-P. Siegers, D. Bumann, G. Bareton, and M. Younes,Canc. Lttr. 41, 251–256 (1988).
R. L. Nelson, S. J. Yoo, J. C. Tanure, G. Andrianopoulos, and A. Misumi,Anticanc. Res. 9, 1477–1482 (1989).
A. G. Smith, J. E. Francis, and P. Carthew,Carcinogenesis 11, 437–444 (1990).
H. J. Thompson, K. Kennedy, M. Witt, and J. Juzefyk,Carcinogenesis 12, 111–114 (1991).
R. W. Ammann, E. Muller, J. Bansky, G. Schüler, and W. H. Häcki,Scand. J. Gastroenterol. 15, 733–736 (1980).
C. Niederau, R. Fischer, F. Sonnenberg, W. Stremmel, H. J. Trampisch, and G. Strohmeyer,N. Engl. J. Med. 313, 1256–1262 (1985).
R. A. Bradbear, C. Bain, V. Siskind, F. D. Schofield, S. Webb, E. M. Axelson, J. W. Halliday, M. L. Bassett, and L. W. Powell,J. Natl. Canc. Inst. 75, 81–84 (1985).
R. G. Stevens, R. P. Beasley, and B. S. Blumberg,J. Natl. Canc. Inst. 76, 605–610 (1986).
D. Potaznik, S. Groshen, D. Miller, R. Bagin, R. Bhalla, M. Schwartz, and M. deSousa,Am. J. Ped. Hematol. Oncol. 9, 350–355 (1987).
A. E. Evans, G. J. D'Angio, K. Propert, J. Anderson, and H. W. L. Hann,Cancer 59, 1853–1859 (1987).
R. G. Stevens, D. Y. Jones, M. C. Micozzi, and P. R. Taylor,N. Engl. J. Med. 319, 1047–1052 (1988).
J. V. Selby and G. D. Friedman,Internat. J. Canc. 41, 677–682 (1988).
H-W. L. Hann, C. Y. Kim, W. T. London, and B. S. Blumberg,Internat. J. Canc. 43, 376–379 (1989).
H-W. L. Hann, B. Lange, M. W. Stahlhut, and K. A. McGlynn,Cancer 66, 313–316 (1990).
S. Akiba, K. Nerlishi, W. J. Blot, M. Kabuto, R. F. Stevens, H. Kato, and C. E. Land,Cancer 67, 1707–1712 (1991).
J. M. Heal, C. Chuang, and N. Blumberg,Am. J. Surg. 156, 374–380 (1988).
N. Blumberg, J. M. Heal, and C. Chuang,Ann. Surg. 207, 410–415 (1988).
J. L. Israel, K. A. McGlynn, H-W. L. Hann, and B. S. Blumberg, inIron in Immunity, Cancer and Inflammation, M. de Sousa and J. H. Brock, eds., J. Wiley & Sons, Chichester, 1989, pp. 301–316.
J. B. Weinberg and J. B. Hibbs, Jr.,Nature 269, 245–247 (1977).
R. Green, I. Esperaza, and R. Schreiber,Ann. NY Acad. Sci. 526, 301–309 (1988).
M. de Sousa, inIron in Immunity, Cancer and Inflammation, M. de Sousa and J. H. Brock, eds., J. Wiley & Sons, Chichester, 1989, pp. 247–258.
C. F. Bryan, S. H. Leech, P. Kumar, R. Gaumer, B. Bozelka, and J. Morgan,Am. J. Med. Sci. 301, 55–61 (1991).
S. Ritland and J. Aaseth,J. Hepatol. 5, 118–122 (1987).
E. Graf and J. W. Eaton,Cancer 56, 717, 718 (1985).
C. F. Babbs,Free Rad. Biol. Med. 8, 191–200 (1990).
A. Locke, E. R. Main, and D. O. Rosbach,J. Clin. Invest. 11, 527–542 (1932).
M. R. Beamish, P. A. Jones, D. Trevett et al.,Br. J. Canc. 26, 444–452 (1972).
A. Miller, R. B. Chodos, C. Emerson, and J. F. Ross,J. Clin. Invest. 35, 1248–1262 (1956).
A. M. Konin and C. Hershko, inIron in Immunity, Cancer and Inflammation, M. de Sousa and J. H. Brock, eds., J. Wiley & Sons, Chichester, 1989, pp. 111–144.
M. Malkovsky, P. M. Sondel, W. Strober, and A. G. Dalgleish,Clin. Exp. Immunol. 74, 151–161 (1988).
C. Hershko, J. D. Cook, and C. A. Finch,Br. J. Haematol. 28, 67–75 (1974).
A. Deiss,Sem. Hematol. 20, 81–90 (1983).
P. Aisen,Ann. NY Acad. Sci. 526, 93–99 (1988).
H. Wachter, D. Fuchs, A. Hausen, A. Reibnegger, and E. R. Werner,Adv. Clin. Chem. 27, 81–141 (1989).
H. Wachter, E. Artner-Dworzak, D. Fuchs, L. C. Fuith, A. Hausen, G. Reibnegger, E. R. Werner, G. Werner-Felmayer, and M.-P. Dierich,Tumordiagn. u Ther. 11, 229–232 (1990).
J. L. Van Snick, B. Markowetz, and P. L. Masson,J. Exp. Med. 146, 817–826 (1977).
V. E. Price and R. E. Greenfield,Adv. Canc. Res. 5, 199–284 (1958).
A. E. Dumont, R. J. Ford, and F. F. Becker,Cancer 38, 1247 (1976).
T. C. Iancu,Ultrastruct. Pathol. 13, 573–584 (1989).
R. L. Carter,Br. J. Canc. 23, 559–566 (1969).
G. Magnusson, H. Flodh, and T. Malmfors,Scand. J. Haematol. Suppl. 32, 87–98 (1977).
J. B. Hibbs, Jr., R. R. Taintor, and Z. Vavrin,Biochem. Biophys. Res. Commun. 123, 716–723 (1984).
J. L. Krahenbuhl,Canc. Res. 40, 4622–4627 (1980).
J-C. Drapier and J. B. Hibbs, Jr.,J. Clin. Invest. 78, 790–797 (1986).
D. L. Granger and A. L. Lehninger,J. Cell Biol. 95, 527–535 (1982).
J. B. Hibbs, Jr., R. R. Taintor, L. Vavrin, and E. M. Rachlin,Biochem. Biophys. Res. Commun. 157, 87–94 (1988).
M. A. Marletta, P. S. Yoon, R. Iyengar, C. Leaf, and J. S. Wishnok,Biochemistry 27, 8706–8711 (1988).
D. L. Granger, J. B. Hibbs, Jr., J. R. Perfect, and D. T. Durack,J. Clin. Invest. 85, 264–273 (1990).
M. Caldwell and F. Archibald,Biochem. Cell Biol. 65, 651–657 (1987).
M. A. Krikker,Nutr. Today 22, 37–40 (1987).
S. Kent, E. D. Weinberg, and P. Stuart-Macadam,Hum. Nat. 1, 55–79 (1990).
J. D. Cook,Am. J. Clin. Nutr. 51, 301–308 (1990).
E. Graf and J. W. Eaton,Free Rad. Biol. Med. 8, 61–69 (1990).
A. Ullah and A. M. Shamsuddin,Carcinogenesis 11, 2219–2222 (1990).
M. Brune, L. Rossander, and L. Hallberg,Am. J. Clin. Nutr. 49, 542–545 (1989).
W. D. DeWys and W. J. Pories,J. Natl. Canc. Inst. 48, 375–381 (1972).
C. Q. Edwards, L. M. Griffen, D. Goldgar, C. Drummond, M. H. Skolnick, and J. P. Kushner,N. Engl. J. Med. 318, 1355–1362 (1988).
E. D. Weinberg,The Lancet 1, 1399, 1400 (1989).
C. E. Cross, B. Halliwell, E. T. Borish, W. A. Pryor, B. N. Ames, R. L. Saul, J. M. McCord, and D. Harman,Ann. Intern. Med. 107, 526–545 (1987).
S. E. McGowan and S. A. Henley,J. Lab. Clin. Med. 111, 611–617 (1988).
M. J. Pippard, inIron in Immunity, Cancer and Inflammation, M. de Sousa and J. H. Brock, eds., J. Wiley & Sons, Chichester, 1989, pp. 361–392.
J. G. Cory, L. Lasater, and A. Sato,Biochem. Pharmacol. 30, 979–984 (1981).
H-W. L. Hann, M. W. Stahlhut, and C. L. Hann,Hepatology 11, 566–569 (1990).
H-W. L. Hann, M. W. Stahlhut, and W. C. Maddrey,Hepatology 12, 912 (1990).
Z. Estrov, A. Tawa, X-H. Wang, I. D. Dube, H. Sulh, A. Cohen, E. W. Gelfand, and M. H. Freedman,Blood 69, 757–761 (1987).
A. Donfrancesco, G. Deb, C. Dominici, D. Pileggi, M. A. Castello, and L. Nelson,Canc. Res. 50, 4929, 4930 (1990).
R. J. Bergeron and M. J. Ingeno,Canc. Res. 47, 6010–6016 (1987).
R. J. Bergeron, R. Braylan, S. Goldey, and M. Ingeno,Biochem. Biophys. Res. Commun. 136, 273–280 (1986).
I. S. Trowbridge, inIron in Immunity, Cancer and Inflammation, M. de Sousa and J. H. Brock, eds., J. Wiley & Sons, Chichester, 1989, pp. 341–360.
J. D. Kemp, K. M. Smith, L. T. Kanner, F. Gomez, J. A. Thorson, and P. W. Naumann,Blood 76, 991–995 (1990).
G. Kletter, B. R. Parks, Jr., A. Bhatnager, and R. V. Iyer,Oncology 45, 421–423 (1988).
V. S. Sethi, Z. Shihabi, and C. L. Spurr,Canc. Treat. Repts. 68, 933–936 (1984).
E. H. Morgan and B. J. Iacopetta,Clin. Exp. Pharmacol. Physiol. 14, 119–126 (1987).
C. R. Chitambar, H. C. Seigneuret, W. G. Matthaeus, and L. G. Lum,Canc. Res. 49, 1125–1129 (1989).
C. R. Chitambar and J. Narasimhan,Pathobiology 59, 3–10 (1991).
J. H. Lundberg and C. R. Chitambar,Canc. Res. 50, 6466–6470 (1990).
E. D. Weinberg,Fed. Proc. 20, 132–135 (1961).
J. C. Dabrowiak,J. Inorg. Biochem. 13, 317–337 (1980).
W. J. Martin and D. L. Kachel,J. Lab. Clin. Med. 110, 153–158 (1987).
D. B. Chandler and J. D. Fulmer,Am. Rev. Resp. Dis. 131, 596–598 (1985).
C. Myers, L. Gianni, J. Zweier, J. Muindi, B. K. Sinha, and H. Eliot,Fed. Proc. 45, 2792–2797 (1986).
J. H. Doroshow,N. Engl. J. Med. 324, 843–845 (1991).
J. L. Speyer, M. D. Green, E. Kramer, P. Stecy, A. Zelenuich-Jacquotte, M. Rey, J. Sanger, C. Ward, N. Dubin, V. Ferrans, J. Wernz, F. Feit, W. Slater, R. Blum, and F. Muggia,N. Engl. J. Med. 319, 745–752 (1988).
B. Halliwell, O. I. Aruoma, G. Mufti, and A. Bomford,FEBS Lttr. 241, 202–204 (1988).
B. Halliwell and A. Bomford,N. Engl. J. Med. 320, 399, 400 (1989).
R. G. Stevens and D. R. Kalkwarf,Envir. Health Persp. 87, 291–300 (1990).
J. M. Nelson and R. G. Stevens,Cell Prolif. 24, 411 (1991).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Weinberg, E.D. Roles of iron in neoplasia. Biol Trace Elem Res 34, 123–140 (1992). https://doi.org/10.1007/BF02785242
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02785242