Summary
Decreased natural killer (NK) activity as well as interleukin 2 (IL-2) are risk factors for the progression of cervical carcinoma. NK activity and IL-2 may be thymus controlled. Plasma levels of active thymulin, a zinc-dependent thymic hormone (ZnFTS), are reduced in cancer because of the low peripheral zinc bioavailability. Zinc and thymulin are relevant for normal immune functions. α2-Macroglobulin is an inhibitor of matrix metalloproteases (MMPs) against invasive tumour proliferation. Because α2-macroglobulin has a binding affinity (K d) for zinc that is higher than does thymulin, it may play a key role in immune efficiency in cancer. Plasma samples of 22 patients (age range 35–60 years) with locally advanced squamous cervical carcinoma and with FIGO stage Ib2–IIb were examined. They showed reduced active thymulin, decreased NK activity and IL-2 production, increased soluble IL-2 receptor (sIL-2R) and augmented α2-macroglobulin in the circulation, whereas plasma zinc levels were within the normal range for age. Significant positive correlations were found between zinc or active thymulin and α2-macroglobulin (r = 0.75, P< 0.01, r = 0.78, P< 0.01, respectively) in cancer patients. In vitro zinc increases IL-2 production from peripheral blood mononuclear cells (PBMCs) of cancer patients. These data suggest that an increase in α2-macroglobulin, which competes with thymulin for zinc binding, may be involved in causing a thymulin deficit with a consequent decrease of IL-2 and NK cytotoxicity. Thus, physiological zinc treatment in cervical carcinoma maybe restores impaired central and peripheral immune efficiency.
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References
Bach, J. F., Dardenne, M., Pleau, J. M. & Bach, M. A. (1975). Isolation, biochemical characteristics and biological activity of a circulating thymic hormone in the mouse and in the human. Ann NY Acad Sci USA 249: 186–193.
Bardos, P. & Bach, J. F. (1982). Modulation of mouse natural killer cell activity by the serum thymic factor. Scand J Immunol 12: 321–325.
Bontkes, H. J., de Gruijl, T. D., Walboomers, J. M., van den Muysemberg, A. J., Gunther, A. W., Scheper, R. J., Mejier, C. J. & Kummer, J. A. (1997). Assessment of cytotoxic T-lymphocyte phenotype using the specific markers granzyme B and TIA-1 in cervical neoplastic lesions. Br J Cancer 76: 1353–1360.
Bremner, I. & May, P. M. (1989). Systemic interaction of zinc. In Zinc in Human Biology, Mills CF (ed.), pp. 95–108, Springer-Verlag: London
Broder, S. & Negson, M. (1982). The interrelationship between cancer and immune deficiency. In Cancer in the Young, Levin AS (ed.), pp. 29–41. Publishing USA: New York
Burnet, F. M. (1971). Immunological surveillance in neoplasia. Transplant Rev 7: 3–13.
Chandra, R. K. (1984). Excessive intake of zinc impairs immune response. J Am Med Assoc 252: 1443–1446.
Chandra, R. K. (1985). Trace elements regulation and immunity and infection. J Am Coll Nutr 4: 5–16.
Chu, C. T., Howard, G. C., Misra, U. K. & Pizzo, S. V. (1994). α-2 macroglobulin: a sensor of proteolysis. Ann NY Acad Sci USA 737: 291–307.
Csermely, P., Szarme, M., Resch, K. & Somogy, J. (1988). Zinc can increase the activity of protein kinase C and contributes to its binding to plasma membranes in T lymphocytes. J Biochem Chem 263: 6487–6490.
Cunningham-Rundles, S., Bockman, R. S., Lin, A., Giardina, P. V., Hilgartner, M. W., Caldwell-Brown, D. & Carter, D. M. (1990). Physiological and pharmacological effects of zinc on immune response. Ann NY Acad Sci USA 587: 113–118.
Dardenne, M., Pleau, J. M., Nabama, B., Lefancier, P., Denien, M., Choay, J. & Bach, J. F. (1982). Contribution of zinc and other metals to the biological activity of the serum thymic factor. Proc Natl Acad Sci USA 79: 5370–5373.
Dilman, V. M. (1977). Metabolic immunodepression which increases the risk of cancer. Lancet ii: 1207–1210.
Dinarello, C. A. (1984). Interleukin 1. Rev Infect Dis 6: 51–94.
Driessen, C., Hirv, K. & Kirchner, H. (1994). Induction of cytokines by zinc ions in human peripheral blood mononuclear cells and separated monocytes. Lymphokines Cytokines Res 13: 15–20.
Enghlid, J. J., Salvesen, G., Brew, K. & Nagase, H. (1989). Interaction of human rheumatoid synovial collagenase (matrix metalloproteinase 1) and stromelysin (metalloproteinase 3) with human α-2 macroglobulin and chicken ovostatin. Binding kinetics and identification of matrix metalloproteinase cleavage sites. J Biol Chem 264: 8779–8785.
Fabris, N. & Mocchegiani, E. (1995). Zinc, human diseases and aging. A review. Aging Clin Exp Res 7: 77–93.
Fernandez, F. J. & Khan, H. (1971). Clinical methods for atomic absorption spectroscopy. Clin Chem News Lett 3: 24–28.
Garofalo, J. A., Strong, E., Cunningham-Rundles, S., Erlandson, E., Mendez-Botet, C., Schawartz, M. & Good, R. A. (1979). Serum zinc in patients with epidermial cancer of the head and neck. Fed Proc 38: 713–718.
Garzetti, G. G., Ciavattini, A., Lucarini, G., Goteri, G., De Nictolis, M. & Biagini, G. (1996). Microinvasive cervical carcinoma and cervical intraepithelial neoplasia: biologic significance and clinical implications of 72-kDa metalloproteinase immunostaining. Gynecol Oncol 61: 197–203.
Gastinel, L. N., Dardenne, M., Pleau, J. M. & Bach, J. F. (1984). Studies on the zinc binding site to the serum hymic factor. Biochim Biophys Acta 797: 147–155.
Getting, P. G. W. & Crews, B. C. (1994). Binding of epidermal growth factor to human α-2 macroglobulin. Significance for cytokines α-2 macroglobulin interactions. Ann NY Acad Sci USA 737: 383–398.
Giroux, E. L. (1975). Determination of zinc distribution between albumin and α-2 macroglobulin in human serum. Biochem Med 12: 258–266.
Goldstein, A. L. (1984). Thymic Hormones and Lymphokines, Plenum Press: New York
Gooding, R., Riches, P., Dadian, G. & Gore, M. (1995). Increased soluble interleukin-2 receptor concentration in plasma predicts a decreased cellular response to IL-2. Br J Cancer 72: 452–455.
Gorodetsky, R., Fuks, Z., Sulkes, A., Ginsburg, H. & Wesheler, Z. (1985). Correlation of erythrocyte and plasma levels of zinc, copper and iron with evidence of metastatic spread in cancer patients. Cancer 55: 779–786.
Grigsby, P. W. (1996). Stage IB1 vs IB2 carcinoma of the cervix: should the new FIGO staging system define therapy. Gynaecol Oncol 62: 135–136.
Hamoudi, A. B., Newton, W. A., Mancer, R. & Penn, G. D. (1982). Thymic changes in histiocitosis. Am J Clin Pathol 77: 169–172.
Henney, C. S., Kuribayashi, K., Kern, D. E. & Gills, S. (1981). Interleukin-2 augments natural killer cell activity. Nature 291: 335–340.
Kahari, V. M. & Saarialho-Kere, U. (1997). Matrix metalloteinase in skin. A review. Exp Dermatol 6: 199–213.
James, K. (1990). Interactions between cytokines and α-2 macroglobulin. Immunol Today 11: 163–166.
Mackiewicz, A., Kushner, I. & Baumann, H. (1993). Acute Phase Proteins: Molecular Biology, Biochemistry, Clinical Application, CRC Press: Boca Raton, FL
Matoska, J., Wahlstrom, T., Vaheri, A., Bizik, J. & Grofova, M. (1988). Tumour associated α-2 macroglobulin in human melanoma. Int J Cancer 41: 359–363.
Miller, G. G. & Strittmatter, W. J. (1992). Identification of human T-cells that require zinc for the growth. Scand J Immunol 36: 269–277.
Mocchegiani, E., Cacciatore, L., Talarico, M., Lingetti, M. & Fabris, N. (1990). Recovery of low thymic hormone levels in cancer patients by lysine–arginine combination. Int J Immunopharmacol 12: 365–371.
Mocchegiani, E., Paolucci, P., Granchi, D., Cavallazzi, L., Santarelli, L. & Fabris, N. (1994). Plasma zinc level and thymic hormone activity in young cancer patients. Blood 83: 749–757.
Mocchegiani, E., Verbanac, D., Santarelli, L., Tibaldi, A., Muzzioli, M., Radosevic-Stasic, B. & Milin, C. (1997). Zinc and metallothioneins on cellular immune effectiveness during liver regeneration in young and old mice. Life Sci 61: 1125–1145.
Muzzioli, M., Mocchegiani, E., Bressani, N., Bevilacqua, P. & Fabris, N. (1992). In vitro restoration by thymulin of NK activity of cells from old mice. Int J Immunopharmacol 14: 57–61.
Ogata, K., Tamura, H., Yokose, N., An, E., Dan, K., Hamaguchi, H., Sakamaki, H., Onozawa, Y., Clark, S. C. & Nomura, T. (1995). Effects of interleukin 12 on natural killer cell cytotoxicity and the production of interferon gamma and tumour necrosis factor-alfa in patients with myelodyspastic syndromes. J Haematol 90: 15–21.
Park, T. K. & Kim, S. N. (1989). Cell-mediated immunity in patients with invasive carcinoma of the cervix. Yonsei Med J 30: 164–172.
Pavlidis, N. A., Bairaktari, E., Kalef-Ezra, J., Nicolaides, C., Seferiadis, C. & Fountzilas, G. (1995). Serum soluble interleukin-2 receptors in epithelial ovarian cancer patients. Int J Biol Markers 10: 75–80.
Pleau, J. M., Dardenne, M., Blanot, B., Bricas, E. & Bach, J. F. (1979). Antagonist analogues of serum thymic factor FTS interacting with the FTS cellular receptor. Immunol Lett 1: 179–184.
Provinciali, M., Di Stefano, G. & Fabris, N. (1992). Optimization of cytotoxic assay by target cell retention of the fluorescent dye carboxyfluorescin diacetate (CFDA) and comparison with conventional 51Cr release assay. J Immunol Methods 155: 9–24.
Rani, S., Vaidya, M. C. & Rani, K. (1992). Role of cell growth factor (interleukin-2) and its receptors in carcinoma cervix patients. J Steroid Biochem Mol Biol 41: 837–839.
Robertson, M. J. & Ritz, J. (1990). Biology and clinical relevance of human natural killer cells. Blood 12: 2421–2438.
Rubin, L. A., Jay, G. & Nelsen, D. L. (1986). The released interleukin-2 receptors bind interleukin-2 efficiently. J Immunol 137: 3841–3844.
Savino, W., Huang, P. C., Corrigan, A., Berrih, S. & Dardenne, M. (1984). Thymic hormone-containing cells. V. Immunohistological detection of metallothionein within the cells bearing thymulin (a zinc-containing hormone) in human and mouse thymuses. J Histochem Cytochem 32: 942–946.
Seki, S., Abo, T., Sugiura, K., Otheki, T., Kobata, T., Yagita, H., Okumura, K., Rikiishi, H., Masuda, T. & Kumagai, K. (1991). Reciprocal T-cell response in the liver and in the thymus of mice injected with syngenic tumour cells. Cell Immunol 137: 46–54.
Shiffman, M. H. & Brinton, L. A. (1995). The epidemiology of cervical carcinogenesis. Cancer 76: 1888–1901.
Stetler-Stevenson, W. G., Liotta, L. A. & Kleiner, D. E. (1993). Extracellular matrix 6: role of matrix metalloproteinase in tumour invasion and metastasis. FASEB J 7: 1434–1441.
Tanaka, Y., Shiozawa, S., Moromoto, I. & Fujita, T. (1990). Role of zinc in interleukin-2 (IL-2)-mediated T-cell activation. Scand J Immunol 31: 547–552.
Trinchieri, G. & Scott, P. (1994). The role of interleukin 12 in the immune response, diseases and therapy. Immunol Today 15: 460–463.
Van Antwerp, D. J., Martin, S. J., Kafri, T., Green, D. R. & Verma, I. M. (1996). Suppression of TNF-alfa-induced apoptosis by NF-kB. Science 274: 787–789.
Wasik, K., Vonderheid, E. C., Bigler, R. D., Marti, R., Lessin, S. R., Polanski, M. & Kadin, M. E. (1996). Increased serum concentration of the soluble interleukin-2 soluble receptor in cutaneous T-cell lymphoma. Arch Dermatol 132: 42–47.
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Mocchegiani, E., Ciavattini, A., Santarelli, L. et al. Role of zinc and α2macroglobulin on thymic endocrine activity and on peripheral immune efficiency (natural killer activity and interleukin 2) in cervical carcinoma. Br J Cancer 79, 244–250 (1999). https://doi.org/10.1038/sj.bjc.6690040
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DOI: https://doi.org/10.1038/sj.bjc.6690040
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