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Circulating concentrations of interleukin-6 in cancer patients and their pathogenic role in tumor-induced hypercalcemia

  • Original Articles
  • Cytokines, Interleukin-6, Cancer, Bone Metastases, Hypercalcemia
  • Published:
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Abstract

Circulating interleukin-6 (IL-6) concentrations correlate with disease activity in severe inflammatory conditions, in sepsis and in some hematological malignancies. On the other hand, IL-6 is a potent stimulator of osteoclastogenesis and has been implicated as a contributory factor in the genesis of osteopenic conditions. We measured circulating IL-6 levels by a sensitive (detection limit of 10 U/ml) and specific bioassay in 103 patients with advanced cancer, including 41 with tumor-induced hypercalcemia before any specific hypocalcemic therapy. We related IL-6 concentrations to clinical features and to biochemical parameters of bone metabolism, including blood Ca, Ca2+, Pi, intact parathyroid hormone, parathyroid hormone-related protein, osteocalcin, 1,25-(OH)2-vitamin D and, as markers of bone resorption, the fasting urinary excretion of calcium (Ca/creatinine) and hydroxyproline. IL-6 levels were increased, i.e. detectable, in 23% of the patients, 8/41 (20%) hypercalcemic and 16/62 (26%) normocalcemic patients (NS); the distribution of the values was similar in the two groups. The presence of increased IL-6 concentrations was not related to any clinical characteristic, notably not to the survival nor to the existence of bone metastases, whether in hypercalcemic or normocalcemic patients; e.g., only 3/12 (25%) hypercalcemic subjects without bone metastases had elevated IL-6 levels. We found no significant correlations between IL-6 concentrations and any of the biochemical parameters studied. Hypercalcemic subjects with increased IL-6 had higher urinary Ca/creatinine levels than patients with normal IL-6 levels (P<0.005) but this was not the case in normocalcemic subjects. Mean concentrations of inflammatory or other bone metabolism markers were not significantly different between patients with normal or with elevated IL-6 levels. In summary, circulating IL-6 levels were increased in 23% of 103 patients with advanced cancer, but the frequency of increased IL-6 concentrations was not related to the presence of hypercalcemia or to any marker of calcium metabolism or bone turnover. The pathogenic importance of circulating IL-6 in patients with solid tumors remains to be demonstrated and our data indicate that increased circulating levels of IL-6, possibly reflecting the activation of the immune system, only contribute in a minor way to the osteolytic process in patients with tumor-induced hypercalcemia.

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References

  1. Bataille R, Jourdan M, Zhang XG, Klein B (1989) Serum levels of interleukin 6, a potent myeloma cell growth factor, as a reflect of disease severity in plasma cell dyscrasias. J Clin Invest 84: 2008–2011

    PubMed  Google Scholar 

  2. Beck JT, Hsu SM, Wijdenes J, Bataille R, Klein B, Vesole D, Hayden K, Jagannath S, Barlogie B (1994) Alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody. N Engl J Med 330: 602–605

    PubMed  Google Scholar 

  3. Black K, Garrett IR, Mundy GR (1991) Chinese hamster ovarian cells transfected with the murine interleukin-6 gene cause hypercalcemia as well as cachexia, leukocytosis and thromobocytosis in tumor-bearing nude mice. Endocrinology 128: 2657–2659

    PubMed  Google Scholar 

  4. Body JJ (1992) Bone metastases and tumor-induced hypercalcemia. Curr Opin Oncol 4: 624–631

    PubMed  Google Scholar 

  5. Body JJ, Delmas PD (1992) Urinary pyridinium cross-links as markers of bone resorption in tumor-associated hypercalcemia. J Clin Endocrinol Metab 74: 471–475

    PubMed  Google Scholar 

  6. Body JJ, Cleeren A, Pot M, Borkowski A (1986) Serum osteocalcin (BGP) in tumor-associated hypercalcemia. J Bone Miner Res 1: 523–527

    PubMed  Google Scholar 

  7. Body JJ, Dumon JC, Seraj F, Cleeren A (1992) Recovery of parathyroid hormone secretion during correction of tumor-associated hypercalcemia. J Clin Endocrinol Metab 74: 1385–1388

    PubMed  Google Scholar 

  8. Body JJ, Dumon JC, Thirion M, Cleeren A (1993) Circulating PTHrP concentrations in tumor-induced hypercalcemia: influence on the response to bisphosphonate and changes after therapy. J Bone Miner Res 8: 701–706.

    PubMed  Google Scholar 

  9. Body JJ, Dumon JC (1994) Treatment of tumor-induced hypercalcaemia with the bisphosphonate pamidronate: dose-response relationship and influence of the tumor type. Ann Oncol 5: 359–363

    PubMed  Google Scholar 

  10. Burits WJ (1992) Parathyroid hormone-related protein: structure, function and measurement. Clin Chem 38: 2171–2183

    PubMed  Google Scholar 

  11. Calandra T, Gerain J, Heumann D, Baumgartner JD, Glauser MP and the Swiss-Dutch J5 Immunoglobulin Study Group (1991) High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. Am J Med 91: 23–29

    PubMed  Google Scholar 

  12. Fukumoto S, Matsumoto T, Harada SI, Fujisaki J, Kawano M, Ogata E (1991) Pheochromocytoma with pyrexia and marked inflammatory signs: a paraneoplastic syndrome with possible relation to interleukin-6 production. J Clin Endocrinol Metab 73: 877–881

    PubMed  Google Scholar 

  13. Gabay C, Roux-Lombard P, Moerloose P de, Dayer JM, Vischer T, Guerne PA (1993) Absence of correlation between interleukin 6 and C-reactive protein blood levels in systemic lupus erythematosus compared with rheumatoid arthritis. J Rheumatol 20: 815–821

    PubMed  Google Scholar 

  14. Gaillard JP, Bataille R, Brailly H, Zuber C, Yasukawa K, Attal M, Marvo N, Taga T, Kishimoto T, Klein B (1993) Increased and highly stable levels of functional soluble interleukin-6 receptor in sera of patients with monoclonal gammopathy. Eur J Immunol 23: 820–824

    PubMed  Google Scholar 

  15. Gallo O, Gori AM, Attanasio M, Martini F, Fini-Storchi O, Abbate R (1992) Interleukin-6 serum level and monocyte production in head and neck cancer. Br J Cancer 65: 479–480

    PubMed  Google Scholar 

  16. Garrett IR (1993) Bone destruction in cancer. Semin Oncol 20: 4–9

    PubMed  Google Scholar 

  17. Grill V, Ho P, Body JJ, Johanson N, Lee SC, Kukreja SC, Moseley JM, Martin TJ (1991) Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breas cancer. J Clin Endocrinol Metab 73: 1309–1315

    PubMed  Google Scholar 

  18. Hack CE, De Groot ER, Felt-Bersma RJF, Nuijens JH, Strack Van Schijndel RJM, Eerenberg-Belmer AJM, Thijs LG, Aarden LA (1989) Increased plasma levels of interleukin-6 in sepsis. Blood 74: 1704–1710

    PubMed  Google Scholar 

  19. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, Kuramoto A, Kishimoto T (1988) Autocrine generation and essential requirement of BSF-2/JL-6 for human multiple myelomas. Nature 332: 83–85

    PubMed  Google Scholar 

  20. Kurihara N, Bertolini D, Suda T, Akiyama Y, Roodman GD (1990) IL-6 stimulates osteoclast-like multinucleated cell formation in long term human marrow cultures by inducing IL-1 release. J Immunol 144:4226–4230

    PubMed  Google Scholar 

  21. Kurzrock R, Redman J, Cabanillas F, Jones, D, Rothberg J, Talpaz M (1993) Serum interleukin 6 levels are elevated in lymphoma patients and correlate with survival in advanced Hodgkin's disease and with B symptoms. Cancer Res 53: 2118–2122

    PubMed  Google Scholar 

  22. Lorenzo JA (1991) The role of cytokines in the regulation of local bone resorption. Crit Rev Immunol 11: 195–213

    PubMed  Google Scholar 

  23. Madhok R, Crilly A, Watson J, Capell HA (1993) Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 52: 232–234

    PubMed  Google Scholar 

  24. Miki S, Iwano M, Miki Y, Yamamoto M, Tang B, Yokokawa K, Sonoda T, Hirano T, Kishimoto T (1989) Interleukin-6 functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Lett 250: 607–610

    PubMed  Google Scholar 

  25. Nachbaur DM, Herold M, Maneschg A, Huber H (1991) Serum levels of interleukin-6 in multiple myeloma and other hematological disorders: correlation with disease activity and other prognostic parameters. Ann Hematol 62: 54–58

    PubMed  Google Scholar 

  26. Pacifici R, Brown C, Puscheck E, Friedrich E, Slatopolsky E, Maggio D, McCracken R, Avioli LV (1991) Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci USA 88: 5134–5138

    PubMed  Google Scholar 

  27. Roodman GD (1992) Interleukin-6: an osteotropic factor? J Bone Miner Res 7: 475–478

    PubMed  Google Scholar 

  28. Tabibzadeh SS, Poubouridis D, May LT, Sehgal PB (1989) Interleukin-6 immunoreactivity in human tumors. Am J Pathol 135: 427–433

    PubMed  Google Scholar 

  29. Van Snick J (1990) Interleukin-6: an overview. Annu Rev Immunol 8: 253–278

    PubMed  Google Scholar 

  30. Van Snick J, Cayphas S, Vink A, Uytenhove C, Coulie PG, Rubira MR, Simpson RJ (1986) Purification and NH2-terminal amino acid sequences of a T-cell-derived lymphokine with growth factor activity for B-cell hybridomas. Proc Natl Acad Sci USA 83: 9679–9683

    PubMed  Google Scholar 

  31. Watson JM, Sensintaffar JL, Berek JS, Martinez-Maza O (1990) Constitutive production of interleukin-6 ovarian cancer cell lines and by primary ovarian tumor cultures. Cancer Res 50: 6959–6965

    PubMed  Google Scholar 

  32. Yoneda T, Nakai M, Moriyama K, Scott L, Ida N, Kunitomo T, Mundy GR (1993) Neutralizing antibodies to human interleukin 6 reverse hypercalcemia associated with a human squamous carcinoma. Cancer Res 53: 737–740

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Bone Metabolism Unit and Infectious Diseases Unit, Institut Jules Bordet, Université Libre de Bruxelles, Rue Héger-Bordet 1, 1000, Brussels, Belgium

    B. Vanderschueren, J. C. Dumon, V. Oleffe, C. Heymans, J. Gérain & J. J. Body

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  1. B. Vanderschueren
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  2. J. C. Dumon
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  3. V. Oleffe
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  4. C. Heymans
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  5. J. Gérain
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  6. J. J. Body
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Vanderschueren, B., Dumon, J.C., Oleffe, V. et al. Circulating concentrations of interleukin-6 in cancer patients and their pathogenic role in tumor-induced hypercalcemia. Cancer Immunol Immunother 39, 286–290 (1994). https://doi.org/10.1007/BF01519980

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  • DOI: https://doi.org/10.1007/BF01519980

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